PubAnnotation

Id	Subject	Object	Predicate	Lexical cue
TextSentencer_T1	0-32	Sentence	denotes	Remyelination as Neuroprotection
TextSentencer_T1	0-32	Sentence	denotes	Remyelination as Neuroprotection
T69746	0-32	Sentence	denotes	Remyelination as Neuroprotection
TextSentencer_T2	34-42	Sentence	denotes	Abstract
TextSentencer_T2	34-42	Sentence	denotes	Abstract
T51567	34-42	Sentence	denotes	Abstract
TextSentencer_T3	45-179	Sentence	denotes	A major area of investigation in the neurosciences is directed at understanding the factors that participate in neurological deficits.
TextSentencer_T3	45-179	Sentence	denotes	A major area of investigation in the neurosciences is directed at understanding the factors that participate in neurological deficits.
T99813	45-179	Sentence	denotes	A major area of investigation in the neurosciences is directed at understanding the factors that participate in neurological deficits.
TextSentencer_T4	180-327	Sentence	denotes	In demyelinating diseases of the central nervous system (CNS), it has been assumed that demyelination by itself contributes to functional deficits.
TextSentencer_T4	180-327	Sentence	denotes	In demyelinating diseases of the central nervous system (CNS), it has been assumed that demyelination by itself contributes to functional deficits.
T11175	180-327	Sentence	denotes	In demyelinating diseases of the central nervous system (CNS), it has been assumed that demyelination by itself contributes to functional deficits.
TextSentencer_T5	328-484	Sentence	denotes	Previous physiological studies demonstrated that demyelination in the CNS can result in conduction slowing and conduction block (McDonald and Sears, 1969) .
TextSentencer_T5	328-484	Sentence	denotes	Previous physiological studies demonstrated that demyelination in the CNS can result in conduction slowing and conduction block (McDonald and Sears, 1969) .
T24544	328-484	Sentence	denotes	Previous physiological studies demonstrated that demyelination in the CNS can result in conduction slowing and conduction block (McDonald and Sears, 1969) .
TextSentencer_T6	485-623	Sentence	denotes	Such observations appeared sufficient to explain the majority of deficits in demyelinating human diseases such as multiple sclerosis (MS).
TextSentencer_T6	485-623	Sentence	denotes	Such observations appeared sufficient to explain the majority of deficits in demyelinating human diseases such as multiple sclerosis (MS).
T35322	485-623	Sentence	denotes	Such observations appeared sufficient to explain the majority of deficits in demyelinating human diseases such as multiple sclerosis (MS).
TextSentencer_T7	624-713	Sentence	denotes	However, clinical and basic science observations have begun to challenge this hypothesis.
TextSentencer_T7	624-713	Sentence	denotes	However, clinical and basic science observations have begun to challenge this hypothesis.
T7964	624-713	Sentence	denotes	However, clinical and basic science observations have begun to challenge this hypothesis.
TextSentencer_T8	714-924	Sentence	denotes	MS is one of the most frequent neurological diseases of early adulthood, affecting as many as 400,000 patients in the United States, 85% of whom are between the ages of 20 and 50 years old (Mayr et al., 2003) .
TextSentencer_T8	714-924	Sentence	denotes	MS is one of the most frequent neurological diseases of early adulthood, affecting as many as 400,000 patients in the United States, 85% of whom are between the ages of 20 and 50 years old (Mayr et al., 2003) .
T13283	714-924	Sentence	denotes	MS is one of the most frequent neurological diseases of early adulthood, affecting as many as 400,000 patients in the United States, 85% of whom are between the ages of 20 and 50 years old (Mayr et al., 2003) .
TextSentencer_T9	925-1189	Sentence	denotes	Clinically, this disease is most often marked by a relapsing and remitting pattern of neurological dysfunction, frequently leading over time to a secondary progressive disease pattern marked by accumulative loss of neurological function (Noseworthy et al., 2000) .
TextSentencer_T9	925-1189	Sentence	denotes	Clinically, this disease is most often marked by a relapsing and remitting pattern of neurological dysfunction, frequently leading over time to a secondary progressive disease pattern marked by accumulative loss of neurological function (Noseworthy et al., 2000) .
T60915	925-1189	Sentence	denotes	Clinically, this disease is most often marked by a relapsing and remitting pattern of neurological dysfunction, frequently leading over time to a secondary progressive disease pattern marked by accumulative loss of neurological function (Noseworthy et al., 2000) .
TextSentencer_T10	1190-1463	Sentence	denotes	The relapsing-remitting phase is characterized by clinical symptoms such as loss of visual acuity, weakness, ataxia, fatigue, and clumsiness that develop over a period of several days, stabilize, and then resolve over the course of several weeks (Noseworthy et al., 2000) .
TextSentencer_T10	1190-1463	Sentence	denotes	The relapsing-remitting phase is characterized by clinical symptoms such as loss of visual acuity, weakness, ataxia, fatigue, and clumsiness that develop over a period of several days, stabilize, and then resolve over the course of several weeks (Noseworthy et al., 2000) .
T18666	1190-1463	Sentence	denotes	The relapsing-remitting phase is characterized by clinical symptoms such as loss of visual acuity, weakness, ataxia, fatigue, and clumsiness that develop over a period of several days, stabilize, and then resolve over the course of several weeks (Noseworthy et al., 2000) .
TextSentencer_T11	1464-1563	Sentence	denotes	At least early in the disease, corticosteroid treatment accelerates recovery from clinical deficit.
TextSentencer_T11	1464-1563	Sentence	denotes	At least early in the disease, corticosteroid treatment accelerates recovery from clinical deficit.
T14006	1464-1563	Sentence	denotes	At least early in the disease, corticosteroid treatment accelerates recovery from clinical deficit.
TextSentencer_T12	1564-1782	Sentence	denotes	Frequently, some dysfunction may persist after relapse, and an accumulation of such persistant clinical deficit ultimately results in a progressive impairment termed secondary progressive MS (Noseworthy et al., 2000) .
TextSentencer_T12	1564-1782	Sentence	denotes	Frequently, some dysfunction may persist after relapse, and an accumulation of such persistant clinical deficit ultimately results in a progressive impairment termed secondary progressive MS (Noseworthy et al., 2000) .
T33108	1564-1782	Sentence	denotes	Frequently, some dysfunction may persist after relapse, and an accumulation of such persistant clinical deficit ultimately results in a progressive impairment termed secondary progressive MS (Noseworthy et al., 2000) .
TextSentencer_T13	1783-2040	Sentence	denotes	Although clinically characterized by pathological and functional hallmarks such as focally demyelinated lesions and gadolinium enhancement, as detected by magnetic resonance imaging (MRI), the cellular and molecular locus of MS is distinctly heterogeneous .
TextSentencer_T13	1783-2040	Sentence	denotes	Although clinically characterized by pathological and functional hallmarks such as focally demyelinated lesions and gadolinium enhancement, as detected by magnetic resonance imaging (MRI), the cellular and molecular locus of MS is distinctly heterogeneous .
T6992	1783-2040	Sentence	denotes	Although clinically characterized by pathological and functional hallmarks such as focally demyelinated lesions and gadolinium enhancement, as detected by magnetic resonance imaging (MRI), the cellular and molecular locus of MS is distinctly heterogeneous .
TextSentencer_T14	2041-2224	Sentence	denotes	Although all lesions contain an inflammatory infiltration of T-cells and macrophages, further analysis suggests that four distinct patterns of pathology are present in active lesions.
TextSentencer_T14	2041-2224	Sentence	denotes	Although all lesions contain an inflammatory infiltration of T-cells and macrophages, further analysis suggests that four distinct patterns of pathology are present in active lesions.
T20474	2041-2224	Sentence	denotes	Although all lesions contain an inflammatory infiltration of T-cells and macrophages, further analysis suggests that four distinct patterns of pathology are present in active lesions.
TextSentencer_T15	2225-2532	Sentence	denotes	The first two patterns are marked by well-delineated perivascular demyelination and simultaneous loss of immunoreactivity for all myelin proteins within the lesion, but relative sparing of oligodendrocytes and active repopulation of demyelinated lesions with oligodendrocytes during remyelination (Fig. 1) .
TextSentencer_T15	2225-2532	Sentence	denotes	The first two patterns are marked by well-delineated perivascular demyelination and simultaneous loss of immunoreactivity for all myelin proteins within the lesion, but relative sparing of oligodendrocytes and active repopulation of demyelinated lesions with oligodendrocytes during remyelination (Fig. 1) .
T79878	2225-2532	Sentence	denotes	The first two patterns are marked by well-delineated perivascular demyelination and simultaneous loss of immunoreactivity for all myelin proteins within the lesion, but relative sparing of oligodendrocytes and active repopulation of demyelinated lesions with oligodendrocytes during remyelination (Fig. 1) .
TextSentencer_T16	2533-2730	Sentence	denotes	This is consistent with previous reports show- 390 Remyelination as Neuroprotection ing abortive attempts at remyelination in MS lesions (Prineas and Connell, 1979; Prineas et al., 1989) (Fig. 2) .
TextSentencer_T16	2533-2730	Sentence	denotes	This is consistent with previous reports show- 390 Remyelination as Neuroprotection ing abortive attempts at remyelination in MS lesions (Prineas and Connell, 1979; Prineas et al., 1989) (Fig. 2) .
T49204	2533-2730	Sentence	denotes	This is consistent with previous reports show- 390 Remyelination as Neuroprotection ing abortive attempts at remyelination in MS lesions (Prineas and Connell, 1979; Prineas et al., 1989) (Fig. 2) .
TextSentencer_T17	2731-2869	Sentence	denotes	The second pattern is unique in that actively degenerating myelin is associated with pronounced immunoglobulin and complement reactivity .
TextSentencer_T17	2731-2869	Sentence	denotes	The second pattern is unique in that actively degenerating myelin is associated with pronounced immunoglobulin and complement reactivity .
T70532	2731-2869	Sentence	denotes	The second pattern is unique in that actively degenerating myelin is associated with pronounced immunoglobulin and complement reactivity .
TextSentencer_T18	2870-3000	Sentence	denotes	The third and fourth patterns do not exhibit perivascular localization, and the borders of active lesions are only poorly defined.
TextSentencer_T18	2870-3000	Sentence	denotes	The third and fourth patterns do not exhibit perivascular localization, and the borders of active lesions are only poorly defined.
T94439	2870-3000	Sentence	denotes	The third and fourth patterns do not exhibit perivascular localization, and the borders of active lesions are only poorly defined.
TextSentencer_T19	3001-3077	Sentence	denotes	Oligodendrocytes are not spared and repopulation of lesions is not observed.
TextSentencer_T19	3001-3077	Sentence	denotes	Oligodendrocytes are not spared and repopulation of lesions is not observed.
T68175	3001-3077	Sentence	denotes	Oligodendrocytes are not spared and repopulation of lesions is not observed.
TextSentencer_T20	3078-3225	Sentence	denotes	Finally, the third pattern is uniquely associated with greater loss of myelin-associated glycoprotein immunoreactivity than other myelin proteins .
TextSentencer_T20	3078-3225	Sentence	denotes	Finally, the third pattern is uniquely associated with greater loss of myelin-associated glycoprotein immunoreactivity than other myelin proteins .
T88632	3078-3225	Sentence	denotes	Finally, the third pattern is uniquely associated with greater loss of myelin-associated glycoprotein immunoreactivity than other myelin proteins .
TextSentencer_T21	3226-3362	Sentence	denotes	This pattern is consistent with the concept of "dying-back oligodendrogliopathy," in which the primary injury is to the oligodendrocyte.
TextSentencer_T21	3226-3362	Sentence	denotes	This pattern is consistent with the concept of "dying-back oligodendrogliopathy," in which the primary injury is to the oligodendrocyte.
T92740	3226-3362	Sentence	denotes	This pattern is consistent with the concept of "dying-back oligodendrogliopathy," in which the primary injury is to the oligodendrocyte.
TextSentencer_T22	3363-3569	Sentence	denotes	The earliest morphological manifestation of this pattern is degeneration of the inner myelin sheath and oligodendroglial loops, the most distal extensions of the oligodendrocyte (Rodriguez, 2003) (Fig. 3) .
TextSentencer_T22	3363-3569	Sentence	denotes	The earliest morphological manifestation of this pattern is degeneration of the inner myelin sheath and oligodendroglial loops, the most distal extensions of the oligodendrocyte (Rodriguez, 2003) (Fig. 3) .
T51407	3363-3569	Sentence	denotes	The earliest morphological manifestation of this pattern is degeneration of the inner myelin sheath and oligodendroglial loops, the most distal extensions of the oligodendrocyte (Rodriguez, 2003) (Fig. 3) .
TextSentencer_T23	3570-3650	Sentence	denotes	Of importance, heterogeneity is found among patients but not within individuals.
TextSentencer_T23	3570-3650	Sentence	denotes	Of importance, heterogeneity is found among patients but not within individuals.
T13220	3570-3650	Sentence	denotes	Of importance, heterogeneity is found among patients but not within individuals.
TextSentencer_T24	3651-3815	Sentence	denotes	All lesions of any given patient are of the same phenotype, suggesting a single pathogenic mechanism within a patient but multiple mechanisms across the population.
TextSentencer_T24	3651-3815	Sentence	denotes	All lesions of any given patient are of the same phenotype, suggesting a single pathogenic mechanism within a patient but multiple mechanisms across the population.
T95611	3651-3815	Sentence	denotes	All lesions of any given patient are of the same phenotype, suggesting a single pathogenic mechanism within a patient but multiple mechanisms across the population.
TextSentencer_T25	3816-3904	Sentence	denotes	The heterogeneity observed in patients with MS is also reflected in animal models of MS.
TextSentencer_T25	3816-3904	Sentence	denotes	The heterogeneity observed in patients with MS is also reflected in animal models of MS.
T50257	3816-3904	Sentence	denotes	The heterogeneity observed in patients with MS is also reflected in animal models of MS.
TextSentencer_T26	3905-4058	Sentence	denotes	The two best studied models of human MS are immune-mediated encephalo-myelitis induced by immunization with CNS antigens and viral-induced demyelination.
TextSentencer_T26	3905-4058	Sentence	denotes	The two best studied models of human MS are immune-mediated encephalo-myelitis induced by immunization with CNS antigens and viral-induced demyelination.
T51372	3905-4058	Sentence	denotes	The two best studied models of human MS are immune-mediated encephalo-myelitis induced by immunization with CNS antigens and viral-induced demyelination.
TextSentencer_T27	4059-4240	Sentence	denotes	Lesions commonly found in patients with the first and second pattern of MS pathology are similar to those observed in T-cell-mediated and antibody-mediated autoimmune demyelination.
TextSentencer_T27	4059-4240	Sentence	denotes	Lesions commonly found in patients with the first and second pattern of MS pathology are similar to those observed in T-cell-mediated and antibody-mediated autoimmune demyelination.
T5626	4059-4240	Sentence	denotes	Lesions commonly found in patients with the first and second pattern of MS pathology are similar to those observed in T-cell-mediated and antibody-mediated autoimmune demyelination.
TextSentencer_T28	4241-4448	Sentence	denotes	Likewise, lesions observed in the third and fourth patterns of human MS are typical of the oligodendrogliopathy and demyelination induced by viral infection Paz Soldan and Rodriguez, 2002; Rodriguez, 1985) .
TextSentencer_T28	4241-4448	Sentence	denotes	Likewise, lesions observed in the third and fourth patterns of human MS are typical of the oligodendrogliopathy and demyelination induced by viral infection Paz Soldan and Rodriguez, 2002; Rodriguez, 1985) .
T16426	4241-4448	Sentence	denotes	Likewise, lesions observed in the third and fourth patterns of human MS are typical of the oligodendrogliopathy and demyelination induced by viral infection Paz Soldan and Rodriguez, 2002; Rodriguez, 1985) .
TextSentencer_T29	4449-4601	Sentence	denotes	The functional correlate of any of the patterns described previously is generally considered to be loss of axon conduction resulting from demyelination.
TextSentencer_T29	4449-4601	Sentence	denotes	The functional correlate of any of the patterns described previously is generally considered to be loss of axon conduction resulting from demyelination.
T47363	4449-4601	Sentence	denotes	The functional correlate of any of the patterns described previously is generally considered to be loss of axon conduction resulting from demyelination.
TextSentencer_T30	4602-4775	Sentence	denotes	During the relapsing-remitting phase of MS, the regression of symptoms is likely due to resolution of inflammation and remyelination, resulting in a return of axon function.
TextSentencer_T30	4602-4775	Sentence	denotes	During the relapsing-remitting phase of MS, the regression of symptoms is likely due to resolution of inflammation and remyelination, resulting in a return of axon function.
T57350	4602-4775	Sentence	denotes	During the relapsing-remitting phase of MS, the regression of symptoms is likely due to resolution of inflammation and remyelination, resulting in a return of axon function.
TextSentencer_T31	4776-4952	Sentence	denotes	However, as the disease progresses and as each round of repair accumulates demyelination that is not resolved, axonal function deteriorates (Noseworthy et al., 2000) (Fig. 4 ).
TextSentencer_T31	4776-4952	Sentence	denotes	However, as the disease progresses and as each round of repair accumulates demyelination that is not resolved, axonal function deteriorates (Noseworthy et al., 2000) (Fig. 4 ).
T16969	4776-4952	Sentence	denotes	However, as the disease progresses and as each round of repair accumulates demyelination that is not resolved, axonal function deteriorates (Noseworthy et al., 2000) (Fig. 4 ).
TextSentencer_T32	4953-5139	Sentence	denotes	This is marked by redistribution of sodium channels along demyelinated axon segments, and eventually by loss of the axon altogether (Rivera-Quinones et al., 1998) (see Chapters 7 and 8).
TextSentencer_T32	4953-5139	Sentence	denotes	This is marked by redistribution of sodium channels along demyelinated axon segments, and eventually by loss of the axon altogether (Rivera-Quinones et al., 1998) (see Chapters 7 and 8).
T10364	4953-5139	Sentence	denotes	This is marked by redistribution of sodium channels along demyelinated axon segments, and eventually by loss of the axon altogether (Rivera-Quinones et al., 1998) (see Chapters 7 and 8).
TextSentencer_T33	5140-5338	Sentence	denotes	Because axons are the absolute locus of neuronal function and transmission, it is likely that understanding and reversing axon failure and loss will be required for any rational therapeutic program.
TextSentencer_T33	5140-5338	Sentence	denotes	Because axons are the absolute locus of neuronal function and transmission, it is likely that understanding and reversing axon failure and loss will be required for any rational therapeutic program.
T15260	5140-5338	Sentence	denotes	Because axons are the absolute locus of neuronal function and transmission, it is likely that understanding and reversing axon failure and loss will be required for any rational therapeutic program.
TextSentencer_T34	5339-5508	Sentence	denotes	Magnetic resonance imaging (MRI) studies in patients with MS have demonstrated only a weak correlation between lesion load and clinical deficits (Stevens et al., 1986) .
TextSentencer_T34	5339-5508	Sentence	denotes	Magnetic resonance imaging (MRI) studies in patients with MS have demonstrated only a weak correlation between lesion load and clinical deficits (Stevens et al., 1986) .
T23329	5339-5508	Sentence	denotes	Magnetic resonance imaging (MRI) studies in patients with MS have demonstrated only a weak correlation between lesion load and clinical deficits (Stevens et al., 1986) .
TextSentencer_T35	5509-5737	Sentence	denotes	Moreover, pathological studies have demonstrated that some lesions observed by MRI are indeed demyelinated and frequently involve areas of CNS that should have resulted in neurological deficits, but do not (Bruck et al., 1997) .
TextSentencer_T35	5509-5737	Sentence	denotes	Moreover, pathological studies have demonstrated that some lesions observed by MRI are indeed demyelinated and frequently involve areas of CNS that should have resulted in neurological deficits, but do not (Bruck et al., 1997) .
T49460	5509-5737	Sentence	denotes	Moreover, pathological studies have demonstrated that some lesions observed by MRI are indeed demyelinated and frequently involve areas of CNS that should have resulted in neurological deficits, but do not (Bruck et al., 1997) .
TextSentencer_T36	5738-5964	Sentence	denotes	Likewise, autopsy analysis has demonstrated that demyelination, sufficient to make the pathological diagnosis of MS, can be observed in individuals who during life remained normal in neurological function (Mews et al., 1998) .
TextSentencer_T36	5738-5964	Sentence	denotes	Likewise, autopsy analysis has demonstrated that demyelination, sufficient to make the pathological diagnosis of MS, can be observed in individuals who during life remained normal in neurological function (Mews et al., 1998) .
T69035	5738-5964	Sentence	denotes	Likewise, autopsy analysis has demonstrated that demyelination, sufficient to make the pathological diagnosis of MS, can be observed in individuals who during life remained normal in neurological function (Mews et al., 1998) .
TextSentencer_T37	5965-6108	Sentence	denotes	These observations have suggested that demyelination may be required but not sufficient for the development of permanent neurological deficits.
TextSentencer_T37	5965-6108	Sentence	denotes	These observations have suggested that demyelination may be required but not sufficient for the development of permanent neurological deficits.
T82056	5965-6108	Sentence	denotes	These observations have suggested that demyelination may be required but not sufficient for the development of permanent neurological deficits.
TextSentencer_T38	6109-6324	Sentence	denotes	Further challenge to the demyelination hypothesis is provided by studies that use magnetic resonance spectroscopy to sensitively and quantitatively measure axon-specific metabolites such as N-acetyl aspartate (NAA).
TextSentencer_T38	6109-6324	Sentence	denotes	Further challenge to the demyelination hypothesis is provided by studies that use magnetic resonance spectroscopy to sensitively and quantitatively measure axon-specific metabolites such as N-acetyl aspartate (NAA).
T41892	6109-6324	Sentence	denotes	Further challenge to the demyelination hypothesis is provided by studies that use magnetic resonance spectroscopy to sensitively and quantitatively measure axon-specific metabolites such as N-acetyl aspartate (NAA).
TextSentencer_T39	6325-6601	Sentence	denotes	These studies found that active lesions are significantly reduced in NAA, and that as the disease progresses from the relapsing-remitting phase to the chronic-progressive phase, a reduction in NAA can be measured even in normal-appearing white matter (Matthews et al., 1996) .
TextSentencer_T39	6325-6601	Sentence	denotes	These studies found that active lesions are significantly reduced in NAA, and that as the disease progresses from the relapsing-remitting phase to the chronic-progressive phase, a reduction in NAA can be measured even in normal-appearing white matter (Matthews et al., 1996) .
T29824	6325-6601	Sentence	denotes	These studies found that active lesions are significantly reduced in NAA, and that as the disease progresses from the relapsing-remitting phase to the chronic-progressive phase, a reduction in NAA can be measured even in normal-appearing white matter (Matthews et al., 1996) .
TextSentencer_T40	6602-6885	Sentence	denotes	This finding suggests that a reduction in NAA may reflect both acute, but potentially reversible, axonal dysfunction associated with temporary demyelination, as well as chronic, irreversible loss of axons as a result of degeneration beyond the scope of any given demyelinated lesion.
TextSentencer_T40	6602-6885	Sentence	denotes	This finding suggests that a reduction in NAA may reflect both acute, but potentially reversible, axonal dysfunction associated with temporary demyelination, as well as chronic, irreversible loss of axons as a result of degeneration beyond the scope of any given demyelinated lesion.
T81958	6602-6885	Sentence	denotes	This finding suggests that a reduction in NAA may reflect both acute, but potentially reversible, axonal dysfunction associated with temporary demyelination, as well as chronic, irreversible loss of axons as a result of degeneration beyond the scope of any given demyelinated lesion.
TextSentencer_T41	6886-7206	Sentence	denotes	The mechanisms by which demyelination induces axon dysfunction and axon degeneration remain unclear (Trapp et al., 1998) , but a number of recent studies suggest that multiple factors may be involved, ranging from increased accessibility of inflammatory mediators and immune effector cells, to a loss of trophic support.
TextSentencer_T41	6886-7206	Sentence	denotes	The mechanisms by which demyelination induces axon dysfunction and axon degeneration remain unclear (Trapp et al., 1998) , but a number of recent studies suggest that multiple factors may be involved, ranging from increased accessibility of inflammatory mediators and immune effector cells, to a loss of trophic support.
T87035	6886-7206	Sentence	denotes	The mechanisms by which demyelination induces axon dysfunction and axon degeneration remain unclear (Trapp et al., 1998) , but a number of recent studies suggest that multiple factors may be involved, ranging from increased accessibility of inflammatory mediators and immune effector cells, to a loss of trophic support.
TextSentencer_T42	7207-7473	Sentence	denotes	For example, CD8 + cytotoxic T-cells have been observed in contact with demyelinated axons in active MS lesions (Neumann et al., 2002) , and the terminal swellings of transected axons have been found to be engulfed by macrophages and microglia (Trapp et al., 1998) .
TextSentencer_T42	7207-7473	Sentence	denotes	For example, CD8 + cytotoxic T-cells have been observed in contact with demyelinated axons in active MS lesions (Neumann et al., 2002) , and the terminal swellings of transected axons have been found to be engulfed by macrophages and microglia (Trapp et al., 1998) .
T41402	7207-7473	Sentence	denotes	For example, CD8 + cytotoxic T-cells have been observed in contact with demyelinated axons in active MS lesions (Neumann et al., 2002) , and the terminal swellings of transected axons have been found to be engulfed by macrophages and microglia (Trapp et al., 1998) .
TextSentencer_T43	7474-7675	Sentence	denotes	Likewise, myelination is known to provide trophic and maintenance cues to axons, controlling axon caliber, and neurofilament phosphorylation and spacing (Sanchez et al., 1996; Windebank et al., 1985) .
TextSentencer_T43	7474-7675	Sentence	denotes	Likewise, myelination is known to provide trophic and maintenance cues to axons, controlling axon caliber, and neurofilament phosphorylation and spacing (Sanchez et al., 1996; Windebank et al., 1985) .
T89708	7474-7675	Sentence	denotes	Likewise, myelination is known to provide trophic and maintenance cues to axons, controlling axon caliber, and neurofilament phosphorylation and spacing (Sanchez et al., 1996; Windebank et al., 1985) .
TextSentencer_T44	7676-7965	Sentence	denotes	Finally, changes in NAA associated with MS may reflect defects or dysregulation of axonal energy-storage mechanisms, as NAA-derived metabolic products such as acetyl coenzyme A may function to meet the high energy demands of axonal electrochemical conduction (Mehta and Namboodiri, 1995) .
TextSentencer_T44	7676-7965	Sentence	denotes	Finally, changes in NAA associated with MS may reflect defects or dysregulation of axonal energy-storage mechanisms, as NAA-derived metabolic products such as acetyl coenzyme A may function to meet the high energy demands of axonal electrochemical conduction (Mehta and Namboodiri, 1995) .
T47562	7676-7965	Sentence	denotes	Finally, changes in NAA associated with MS may reflect defects or dysregulation of axonal energy-storage mechanisms, as NAA-derived metabolic products such as acetyl coenzyme A may function to meet the high energy demands of axonal electrochemical conduction (Mehta and Namboodiri, 1995) .
TextSentencer_T45	7966-7991	Sentence	denotes	This idea is particularly
TextSentencer_T45	7966-7991	Sentence	denotes	This idea is particularly
T56362	7966-7991	Sentence	denotes	This idea is particularly
TextSentencer_T46	7992-8084	Sentence	denotes	Remyelination as Neuroprotection B A Figure 3 Evidence of "dying-back" oligodendrogliopathy.
TextSentencer_T46	7992-8084	Sentence	denotes	Remyelination as Neuroprotection B A Figure 3 Evidence of "dying-back" oligodendrogliopathy.
T17153	7992-8084	Sentence	denotes	Remyelination as Neuroprotection B A Figure 3 Evidence of "dying-back" oligodendrogliopathy.
TextSentencer_T47	8085-8184	Sentence	denotes	Note the degeneration of the inner myelin sheath, presenting an "inside-out" type of myelin damage.
TextSentencer_T47	8085-8184	Sentence	denotes	Note the degeneration of the inner myelin sheath, presenting an "inside-out" type of myelin damage.
T1220	8085-8184	Sentence	denotes	Note the degeneration of the inner myelin sheath, presenting an "inside-out" type of myelin damage.
TextSentencer_T48	8185-8315	Sentence	denotes	This type of pathology is present in Pattern III MS lesions in which the attack is primarily directed against the oligodendrocyte.
TextSentencer_T48	8185-8315	Sentence	denotes	This type of pathology is present in Pattern III MS lesions in which the attack is primarily directed against the oligodendrocyte.
T39276	8185-8315	Sentence	denotes	This type of pathology is present in Pattern III MS lesions in which the attack is primarily directed against the oligodendrocyte.
TextSentencer_T49	8316-8394	Sentence	denotes	The most distal extension of the oligodendrocyte is the inner myelin lamellae.
TextSentencer_T49	8316-8394	Sentence	denotes	The most distal extension of the oligodendrocyte is the inner myelin lamellae.
T88463	8316-8394	Sentence	denotes	The most distal extension of the oligodendrocyte is the inner myelin lamellae.
TextSentencer_T50	8395-8794	Sentence	denotes	Therefore, injury to the inner sheath with relative preservation of the other myelin lamellae is indicative of primary injury to the myelin-producing cell. virus-induced demyelinating disease resembled human MS (Lipton, 1975; Lipton and Dal Canto, 1976a; 1976b; , and numerous investigators have extended our understanding of MS using a variety of TMEV strains (Brahic 2002; Monteyne et al., 1997) .
TextSentencer_T50	8395-8794	Sentence	denotes	Therefore, injury to the inner sheath with relative preservation of the other myelin lamellae is indicative of primary injury to the myelin-producing cell. virus-induced demyelinating disease resembled human MS (Lipton, 1975; Lipton and Dal Canto, 1976a; 1976b; , and numerous investigators have extended our understanding of MS using a variety of TMEV strains (Brahic 2002; Monteyne et al., 1997) .
T28603	8395-8794	Sentence	denotes	Therefore, injury to the inner sheath with relative preservation of the other myelin lamellae is indicative of primary injury to the myelin-producing cell. virus-induced demyelinating disease resembled human MS (Lipton, 1975; Lipton and Dal Canto, 1976a; 1976b; , and numerous investigators have extended our understanding of MS using a variety of TMEV strains (Brahic 2002; Monteyne et al., 1997) .
TextSentencer_T51	8795-9090	Sentence	denotes	After intracerebral injection of Theiler's virus, and during the first 10 to 12 days of infection, the virus replicates primarily in neurons of the hippocampus (Fig. 5) , striatum, cortex, and anterior horn of the spinal cord, and then is rapidly cleared from the brain (Drescher et al., 1999) .
TextSentencer_T51	8795-9090	Sentence	denotes	After intracerebral injection of Theiler's virus, and during the first 10 to 12 days of infection, the virus replicates primarily in neurons of the hippocampus (Fig. 5) , striatum, cortex, and anterior horn of the spinal cord, and then is rapidly cleared from the brain (Drescher et al., 1999) .
T90121	8795-9090	Sentence	denotes	After intracerebral injection of Theiler's virus, and during the first 10 to 12 days of infection, the virus replicates primarily in neurons of the hippocampus (Fig. 5) , striatum, cortex, and anterior horn of the spinal cord, and then is rapidly cleared from the brain (Drescher et al., 1999) .
TextSentencer_T52	9091-9172	Sentence	denotes	Oligodendrocytes and macrophages are also infected early (Njenga et al., 1997a) .
TextSentencer_T52	9091-9172	Sentence	denotes	Oligodendrocytes and macrophages are also infected early (Njenga et al., 1997a) .
T96098	9091-9172	Sentence	denotes	Oligodendrocytes and macrophages are also infected early (Njenga et al., 1997a) .
TextSentencer_T53	9173-9306	Sentence	denotes	In mice of resistant major histocompatibility complex (MHC) haplotypes (H-2 b,d,k ) , no demyelination or viral persistence develops.
TextSentencer_T53	9173-9306	Sentence	denotes	In mice of resistant major histocompatibility complex (MHC) haplotypes (H-2 b,d,k ) , no demyelination or viral persistence develops.
T12360	9173-9306	Sentence	denotes	In mice of resistant major histocompatibility complex (MHC) haplotypes (H-2 b,d,k ) , no demyelination or viral persistence develops.
TextSentencer_T54	9307-9638	Sentence	denotes	However, in animals of susceptible MHC haplotypes (H-2 s,q,r,v,f,p ), the virus is cleared from neurons in the brain but persists in glial cells (Brahic et al., 1981; Rodriguez et al., 1983) and macrophages (Dal Canto and Lipton, 1982; Levy et al., 1992; Rossi et al., 1997) of the spinal cord white matter and brainstem (Fig. 6 ).
TextSentencer_T54	9307-9638	Sentence	denotes	However, in animals of susceptible MHC haplotypes (H-2 s,q,r,v,f,p ), the virus is cleared from neurons in the brain but persists in glial cells (Brahic et al., 1981; Rodriguez et al., 1983) and macrophages (Dal Canto and Lipton, 1982; Levy et al., 1992; Rossi et al., 1997) of the spinal cord white matter and brainstem (Fig. 6 ).
T86444	9307-9638	Sentence	denotes	However, in animals of susceptible MHC haplotypes (H-2 s,q,r,v,f,p ), the virus is cleared from neurons in the brain but persists in glial cells (Brahic et al., 1981; Rodriguez et al., 1983) and macrophages (Dal Canto and Lipton, 1982; Levy et al., 1992; Rossi et al., 1997) of the spinal cord white matter and brainstem (Fig. 6 ).
TextSentencer_T55	9639-9859	Sentence	denotes	This viral persistence is associated with chronic demyelination and stereotypical neurological impairment and paralysis due to the loss of axons (Drescher et al., 1997; Lipton 1975; Rodriguez and Miller, 1994) (Fig. 7) .
TextSentencer_T55	9639-9859	Sentence	denotes	This viral persistence is associated with chronic demyelination and stereotypical neurological impairment and paralysis due to the loss of axons (Drescher et al., 1997; Lipton 1975; Rodriguez and Miller, 1994) (Fig. 7) .
T79191	9639-9859	Sentence	denotes	This viral persistence is associated with chronic demyelination and stereotypical neurological impairment and paralysis due to the loss of axons (Drescher et al., 1997; Lipton 1975; Rodriguez and Miller, 1994) (Fig. 7) .
TextSentencer_T56	9860-10069	Sentence	denotes	Demyelination in this model is in part mediated by a "dying-back" oligoden- drogliopathy (Ludwin and Johnson, 1981) manifested by injury to the most distal extensions of the oligodendrocyte (Rodriguez, 1985) .
TextSentencer_T56	9860-10069	Sentence	denotes	Demyelination in this model is in part mediated by a "dying-back" oligoden- drogliopathy (Ludwin and Johnson, 1981) manifested by injury to the most distal extensions of the oligodendrocyte (Rodriguez, 1985) .
T67871	9860-10069	Sentence	denotes	Demyelination in this model is in part mediated by a "dying-back" oligoden- drogliopathy (Ludwin and Johnson, 1981) manifested by injury to the most distal extensions of the oligodendrocyte (Rodriguez, 1985) .
TextSentencer_T57	10070-10168	Sentence	denotes	Of the H-2 genes, it is the D locus that is of major importance for resistance vs. susceptibility.
TextSentencer_T57	10070-10168	Sentence	denotes	Of the H-2 genes, it is the D locus that is of major importance for resistance vs. susceptibility.
T56444	10070-10168	Sentence	denotes	Of the H-2 genes, it is the D locus that is of major importance for resistance vs. susceptibility.
TextSentencer_T58	10169-10356	Sentence	denotes	Resistance is a dominant trait that maps to H-2D, and genetic deletion or mutation of the D locus results in viral persistance and chronic demyelinating disease (Rodriguez et al., 1986) .
TextSentencer_T58	10169-10356	Sentence	denotes	Resistance is a dominant trait that maps to H-2D, and genetic deletion or mutation of the D locus results in viral persistance and chronic demyelinating disease (Rodriguez et al., 1986) .
T85127	10169-10356	Sentence	denotes	Resistance is a dominant trait that maps to H-2D, and genetic deletion or mutation of the D locus results in viral persistance and chronic demyelinating disease (Rodriguez et al., 1986) .
TextSentencer_T59	10357-10527	Sentence	denotes	Specific introduction of H-2D b or H-2D d genes into normally susceptible mice results in the acquisition of resistance to viral persistence (Rodriguez and David, 1995) .
TextSentencer_T59	10357-10527	Sentence	denotes	Specific introduction of H-2D b or H-2D d genes into normally susceptible mice results in the acquisition of resistance to viral persistence (Rodriguez and David, 1995) .
T1083	10357-10527	Sentence	denotes	Specific introduction of H-2D b or H-2D d genes into normally susceptible mice results in the acquisition of resistance to viral persistence (Rodriguez and David, 1995) .
TextSentencer_T60	10528-10898	Sentence	denotes	This resistance is associated with a robust antiviral cytotoxic Tcell response that develops in the gray matter of infected C57BL6 mice (Pena Rossi et al., 1991) , and immunological depletion of CD8 + T-cells or the genetic deletion of CD8 + T cells observed in β2-microglobulin knock-out mice results in viral persistence within otherwise resistant genetic backgrounds.
TextSentencer_T60	10528-10898	Sentence	denotes	This resistance is associated with a robust antiviral cytotoxic Tcell response that develops in the gray matter of infected C57BL6 mice (Pena Rossi et al., 1991) , and immunological depletion of CD8 + T-cells or the genetic deletion of CD8 + T cells observed in β2-microglobulin knock-out mice results in viral persistence within otherwise resistant genetic backgrounds.
T44052	10528-10898	Sentence	denotes	This resistance is associated with a robust antiviral cytotoxic Tcell response that develops in the gray matter of infected C57BL6 mice (Pena Rossi et al., 1991) , and immunological depletion of CD8 + T-cells or the genetic deletion of CD8 + T cells observed in β2-microglobulin knock-out mice results in viral persistence within otherwise resistant genetic backgrounds.
TextSentencer_T61	10899-11090	Sentence	denotes	Consistent with the genetics of resistance discussed previously, the cytotoxic T-cell response observed during the acute phase of Theiler's virus infection is restricted to the D b molecule .
TextSentencer_T61	10899-11090	Sentence	denotes	Consistent with the genetics of resistance discussed previously, the cytotoxic T-cell response observed during the acute phase of Theiler's virus infection is restricted to the D b molecule .
T86865	10899-11090	Sentence	denotes	Consistent with the genetics of resistance discussed previously, the cytotoxic T-cell response observed during the acute phase of Theiler's virus infection is restricted to the D b molecule .
TextSentencer_T62	11091-11373	Sentence	denotes	Moreover, after Theiler's virus infection of resistant mice of the H-2 b haplotype, we have identified an immunodominant cytotoxic T-cell population within the CNS that is specific for the VP2 121-130 viral capsid peptide presented within the context of D b (Johnson et al., 1999) .
TextSentencer_T62	11091-11373	Sentence	denotes	Moreover, after Theiler's virus infection of resistant mice of the H-2 b haplotype, we have identified an immunodominant cytotoxic T-cell population within the CNS that is specific for the VP2 121-130 viral capsid peptide presented within the context of D b (Johnson et al., 1999) .
T87045	11091-11373	Sentence	denotes	Moreover, after Theiler's virus infection of resistant mice of the H-2 b haplotype, we have identified an immunodominant cytotoxic T-cell population within the CNS that is specific for the VP2 121-130 viral capsid peptide presented within the context of D b (Johnson et al., 1999) .
TextSentencer_T63	11374-11670	Sentence	denotes	We have also previously demonstrated that cytotoxic T-cells appear to play a critical role in the injury of neurons and axons in both the acute (Howe and Rodriguez, unpublished observations) and chronic phases of Theiler's virus infection (Rivera-Quinones et al., 1998; Ure and Rodriguez, 2000; .
TextSentencer_T63	11374-11670	Sentence	denotes	We have also previously demonstrated that cytotoxic T-cells appear to play a critical role in the injury of neurons and axons in both the acute (Howe and Rodriguez, unpublished observations) and chronic phases of Theiler's virus infection (Rivera-Quinones et al., 1998; Ure and Rodriguez, 2000; .
T90913	11374-11670	Sentence	denotes	We have also previously demonstrated that cytotoxic T-cells appear to play a critical role in the injury of neurons and axons in both the acute (Howe and Rodriguez, unpublished observations) and chronic phases of Theiler's virus infection (Rivera-Quinones et al., 1998; Ure and Rodriguez, 2000; .
TextSentencer_T64	11671-11929	Sentence	denotes	Experimental allergic (or autoimmune) encephalomyelitis (EAE) has been a central model of inflammatory demyelinating disease since Rivers and Schwentker induced myelin destruction in monkeys immunized with brain tissue in 1935 (Rivers and Schwentker, 1935) .
TextSentencer_T64	11671-11929	Sentence	denotes	Experimental allergic (or autoimmune) encephalomyelitis (EAE) has been a central model of inflammatory demyelinating disease since Rivers and Schwentker induced myelin destruction in monkeys immunized with brain tissue in 1935 (Rivers and Schwentker, 1935) .
T36212	11671-11929	Sentence	denotes	Experimental allergic (or autoimmune) encephalomyelitis (EAE) has been a central model of inflammatory demyelinating disease since Rivers and Schwentker induced myelin destruction in monkeys immunized with brain tissue in 1935 (Rivers and Schwentker, 1935) .
TextSentencer_T65	11930-12108	Sentence	denotes	Since that time, it has become clear that EAE can be induced in essentially all mammals, from rodents to humans (Lassmann and Wekerle, 1998; Raine and Bornstein, 1970) (Fig. 8) .
TextSentencer_T65	11930-12108	Sentence	denotes	Since that time, it has become clear that EAE can be induced in essentially all mammals, from rodents to humans (Lassmann and Wekerle, 1998; Raine and Bornstein, 1970) (Fig. 8) .
T82055	11930-12108	Sentence	denotes	Since that time, it has become clear that EAE can be induced in essentially all mammals, from rodents to humans (Lassmann and Wekerle, 1998; Raine and Bornstein, 1970) (Fig. 8) .
TextSentencer_T66	12109-12291	Sentence	denotes	CNS proteinreactive T-cells are required for induction of EAE, and adoptive transfer of T-cells from immunized animals into naïve animals can elicit autoimmune-mediated inflammation.
TextSentencer_T66	12109-12291	Sentence	denotes	CNS proteinreactive T-cells are required for induction of EAE, and adoptive transfer of T-cells from immunized animals into naïve animals can elicit autoimmune-mediated inflammation.
T61122	12109-12291	Sentence	denotes	CNS proteinreactive T-cells are required for induction of EAE, and adoptive transfer of T-cells from immunized animals into naïve animals can elicit autoimmune-mediated inflammation.
TextSentencer_T67	12292-12494	Sentence	denotes	In contrast to Theiler's virus-mediated demyelination, EAErelated encephalitogenic T-cells are almost entirely CD4 + , recognizing CNS antigens only within the context of MHC class II (Swanborg, 2001) .
TextSentencer_T67	12292-12494	Sentence	denotes	In contrast to Theiler's virus-mediated demyelination, EAErelated encephalitogenic T-cells are almost entirely CD4 + , recognizing CNS antigens only within the context of MHC class II (Swanborg, 2001) .
T65698	12292-12494	Sentence	denotes	In contrast to Theiler's virus-mediated demyelination, EAErelated encephalitogenic T-cells are almost entirely CD4 + , recognizing CNS antigens only within the context of MHC class II (Swanborg, 2001) .
TextSentencer_T68	12495-12694	Sentence	denotes	While some evidence suggests that CD8 + and γδ-T cells may play a regulatory role in EAE (Segal, 2003) , CD4 + T-cells are considered to be the primary mediators of autoimmune-mediated demyelination.
TextSentencer_T68	12495-12694	Sentence	denotes	While some evidence suggests that CD8 + and γδ-T cells may play a regulatory role in EAE (Segal, 2003) , CD4 + T-cells are considered to be the primary mediators of autoimmune-mediated demyelination.
T11279	12495-12694	Sentence	denotes	While some evidence suggests that CD8 + and γδ-T cells may play a regulatory role in EAE (Segal, 2003) , CD4 + T-cells are considered to be the primary mediators of autoimmune-mediated demyelination.
TextSentencer_T69	12695-12800	Sentence	denotes	This is an important distinction, as well as an important difference between human MS and EAE in animals.
TextSentencer_T69	12695-12800	Sentence	denotes	This is an important distinction, as well as an important difference between human MS and EAE in animals.
T37138	12695-12800	Sentence	denotes	This is an important distinction, as well as an important difference between human MS and EAE in animals.
TextSentencer_T70	12801-13139	Sentence	denotes	Remyelination as Neuroprotection Axon damage is also associated with EAE (Ahmed et al., 2002; Kornek et al., 2000 Kornek et al., , 2001 Linker et al., 2002; Madrid and Wisniewski, 1977; Mancardi et al., 2001; Mead et al., 2002; Petzold et al., 2003; Pluchino et al., 2003; Raine and Cross, 1989; Raine et al., 1984; Storch et al., 2002) .
TextSentencer_T70	12801-13139	Sentence	denotes	Remyelination as Neuroprotection Axon damage is also associated with EAE (Ahmed et al., 2002; Kornek et al., 2000 Kornek et al., , 2001 Linker et al., 2002; Madrid and Wisniewski, 1977; Mancardi et al., 2001; Mead et al., 2002; Petzold et al., 2003; Pluchino et al., 2003; Raine and Cross, 1989; Raine et al., 1984; Storch et al., 2002) .
T36155	12801-13139	Sentence	denotes	Remyelination as Neuroprotection Axon damage is also associated with EAE (Ahmed et al., 2002; Kornek et al., 2000 Kornek et al., , 2001 Linker et al., 2002; Madrid and Wisniewski, 1977; Mancardi et al., 2001; Mead et al., 2002; Petzold et al., 2003; Pluchino et al., 2003; Raine and Cross, 1989; Raine et al., 1984; Storch et al., 2002) .
TextSentencer_T71	13140-13331	Sentence	denotes	Both acute axonal damage within actively demyelinating lesions, and chronic axonal injury within inactive lesions and normal-appearing white matter are observed in EAE (Kornek et al., 2000) .
TextSentencer_T71	13140-13331	Sentence	denotes	Both acute axonal damage within actively demyelinating lesions, and chronic axonal injury within inactive lesions and normal-appearing white matter are observed in EAE (Kornek et al., 2000) .
T1961	13140-13331	Sentence	denotes	Both acute axonal damage within actively demyelinating lesions, and chronic axonal injury within inactive lesions and normal-appearing white matter are observed in EAE (Kornek et al., 2000) .
TextSentencer_T72	13332-13595	Sentence	denotes	However, the mechanisms responsible for this axon damage are unclear, and, in contrast to the Theiler's virus model of MS, no study to date has identified a specific effector cell or process that is indispensable for axon injury but dispensable for demyelination.
TextSentencer_T72	13332-13595	Sentence	denotes	However, the mechanisms responsible for this axon damage are unclear, and, in contrast to the Theiler's virus model of MS, no study to date has identified a specific effector cell or process that is indispensable for axon injury but dispensable for demyelination.
T6065	13332-13595	Sentence	denotes	However, the mechanisms responsible for this axon damage are unclear, and, in contrast to the Theiler's virus model of MS, no study to date has identified a specific effector cell or process that is indispensable for axon injury but dispensable for demyelination.
TextSentencer_T73	13596-13781	Sentence	denotes	A variety of toxins, when injected into the spinal cord, rapidly induce demyelinating lesions without significant impact on cells other than oligodendrocytes van Engelen et al., 1997) .
TextSentencer_T73	13596-13781	Sentence	denotes	A variety of toxins, when injected into the spinal cord, rapidly induce demyelinating lesions without significant impact on cells other than oligodendrocytes van Engelen et al., 1997) .
T84695	13596-13781	Sentence	denotes	A variety of toxins, when injected into the spinal cord, rapidly induce demyelinating lesions without significant impact on cells other than oligodendrocytes van Engelen et al., 1997) .
TextSentencer_T74	13782-13905	Sentence	denotes	These include lysolecithin (lysophosphatidylcholine), an activator of phospholipase A 2 , and cuprizone, a copper chelator.
TextSentencer_T74	13782-13905	Sentence	denotes	These include lysolecithin (lysophosphatidylcholine), an activator of phospholipase A 2 , and cuprizone, a copper chelator.
T14715	13782-13905	Sentence	denotes	These include lysolecithin (lysophosphatidylcholine), an activator of phospholipase A 2 , and cuprizone, a copper chelator.
TextSentencer_T75	13906-14160	Sentence	denotes	Although a significant amount of evidence supports the role of the immune system in mediating and repairing the myelin damage induced by these two toxins, very little evidence is available regarding the extent of axon damage associated with these models.
TextSentencer_T75	13906-14160	Sentence	denotes	Although a significant amount of evidence supports the role of the immune system in mediating and repairing the myelin damage induced by these two toxins, very little evidence is available regarding the extent of axon damage associated with these models.
T87300	13906-14160	Sentence	denotes	Although a significant amount of evidence supports the role of the immune system in mediating and repairing the myelin damage induced by these two toxins, very little evidence is available regarding the extent of axon damage associated with these models.
TextSentencer_T76	14161-14417	Sentence	denotes	That said, Redford et al. (1997) showed that lysolecithin-induced demyelination sensitizes axons to conduction blockade induced by nitric oxide donors, suggesting that naked axons are more susceptible to soluble effector molecules released by immune cells.
TextSentencer_T76	14161-14417	Sentence	denotes	That said, Redford et al. (1997) showed that lysolecithin-induced demyelination sensitizes axons to conduction blockade induced by nitric oxide donors, suggesting that naked axons are more susceptible to soluble effector molecules released by immune cells.
T28081	14161-14417	Sentence	denotes	That said, Redford et al. (1997) showed that lysolecithin-induced demyelination sensitizes axons to conduction blockade induced by nitric oxide donors, suggesting that naked axons are more susceptible to soluble effector molecules released by immune cells.
TextSentencer_T77	14418-14683	Sentence	denotes	Likewise, Jean et al. (2002) have described a dramatic reduction in neurofilament staining of axons within lysolecithin-damaged areas, and have shown that acceleration of remyelination with plateletderived growth factor ameliorates this loss of axon immunolabeling.
TextSentencer_T77	14418-14683	Sentence	denotes	Likewise, Jean et al. (2002) have described a dramatic reduction in neurofilament staining of axons within lysolecithin-damaged areas, and have shown that acceleration of remyelination with plateletderived growth factor ameliorates this loss of axon immunolabeling.
T65746	14418-14683	Sentence	denotes	Likewise, Jean et al. (2002) have described a dramatic reduction in neurofilament staining of axons within lysolecithin-damaged areas, and have shown that acceleration of remyelination with plateletderived growth factor ameliorates this loss of axon immunolabeling.
TextSentencer_T78	14684-14735	Sentence	denotes	Finally, a subtantial reduction in axon caliber was
TextSentencer_T78	14684-14735	Sentence	denotes	Finally, a subtantial reduction in axon caliber was
T10318	14684-14735	Sentence	denotes	Finally, a subtantial reduction in axon caliber was
TextSentencer_T79	14736-14922	Sentence	denotes	Remyelination as Neuroprotection associated with chronic demyelination induced by cuprizone treatment, with axon diameter being reduced to 60% of normal after 16 weeks of demyelination .
TextSentencer_T79	14736-14922	Sentence	denotes	Remyelination as Neuroprotection associated with chronic demyelination induced by cuprizone treatment, with axon diameter being reduced to 60% of normal after 16 weeks of demyelination .
T49121	14736-14922	Sentence	denotes	Remyelination as Neuroprotection associated with chronic demyelination induced by cuprizone treatment, with axon diameter being reduced to 60% of normal after 16 weeks of demyelination .
TextSentencer_T80	14923-15010	Sentence	denotes	Thus, every major animal model of demyelinating disease is associated with axon damage.
TextSentencer_T80	14923-15010	Sentence	denotes	Thus, every major animal model of demyelinating disease is associated with axon damage.
T31539	14923-15010	Sentence	denotes	Thus, every major animal model of demyelinating disease is associated with axon damage.
TextSentencer_T81	15011-15317	Sentence	denotes	Because the methods used to induce demyelination in these models are extremely disparate, and because the cellular effectors of demyelination are variable across each of these models, it seems that axon failure, rather than mechanism of demyelination, is the critical feature of MS and animal models of MS.
TextSentencer_T81	15011-15317	Sentence	denotes	Because the methods used to induce demyelination in these models are extremely disparate, and because the cellular effectors of demyelination are variable across each of these models, it seems that axon failure, rather than mechanism of demyelination, is the critical feature of MS and animal models of MS.
T18046	15011-15317	Sentence	denotes	Because the methods used to induce demyelination in these models are extremely disparate, and because the cellular effectors of demyelination are variable across each of these models, it seems that axon failure, rather than mechanism of demyelination, is the critical feature of MS and animal models of MS.
TextSentencer_T82	15318-15550	Sentence	denotes	Therefore, from the perspective of controlling and reversing the neurological dysfunction associated with MS, it is important to understand the cellular mechanisms and the cellular effectors involved in axon damage and axon dropout.
TextSentencer_T82	15318-15550	Sentence	denotes	Therefore, from the perspective of controlling and reversing the neurological dysfunction associated with MS, it is important to understand the cellular mechanisms and the cellular effectors involved in axon damage and axon dropout.
T20250	15318-15550	Sentence	denotes	Therefore, from the perspective of controlling and reversing the neurological dysfunction associated with MS, it is important to understand the cellular mechanisms and the cellular effectors involved in axon damage and axon dropout.
TextSentencer_T83	15551-15677	Sentence	denotes	Experiments carried out by our group suggest that at least one important cellular effector of axon damage is the CD8 + T-cell.
TextSentencer_T83	15551-15677	Sentence	denotes	Experiments carried out by our group suggest that at least one important cellular effector of axon damage is the CD8 + T-cell.
T73093	15551-15677	Sentence	denotes	Experiments carried out by our group suggest that at least one important cellular effector of axon damage is the CD8 + T-cell.
TextSentencer_T84	15678-15867	Sentence	denotes	Using the Theiler's virus model of MS, we have investigated the role of MHC class I and class II in the progression of demyelination and the development of functional neurological deficits.
TextSentencer_T84	15678-15867	Sentence	denotes	Using the Theiler's virus model of MS, we have investigated the role of MHC class I and class II in the progression of demyelination and the development of functional neurological deficits.
T87122	15678-15867	Sentence	denotes	Using the Theiler's virus model of MS, we have investigated the role of MHC class I and class II in the progression of demyelination and the development of functional neurological deficits.
TextSentencer_T85	15868-16017	Sentence	denotes	We found that C57BL/6 × 129/J mice (H-2 b haplotype) were resistant to demyelination induced by Theiler's virus and never developed clinical disease.
TextSentencer_T85	15868-16017	Sentence	denotes	We found that C57BL/6 × 129/J mice (H-2 b haplotype) were resistant to demyelination induced by Theiler's virus and never developed clinical disease.
T60910	15868-16017	Sentence	denotes	We found that C57BL/6 × 129/J mice (H-2 b haplotype) were resistant to demyelination induced by Theiler's virus and never developed clinical disease.
TextSentencer_T86	16018-16198	Sentence	denotes	In contrast, mice of the identical haplotype that were deficient in expression of MHC class I (C57BL/6 × 129/J β 2 -microglobulin −/− ) developed extensive demyelination (Fig. 9 ).
TextSentencer_T86	16018-16198	Sentence	denotes	In contrast, mice of the identical haplotype that were deficient in expression of MHC class I (C57BL/6 × 129/J β 2 -microglobulin −/− ) developed extensive demyelination (Fig. 9 ).
T4100	16018-16198	Sentence	denotes	In contrast, mice of the identical haplotype that were deficient in expression of MHC class I (C57BL/6 × 129/J β 2 -microglobulin −/− ) developed extensive demyelination (Fig. 9 ).
TextSentencer_T87	16199-16559	Sentence	denotes	These animals failed to develop significant clinical signs of functional deficit as measured by hind-limb motor-evoked potentials, spontaneous vertical and horizontal movement assessment, rotarod performance, and activity wheel behavior (Fiette et al., 1993; Pullen et al., 1993; Rivera-Quinones et al., 1998; Rodriguez et al., 1993; Ure and Rodriguez, 2002) .
TextSentencer_T87	16199-16559	Sentence	denotes	These animals failed to develop significant clinical signs of functional deficit as measured by hind-limb motor-evoked potentials, spontaneous vertical and horizontal movement assessment, rotarod performance, and activity wheel behavior (Fiette et al., 1993; Pullen et al., 1993; Rivera-Quinones et al., 1998; Rodriguez et al., 1993; Ure and Rodriguez, 2002) .
T31356	16199-16559	Sentence	denotes	These animals failed to develop significant clinical signs of functional deficit as measured by hind-limb motor-evoked potentials, spontaneous vertical and horizontal movement assessment, rotarod performance, and activity wheel behavior (Fiette et al., 1993; Pullen et al., 1993; Rivera-Quinones et al., 1998; Rodriguez et al., 1993; Ure and Rodriguez, 2002) .
TextSentencer_T88	16560-16882	Sentence	denotes	On the other hand, mice of the same haplotype that were deficient in expression of MHC class II (C57BL/6 × 129/J Ab 0 ) developed not only extensive demyelination but also severe neurological impairment, and were, in fact, frequently moribund by 120 days postinfection (Njenga et al., 1996; Rivera-Quinones et al., 1998) .
TextSentencer_T88	16560-16882	Sentence	denotes	On the other hand, mice of the same haplotype that were deficient in expression of MHC class II (C57BL/6 × 129/J Ab 0 ) developed not only extensive demyelination but also severe neurological impairment, and were, in fact, frequently moribund by 120 days postinfection (Njenga et al., 1996; Rivera-Quinones et al., 1998) .
T91706	16560-16882	Sentence	denotes	On the other hand, mice of the same haplotype that were deficient in expression of MHC class II (C57BL/6 × 129/J Ab 0 ) developed not only extensive demyelination but also severe neurological impairment, and were, in fact, frequently moribund by 120 days postinfection (Njenga et al., 1996; Rivera-Quinones et al., 1998) .
TextSentencer_T89	16883-17047	Sentence	denotes	Our findings indicate that physiological function was likely preserved secondary to the upregulation and redistribution of sodium channels along demyelinated axons.
TextSentencer_T89	16883-17047	Sentence	denotes	Our findings indicate that physiological function was likely preserved secondary to the upregulation and redistribution of sodium channels along demyelinated axons.
T60739	16883-17047	Sentence	denotes	Our findings indicate that physiological function was likely preserved secondary to the upregulation and redistribution of sodium channels along demyelinated axons.
TextSentencer_T90	17048-17494	Sentence	denotes	In fact, whereas chronically infected mice of a susceptible haplotype (SJL/J mice) showed a severe loss of sodium channel density and intensity along axons, chronically infected β 2 -microglobulin −/− mice showed a dramatic upregulation and redistribution of axonal sodium channels, even though overall levels of myelin loss and distribution of demyelinated lesions were similiar between the two strains (Rivera-Quinones et al., 1998) (Fig. 10) .
TextSentencer_T90	17048-17494	Sentence	denotes	In fact, whereas chronically infected mice of a susceptible haplotype (SJL/J mice) showed a severe loss of sodium channel density and intensity along axons, chronically infected β 2 -microglobulin −/− mice showed a dramatic upregulation and redistribution of axonal sodium channels, even though overall levels of myelin loss and distribution of demyelinated lesions were similiar between the two strains (Rivera-Quinones et al., 1998) (Fig. 10) .
T10912	17048-17494	Sentence	denotes	In fact, whereas chronically infected mice of a susceptible haplotype (SJL/J mice) showed a severe loss of sodium channel density and intensity along axons, chronically infected β 2 -microglobulin −/− mice showed a dramatic upregulation and redistribution of axonal sodium channels, even though overall levels of myelin loss and distribution of demyelinated lesions were similiar between the two strains (Rivera-Quinones et al., 1998) (Fig. 10) .
TextSentencer_T91	17495-17736	Sentence	denotes	Furthermore, axons, as marked by either Bielschowski staining or antineurofilament staining, were preserved in chronically infected β 2 -microglobulin −/− mice, even in regions of significant cellular infiltrate and demyelination (Fig. 11 ).
TextSentencer_T91	17495-17736	Sentence	denotes	Furthermore, axons, as marked by either Bielschowski staining or antineurofilament staining, were preserved in chronically infected β 2 -microglobulin −/− mice, even in regions of significant cellular infiltrate and demyelination (Fig. 11 ).
T44165	17495-17736	Sentence	denotes	Furthermore, axons, as marked by either Bielschowski staining or antineurofilament staining, were preserved in chronically infected β 2 -microglobulin −/− mice, even in regions of significant cellular infiltrate and demyelination (Fig. 11 ).
TextSentencer_T92	17737-17876	Sentence	denotes	In contrast, there was significant disruption and degeneration of axons in chronically infected SJL/J mice (Rivera-Quinones et al., 1998) .
TextSentencer_T92	17737-17876	Sentence	denotes	In contrast, there was significant disruption and degeneration of axons in chronically infected SJL/J mice (Rivera-Quinones et al., 1998) .
T87461	17737-17876	Sentence	denotes	In contrast, there was significant disruption and degeneration of axons in chronically infected SJL/J mice (Rivera-Quinones et al., 1998) .
TextSentencer_T93	17877-18124	Sentence	denotes	These findings indicate Infected β2m +/+ mice do not exhibit demyelination, whereas the extent and distribution of demyelinated lesions is qualitatively similar in class I-deficient mice (β2m −/− ), SJL/J mice, and class II-deficient mice (Ab 0 ).
TextSentencer_T93	17877-18124	Sentence	denotes	These findings indicate Infected β2m +/+ mice do not exhibit demyelination, whereas the extent and distribution of demyelinated lesions is qualitatively similar in class I-deficient mice (β2m −/− ), SJL/J mice, and class II-deficient mice (Ab 0 ).
T44062	17877-18124	Sentence	denotes	These findings indicate Infected β2m +/+ mice do not exhibit demyelination, whereas the extent and distribution of demyelinated lesions is qualitatively similar in class I-deficient mice (β2m −/− ), SJL/J mice, and class II-deficient mice (Ab 0 ).
TextSentencer_T94	18125-18330	Sentence	denotes	For each pair of reconstructions, the left profile shows gray matter (green) with an overlay of demyelinated areas (red); the right profile shows normal white matter (white) and demyelinated lesions (red).
TextSentencer_T94	18125-18330	Sentence	denotes	For each pair of reconstructions, the left profile shows gray matter (green) with an overlay of demyelinated areas (red); the right profile shows normal white matter (white) and demyelinated lesions (red).
T66873	18125-18330	Sentence	denotes	For each pair of reconstructions, the left profile shows gray matter (green) with an overlay of demyelinated areas (red); the right profile shows normal white matter (white) and demyelinated lesions (red).
TextSentencer_T95	18331-18497	Sentence	denotes	that MHC class I-restricted CD8 + T-cells are likely to be critical mediators of axon damage associated with demyelination in susceptible strains of mice ( Fig. 12 ).
TextSentencer_T95	18331-18497	Sentence	denotes	that MHC class I-restricted CD8 + T-cells are likely to be critical mediators of axon damage associated with demyelination in susceptible strains of mice ( Fig. 12 ).
T17976	18331-18497	Sentence	denotes	that MHC class I-restricted CD8 + T-cells are likely to be critical mediators of axon damage associated with demyelination in susceptible strains of mice ( Fig. 12 ).
TextSentencer_T96	18498-18646	Sentence	denotes	Further evidence in support of this CD8 + T-cell hypothesis is provided by our recent studies assessing axon transport in chronically infected mice.
TextSentencer_T96	18498-18646	Sentence	denotes	Further evidence in support of this CD8 + T-cell hypothesis is provided by our recent studies assessing axon transport in chronically infected mice.
T27532	18498-18646	Sentence	denotes	Further evidence in support of this CD8 + T-cell hypothesis is provided by our recent studies assessing axon transport in chronically infected mice.
TextSentencer_T97	18647-18844	Sentence	denotes	Using retrograde labeling of spinal axon tracts, we have demonstrated a failure of retrograde axon transport in mice with demyelination and functional deficits (Ure and Rodriguez, 2000) (Fig. 13 ).
TextSentencer_T97	18647-18844	Sentence	denotes	Using retrograde labeling of spinal axon tracts, we have demonstrated a failure of retrograde axon transport in mice with demyelination and functional deficits (Ure and Rodriguez, 2000) (Fig. 13 ).
T6621	18647-18844	Sentence	denotes	Using retrograde labeling of spinal axon tracts, we have demonstrated a failure of retrograde axon transport in mice with demyelination and functional deficits (Ure and Rodriguez, 2000) (Fig. 13 ).
TextSentencer_T98	18845-19139	Sentence	denotes	However, we found that retrograde axonal transport was preserved in demyelinated mice with deletion of MHC class I (Ure and Rodriguez, 2002) , suggesting that the lack of CD8 + cytotoxic T-cells protected axonal integrity while not affecting demyelinated lesion load (Ure and Rodriguez, 2002) .
TextSentencer_T98	18845-19139	Sentence	denotes	However, we found that retrograde axonal transport was preserved in demyelinated mice with deletion of MHC class I (Ure and Rodriguez, 2002) , suggesting that the lack of CD8 + cytotoxic T-cells protected axonal integrity while not affecting demyelinated lesion load (Ure and Rodriguez, 2002) .
T76450	18845-19139	Sentence	denotes	However, we found that retrograde axonal transport was preserved in demyelinated mice with deletion of MHC class I (Ure and Rodriguez, 2002) , suggesting that the lack of CD8 + cytotoxic T-cells protected axonal integrity while not affecting demyelinated lesion load (Ure and Rodriguez, 2002) .
TextSentencer_T99	19140-19437	Sentence	denotes	A specific CD8+ T-cell-mediated response is further supported by our experiments showing that depletion of antigen-specific cytotoxic T-cells restricted to a viral peptide (VP2 121-130 ) resulted in preservation of neurological function, as measured by rotarod performance (Johnson et al., 2001) .
TextSentencer_T99	19140-19437	Sentence	denotes	A specific CD8+ T-cell-mediated response is further supported by our experiments showing that depletion of antigen-specific cytotoxic T-cells restricted to a viral peptide (VP2 121-130 ) resulted in preservation of neurological function, as measured by rotarod performance (Johnson et al., 2001) .
T18711	19140-19437	Sentence	denotes	A specific CD8+ T-cell-mediated response is further supported by our experiments showing that depletion of antigen-specific cytotoxic T-cells restricted to a viral peptide (VP2 121-130 ) resulted in preservation of neurological function, as measured by rotarod performance (Johnson et al., 2001) .
TextSentencer_T100	19438-19779	Sentence	denotes	Therefore, specific presentation of a Theiler's viral epitope within the context of H-2D b is necessary for at least a component of the neurological dysfunction associated with infection, although VP2 peptide depletion has no effect on the extent of viral infection or the level of demyelination induced by infection (Johnson et al., 2001) .
TextSentencer_T100	19438-19779	Sentence	denotes	Therefore, specific presentation of a Theiler's viral epitope within the context of H-2D b is necessary for at least a component of the neurological dysfunction associated with infection, although VP2 peptide depletion has no effect on the extent of viral infection or the level of demyelination induced by infection (Johnson et al., 2001) .
T16835	19438-19779	Sentence	denotes	Therefore, specific presentation of a Theiler's viral epitope within the context of H-2D b is necessary for at least a component of the neurological dysfunction associated with infection, although VP2 peptide depletion has no effect on the extent of viral infection or the level of demyelination induced by infection (Johnson et al., 2001) .
TextSentencer_T101	19780-20039	Sentence	denotes	Finally, ongoing experiments in our laboratory indicate that VP2 peptide depletion of the MHC class I cytotoxic T-cell response to Theiler's virus infection preserves spinal axons, as measured by neurofilament staining, axon counting, and retrograde labeling.
TextSentencer_T101	19780-20039	Sentence	denotes	Finally, ongoing experiments in our laboratory indicate that VP2 peptide depletion of the MHC class I cytotoxic T-cell response to Theiler's virus infection preserves spinal axons, as measured by neurofilament staining, axon counting, and retrograde labeling.
T87816	19780-20039	Sentence	denotes	Finally, ongoing experiments in our laboratory indicate that VP2 peptide depletion of the MHC class I cytotoxic T-cell response to Theiler's virus infection preserves spinal axons, as measured by neurofilament staining, axon counting, and retrograde labeling.
TextSentencer_T102	20040-20241	Sentence	denotes	Thus, antiviral CD8 + cytotoxic T-cells are clearly important for the loss of axons and development of neurological dysfunction associated with chronic demyelination in the Theiler's virus model of MS.
TextSentencer_T102	20040-20241	Sentence	denotes	Thus, antiviral CD8 + cytotoxic T-cells are clearly important for the loss of axons and development of neurological dysfunction associated with chronic demyelination in the Theiler's virus model of MS.
T86103	20040-20241	Sentence	denotes	Thus, antiviral CD8 + cytotoxic T-cells are clearly important for the loss of axons and development of neurological dysfunction associated with chronic demyelination in the Theiler's virus model of MS.
TextSentencer_T103	20242-20394	Sentence	denotes	The hypothesis that CD8 + T-cells are critical in the pathogenesis of Theiler's virus infection is relevant specifically to mice of the H-2 b haplotype.
TextSentencer_T103	20242-20394	Sentence	denotes	The hypothesis that CD8 + T-cells are critical in the pathogenesis of Theiler's virus infection is relevant specifically to mice of the H-2 b haplotype.
T50307	20242-20394	Sentence	denotes	The hypothesis that CD8 + T-cells are critical in the pathogenesis of Theiler's virus infection is relevant specifically to mice of the H-2 b haplotype.
TextSentencer_T104	20395-20727	Sentence	denotes	Observations regarding the role of MHC class I in resistance vs. susceptibility to viral persistance and demyelination were made in recombinant inbred strains of the C57BL background (Rodriguez and David, 1985; Rodriguez et al., 1986) , and the immunodominant VP2 121-130 peptide response was observed only in H-2 b mice (Fig. 14) .
TextSentencer_T104	20395-20727	Sentence	denotes	Observations regarding the role of MHC class I in resistance vs. susceptibility to viral persistance and demyelination were made in recombinant inbred strains of the C57BL background (Rodriguez and David, 1985; Rodriguez et al., 1986) , and the immunodominant VP2 121-130 peptide response was observed only in H-2 b mice (Fig. 14) .
T80880	20395-20727	Sentence	denotes	Observations regarding the role of MHC class I in resistance vs. susceptibility to viral persistance and demyelination were made in recombinant inbred strains of the C57BL background (Rodriguez and David, 1985; Rodriguez et al., 1986) , and the immunodominant VP2 121-130 peptide response was observed only in H-2 b mice (Fig. 14) .
TextSentencer_T105	20728-20885	Sentence	denotes	The hypothesis probably does not explain the mechanism of demyelination and neurological deficit in susceptible strains such as SJL/J mice (H-2 s haplotype).
TextSentencer_T105	20728-20885	Sentence	denotes	The hypothesis probably does not explain the mechanism of demyelination and neurological deficit in susceptible strains such as SJL/J mice (H-2 s haplotype).
T91490	20728-20885	Sentence	denotes	The hypothesis probably does not explain the mechanism of demyelination and neurological deficit in susceptible strains such as SJL/J mice (H-2 s haplotype).
TextSentencer_T106	20886-21337	Sentence	denotes	For example, disruption of MHC class I function by deletion of β 2 -microglobulin in SJL/J mice results in more demyelination and increased neurological deficit (Begolka et al., 2001) , and in the SJL/J strain it has been suggested that MHC class II-restricted T-cell response (Miller et al., 1987) , and epitope-spreading to myelin antigens may be the mechanism of demyelination and neurological deficit (Croxford et al., 2002; Miller et al., 1997) .
TextSentencer_T106	20886-21337	Sentence	denotes	For example, disruption of MHC class I function by deletion of β 2 -microglobulin in SJL/J mice results in more demyelination and increased neurological deficit (Begolka et al., 2001) , and in the SJL/J strain it has been suggested that MHC class II-restricted T-cell response (Miller et al., 1987) , and epitope-spreading to myelin antigens may be the mechanism of demyelination and neurological deficit (Croxford et al., 2002; Miller et al., 1997) .
T46970	20886-21337	Sentence	denotes	For example, disruption of MHC class I function by deletion of β 2 -microglobulin in SJL/J mice results in more demyelination and increased neurological deficit (Begolka et al., 2001) , and in the SJL/J strain it has been suggested that MHC class II-restricted T-cell response (Miller et al., 1987) , and epitope-spreading to myelin antigens may be the mechanism of demyelination and neurological deficit (Croxford et al., 2002; Miller et al., 1997) .
TextSentencer_T107	21338-21595	Sentence	denotes	However, CD8 + MHC class I-restricted cytotoxic T-cells have definitely been implicated in human MS, and it is likely that demyelination and neurological dysfunction in humans are a combination of both CD8 + -and CD4 + -mediated mechanisms (Neumann, 2003) .
TextSentencer_T107	21338-21595	Sentence	denotes	However, CD8 + MHC class I-restricted cytotoxic T-cells have definitely been implicated in human MS, and it is likely that demyelination and neurological dysfunction in humans are a combination of both CD8 + -and CD4 + -mediated mechanisms (Neumann, 2003) .
T95181	21338-21595	Sentence	denotes	However, CD8 + MHC class I-restricted cytotoxic T-cells have definitely been implicated in human MS, and it is likely that demyelination and neurological dysfunction in humans are a combination of both CD8 + -and CD4 + -mediated mechanisms (Neumann, 2003) .
TextSentencer_T108	21596-21782	Sentence	denotes	Recent pathological studies have shown that CD8 + T-cells may be the most common subset of T-cells in the MS brain and appear to be clonally expanded in MS lesions (Babbe et al., 2000) .
TextSentencer_T108	21596-21782	Sentence	denotes	Recent pathological studies have shown that CD8 + T-cells may be the most common subset of T-cells in the MS brain and appear to be clonally expanded in MS lesions (Babbe et al., 2000) .
T44800	21596-21782	Sentence	denotes	Recent pathological studies have shown that CD8 + T-cells may be the most common subset of T-cells in the MS brain and appear to be clonally expanded in MS lesions (Babbe et al., 2000) .
TextSentencer_T109	21783-22121	Sentence	denotes	Recent experiments in collaboration with Hans Lassmann have demonstrated intense expression of MHC class I in oligodendrocytes, neurons, axons, and astrocytes in the MS lesion (Hoftberger et al., 2003) , and autopsy studies have demonstrated that CD8 + T-cells are statistically associated with axonal injury in MS (Bitsch et al., 2000) .
TextSentencer_T109	21783-22121	Sentence	denotes	Recent experiments in collaboration with Hans Lassmann have demonstrated intense expression of MHC class I in oligodendrocytes, neurons, axons, and astrocytes in the MS lesion (Hoftberger et al., 2003) , and autopsy studies have demonstrated that CD8 + T-cells are statistically associated with axonal injury in MS (Bitsch et al., 2000) .
T29420	21783-22121	Sentence	denotes	Recent experiments in collaboration with Hans Lassmann have demonstrated intense expression of MHC class I in oligodendrocytes, neurons, axons, and astrocytes in the MS lesion (Hoftberger et al., 2003) , and autopsy studies have demonstrated that CD8 + T-cells are statistically associated with axonal injury in MS (Bitsch et al., 2000) .
TextSentencer_T110	22122-22428	Sentence	denotes	In addition, CD8 + T-cells have been shown to injure neurons and transect axons in vitro (Medana et al., 2000 (Medana et al., , 2001 , and imaging studies have indicated that axonal loss in MS is a direct correlate for disability (Narayanan et al., 1997; Truyen et al., 1996; van Waesberghe et al., 1999) .
TextSentencer_T110	22122-22428	Sentence	denotes	In addition, CD8 + T-cells have been shown to injure neurons and transect axons in vitro (Medana et al., 2000 (Medana et al., , 2001 , and imaging studies have indicated that axonal loss in MS is a direct correlate for disability (Narayanan et al., 1997; Truyen et al., 1996; van Waesberghe et al., 1999) .
T42580	22122-22428	Sentence	denotes	In addition, CD8 + T-cells have been shown to injure neurons and transect axons in vitro (Medana et al., 2000 (Medana et al., , 2001 , and imaging studies have indicated that axonal loss in MS is a direct correlate for disability (Narayanan et al., 1997; Truyen et al., 1996; van Waesberghe et al., 1999) .
TextSentencer_T111	22429-22549	Sentence	denotes	These studies suggest that CD8 + T-cells may be the primary effectors for axonal injury and neurological deficits in MS.
TextSentencer_T111	22429-22549	Sentence	denotes	These studies suggest that CD8 + T-cells may be the primary effectors for axonal injury and neurological deficits in MS.
T78951	22429-22549	Sentence	denotes	These studies suggest that CD8 + T-cells may be the primary effectors for axonal injury and neurological deficits in MS.
TextSentencer_T112	22550-22642	Sentence	denotes	Cytotoxic T-cell-induced cytotoxicity is mediated predominantly by two independent pathways.
TextSentencer_T112	22550-22642	Sentence	denotes	Cytotoxic T-cell-induced cytotoxicity is mediated predominantly by two independent pathways.
T39472	22550-22642	Sentence	denotes	Cytotoxic T-cell-induced cytotoxicity is mediated predominantly by two independent pathways.
TextSentencer_T113	22643-22657	Sentence	denotes	The first is a
TextSentencer_T113	22643-22657	Sentence	denotes	The first is a
T97038	22643-22657	Sentence	denotes	The first is a
TextSentencer_T114	22658-22775	Sentence	denotes	Remyelination as Neuroprotection granule-mediated process involving the pore-forming molecule perforin and granzymes.
TextSentencer_T114	22658-22775	Sentence	denotes	Remyelination as Neuroprotection granule-mediated process involving the pore-forming molecule perforin and granzymes.
T44319	22658-22775	Sentence	denotes	Remyelination as Neuroprotection granule-mediated process involving the pore-forming molecule perforin and granzymes.
TextSentencer_T115	22776-22944	Sentence	denotes	The second is a receptor ligand interaction that induces apoptosis through Fas (CD95/Apo-1) on the target and Fas ligand (FasL/CD95L/ Apo-1ligand) on the effector cell.
TextSentencer_T115	22776-22944	Sentence	denotes	The second is a receptor ligand interaction that induces apoptosis through Fas (CD95/Apo-1) on the target and Fas ligand (FasL/CD95L/ Apo-1ligand) on the effector cell.
T73866	22776-22944	Sentence	denotes	The second is a receptor ligand interaction that induces apoptosis through Fas (CD95/Apo-1) on the target and Fas ligand (FasL/CD95L/ Apo-1ligand) on the effector cell.
TextSentencer_T116	22945-23074	Sentence	denotes	Both mechanisms are implicated in neurological injury, and both require contact between the target cell and the cytotoxic T-cell.
TextSentencer_T116	22945-23074	Sentence	denotes	Both mechanisms are implicated in neurological injury, and both require contact between the target cell and the cytotoxic T-cell.
T29427	22945-23074	Sentence	denotes	Both mechanisms are implicated in neurological injury, and both require contact between the target cell and the cytotoxic T-cell.
TextSentencer_T117	23075-23345	Sentence	denotes	At least one means of such physical contact is the generation of an "immune synapse," formed when the T-cell receptor complex of a cytotoxic T-cell encounters and binds to an MHC class I molecule presenting an appropriate peptide epitope on the surface of a target cell.
TextSentencer_T117	23075-23345	Sentence	denotes	At least one means of such physical contact is the generation of an "immune synapse," formed when the T-cell receptor complex of a cytotoxic T-cell encounters and binds to an MHC class I molecule presenting an appropriate peptide epitope on the surface of a target cell.
T80920	23075-23345	Sentence	denotes	At least one means of such physical contact is the generation of an "immune synapse," formed when the T-cell receptor complex of a cytotoxic T-cell encounters and binds to an MHC class I molecule presenting an appropriate peptide epitope on the surface of a target cell.
TextSentencer_T118	23346-23479	Sentence	denotes	It was assumed previously that neurons escape immune surveillance through their inability to express MHC class I on the cell surface.
TextSentencer_T118	23346-23479	Sentence	denotes	It was assumed previously that neurons escape immune surveillance through their inability to express MHC class I on the cell surface.
T40220	23346-23479	Sentence	denotes	It was assumed previously that neurons escape immune surveillance through their inability to express MHC class I on the cell surface.
TextSentencer_T119	23480-23630	Sentence	denotes	However, it has been shown in vivo that during pathological processes, the expression of MHC class I on the surface of neurons is rapidly upregulated.
TextSentencer_T119	23480-23630	Sentence	denotes	However, it has been shown in vivo that during pathological processes, the expression of MHC class I on the surface of neurons is rapidly upregulated.
T80294	23480-23630	Sentence	denotes	However, it has been shown in vivo that during pathological processes, the expression of MHC class I on the surface of neurons is rapidly upregulated.
TextSentencer_T120	23631-23797	Sentence	denotes	For example, after Theiler's virus infection, MHC class I is rapidly upregulated in most CNS cells, including neurons (Altintas et al., 1993; Lindsley et al., 1991) .
TextSentencer_T120	23631-23797	Sentence	denotes	For example, after Theiler's virus infection, MHC class I is rapidly upregulated in most CNS cells, including neurons (Altintas et al., 1993; Lindsley et al., 1991) .
T48409	23631-23797	Sentence	denotes	For example, after Theiler's virus infection, MHC class I is rapidly upregulated in most CNS cells, including neurons (Altintas et al., 1993; Lindsley et al., 1991) .
TextSentencer_T121	23798-23951	Sentence	denotes	Therefore, after viral infection, axons and neurons become suitable targets for cytotoxic T-cells that are specific for CD8 + -restricted viral epitopes.
TextSentencer_T121	23798-23951	Sentence	denotes	Therefore, after viral infection, axons and neurons become suitable targets for cytotoxic T-cells that are specific for CD8 + -restricted viral epitopes.
T68522	23798-23951	Sentence	denotes	Therefore, after viral infection, axons and neurons become suitable targets for cytotoxic T-cells that are specific for CD8 + -restricted viral epitopes.
TextSentencer_T122	23952-24141	Sentence	denotes	In addition, soluble factors such as interferon-α/β (IFN-α/β), released as a result of infection, appear to be involved in the induction of MHC class I on CNS cells (Njenga et al., 1997b) .
TextSentencer_T122	23952-24141	Sentence	denotes	In addition, soluble factors such as interferon-α/β (IFN-α/β), released as a result of infection, appear to be involved in the induction of MHC class I on CNS cells (Njenga et al., 1997b) .
T44899	23952-24141	Sentence	denotes	In addition, soluble factors such as interferon-α/β (IFN-α/β), released as a result of infection, appear to be involved in the induction of MHC class I on CNS cells (Njenga et al., 1997b) .
TextSentencer_T123	24142-24301	Sentence	denotes	Of interest, electrically silent neurons upregulate MHC class I molecules on their surface (Neumann et al., 1995) , thus predisposing them to cytotoxic attack.
TextSentencer_T123	24142-24301	Sentence	denotes	Of interest, electrically silent neurons upregulate MHC class I molecules on their surface (Neumann et al., 1995) , thus predisposing them to cytotoxic attack.
T80470	24142-24301	Sentence	denotes	Of interest, electrically silent neurons upregulate MHC class I molecules on their surface (Neumann et al., 1995) , thus predisposing them to cytotoxic attack.
TextSentencer_T124	24302-24483	Sentence	denotes	This suggests that pathological processes such as demyelination that lead to conduction block may cause axons to become particularly vulnerable to cytotoxic T-cell-mediated killing.
TextSentencer_T124	24302-24483	Sentence	denotes	This suggests that pathological processes such as demyelination that lead to conduction block may cause axons to become particularly vulnerable to cytotoxic T-cell-mediated killing.
T27214	24302-24483	Sentence	denotes	This suggests that pathological processes such as demyelination that lead to conduction block may cause axons to become particularly vulnerable to cytotoxic T-cell-mediated killing.
TextSentencer_T125	24484-24763	Sentence	denotes	The dominant mechanism for cytotoxic CD8 + T-cellmediated viral clearance and killing of virally infected cells is the release of cytolytic granules containing the pore-forming protein perforin, the proteoglycan serglycin, and a family of serine proteases known as the granzymes.
TextSentencer_T125	24484-24763	Sentence	denotes	The dominant mechanism for cytotoxic CD8 + T-cellmediated viral clearance and killing of virally infected cells is the release of cytolytic granules containing the pore-forming protein perforin, the proteoglycan serglycin, and a family of serine proteases known as the granzymes.
T28754	24484-24763	Sentence	denotes	The dominant mechanism for cytotoxic CD8 + T-cellmediated viral clearance and killing of virally infected cells is the release of cytolytic granules containing the pore-forming protein perforin, the proteoglycan serglycin, and a family of serine proteases known as the granzymes.
TextSentencer_T126	24764-24897	Sentence	denotes	Granzymes A and B are the most abundant granzymes in cytolytic granules, and granzyme B is a mediator of caspase-dependent apoptosis.
TextSentencer_T126	24764-24897	Sentence	denotes	Granzymes A and B are the most abundant granzymes in cytolytic granules, and granzyme B is a mediator of caspase-dependent apoptosis.
T13767	24764-24897	Sentence	denotes	Granzymes A and B are the most abundant granzymes in cytolytic granules, and granzyme B is a mediator of caspase-dependent apoptosis.
TextSentencer_T127	24898-24985	Sentence	denotes	Granzymes appear to be packaged within the cytolytic granule in complex with serglycin.
TextSentencer_T127	24898-24985	Sentence	denotes	Granzymes appear to be packaged within the cytolytic granule in complex with serglycin.
T61168	24898-24985	Sentence	denotes	Granzymes appear to be packaged within the cytolytic granule in complex with serglycin.
TextSentencer_T128	24986-25148	Sentence	denotes	Approximately 30 to 50 granzyme molecules bind to each molecule of serglycin, forming a large granzyme particle that ranges in size from 40 to 200 nm in diameter.
TextSentencer_T128	24986-25148	Sentence	denotes	Approximately 30 to 50 granzyme molecules bind to each molecule of serglycin, forming a large granzyme particle that ranges in size from 40 to 200 nm in diameter.
T27012	24986-25148	Sentence	denotes	Approximately 30 to 50 granzyme molecules bind to each molecule of serglycin, forming a large granzyme particle that ranges in size from 40 to 200 nm in diameter.
TextSentencer_T129	25149-25389	Sentence	denotes	After T-cell receptor recognition of the appropriate peptide/MHC class I complex on target cells and the formation of the immune synapse, the granzyme/serglycin complex and perforin are exocytosed by the cytotoxic T-cell (Lieberman, 2003) .
TextSentencer_T129	25149-25389	Sentence	denotes	After T-cell receptor recognition of the appropriate peptide/MHC class I complex on target cells and the formation of the immune synapse, the granzyme/serglycin complex and perforin are exocytosed by the cytotoxic T-cell (Lieberman, 2003) .
T11465	25149-25389	Sentence	denotes	After T-cell receptor recognition of the appropriate peptide/MHC class I complex on target cells and the formation of the immune synapse, the granzyme/serglycin complex and perforin are exocytosed by the cytotoxic T-cell (Lieberman, 2003) .
TextSentencer_T130	25390-25658	Sentence	denotes	Some confusion currently exists regarding the role of perforin in the steps subsequent to cytolytic granule exocytosis, but the current model suggests that granzymes, either free or in complex with serglycin, bind to the surface of the target cell and are endocytosed.
TextSentencer_T130	25390-25658	Sentence	denotes	Some confusion currently exists regarding the role of perforin in the steps subsequent to cytolytic granule exocytosis, but the current model suggests that granzymes, either free or in complex with serglycin, bind to the surface of the target cell and are endocytosed.
T71423	25390-25658	Sentence	denotes	Some confusion currently exists regarding the role of perforin in the steps subsequent to cytolytic granule exocytosis, but the current model suggests that granzymes, either free or in complex with serglycin, bind to the surface of the target cell and are endocytosed.
TextSentencer_T131	25659-25780	Sentence	denotes	This event appears to occur in the absence of perforin (Froelich et al., 1996; Pinkoski et al., 1998; Shi et al., 1997) .
TextSentencer_T131	25659-25780	Sentence	denotes	This event appears to occur in the absence of perforin (Froelich et al., 1996; Pinkoski et al., 1998; Shi et al., 1997) .
T27645	25659-25780	Sentence	denotes	This event appears to occur in the absence of perforin (Froelich et al., 1996; Pinkoski et al., 1998; Shi et al., 1997) .
TextSentencer_T132	25781-26048	Sentence	denotes	Once endocytosed, however, perforin may function to facilitate the transfer of granzymes from target cell endosomes to the cytosol via endosomolysis, apparently without plasma membrane pore formation (Browne et al., 1999; Froelich et al., 1996; Metkar et al., 2002) .
TextSentencer_T132	25781-26048	Sentence	denotes	Once endocytosed, however, perforin may function to facilitate the transfer of granzymes from target cell endosomes to the cytosol via endosomolysis, apparently without plasma membrane pore formation (Browne et al., 1999; Froelich et al., 1996; Metkar et al., 2002) .
T8087	25781-26048	Sentence	denotes	Once endocytosed, however, perforin may function to facilitate the transfer of granzymes from target cell endosomes to the cytosol via endosomolysis, apparently without plasma membrane pore formation (Browne et al., 1999; Froelich et al., 1996; Metkar et al., 2002) .
TextSentencer_T133	26049-26268	Sentence	denotes	Regardless of the precise mechanism of action, perforin is clearly required for the full killing function of cytotoxic T-cells, and it was therefore logical to assess the role of perforin in Tcell-mediated axon killing.
TextSentencer_T133	26049-26268	Sentence	denotes	Regardless of the precise mechanism of action, perforin is clearly required for the full killing function of cytotoxic T-cells, and it was therefore logical to assess the role of perforin in Tcell-mediated axon killing.
T68535	26049-26268	Sentence	denotes	Regardless of the precise mechanism of action, perforin is clearly required for the full killing function of cytotoxic T-cells, and it was therefore logical to assess the role of perforin in Tcell-mediated axon killing.
TextSentencer_T134	26269-26498	Sentence	denotes	Our laboratory has demonstrated, using Theiler's virus infection of C57BL/6 H-2 b mice, that perforin may be a critical component in the induction of neurological deficits once demyelination is established (Murray et al., 1998) .
TextSentencer_T134	26269-26498	Sentence	denotes	Our laboratory has demonstrated, using Theiler's virus infection of C57BL/6 H-2 b mice, that perforin may be a critical component in the induction of neurological deficits once demyelination is established (Murray et al., 1998) .
T53261	26269-26498	Sentence	denotes	Our laboratory has demonstrated, using Theiler's virus infection of C57BL/6 H-2 b mice, that perforin may be a critical component in the induction of neurological deficits once demyelination is established (Murray et al., 1998) .
TextSentencer_T135	26499-26628	Sentence	denotes	We found that perforin deficiency broke viral resistance, resulting in viral persistence and consequent demyelination (Fig. 15 ).
TextSentencer_T135	26499-26628	Sentence	denotes	We found that perforin deficiency broke viral resistance, resulting in viral persistence and consequent demyelination (Fig. 15 ).
T42218	26499-26628	Sentence	denotes	We found that perforin deficiency broke viral resistance, resulting in viral persistence and consequent demyelination (Fig. 15 ).
TextSentencer_T136	26629-26853	Sentence	denotes	Despite significant demyelination throughout the spinal cord, however, perforin-deficient C57BL/6 H-2 b mice failed to develop the significant functional deficits associated with demyelination in susceptible strains of mice.
TextSentencer_T136	26629-26853	Sentence	denotes	Despite significant demyelination throughout the spinal cord, however, perforin-deficient C57BL/6 H-2 b mice failed to develop the significant functional deficits associated with demyelination in susceptible strains of mice.
T84842	26629-26853	Sentence	denotes	Despite significant demyelination throughout the spinal cord, however, perforin-deficient C57BL/6 H-2 b mice failed to develop the significant functional deficits associated with demyelination in susceptible strains of mice.
TextSentencer_T137	26854-27193	Sentence	denotes	Perforin-deficient mice did not acquire hind-limb paralysis, did not show a decrease in spontaneous activity, and did not develop signficant changes in hind-limb stride, suggesting that neurological deficits associated with demyelination are dependent on perforin, and, by extension, on functional cytotoxic T-cells (Murray et al., 1998) .
TextSentencer_T137	26854-27193	Sentence	denotes	Perforin-deficient mice did not acquire hind-limb paralysis, did not show a decrease in spontaneous activity, and did not develop signficant changes in hind-limb stride, suggesting that neurological deficits associated with demyelination are dependent on perforin, and, by extension, on functional cytotoxic T-cells (Murray et al., 1998) .
T64719	26854-27193	Sentence	denotes	Perforin-deficient mice did not acquire hind-limb paralysis, did not show a decrease in spontaneous activity, and did not develop signficant changes in hind-limb stride, suggesting that neurological deficits associated with demyelination are dependent on perforin, and, by extension, on functional cytotoxic T-cells (Murray et al., 1998) .
TextSentencer_T138	27194-27493	Sentence	denotes	Furthermore, we have recently observed that the number of large axons in the spinal cord does not differ between infected wild-type C57BL/6 mice and perforin-deficient C57BL/6 mice, strengthening the argument that neurological function in these animals is preserved as a result of axon preservation.
TextSentencer_T138	27194-27493	Sentence	denotes	Furthermore, we have recently observed that the number of large axons in the spinal cord does not differ between infected wild-type C57BL/6 mice and perforin-deficient C57BL/6 mice, strengthening the argument that neurological function in these animals is preserved as a result of axon preservation.
T67656	27194-27493	Sentence	denotes	Furthermore, we have recently observed that the number of large axons in the spinal cord does not differ between infected wild-type C57BL/6 mice and perforin-deficient C57BL/6 mice, strengthening the argument that neurological function in these animals is preserved as a result of axon preservation.
TextSentencer_T139	27494-27598	Sentence	denotes	Likewise, perforin contributes to neurological deficit and axon dropout in susceptible B10.Q H-2 q mice.
TextSentencer_T139	27494-27598	Sentence	denotes	Likewise, perforin contributes to neurological deficit and axon dropout in susceptible B10.Q H-2 q mice.
T45404	27494-27598	Sentence	denotes	Likewise, perforin contributes to neurological deficit and axon dropout in susceptible B10.Q H-2 q mice.
TextSentencer_T140	27599-27988	Sentence	denotes	In these experiments, we found that wild-type B10.Q mice developed significant demyelination, a dramatic decrease in the frequency of large axons in the spinal cord, and significant neurological dysfunction, as measured by rotarod performance, but that large axon frequency and neurological function were relatively preserved in perforin-deficient B10.Q mice, despite marked demyelination.
TextSentencer_T140	27599-27988	Sentence	denotes	In these experiments, we found that wild-type B10.Q mice developed significant demyelination, a dramatic decrease in the frequency of large axons in the spinal cord, and significant neurological dysfunction, as measured by rotarod performance, but that large axon frequency and neurological function were relatively preserved in perforin-deficient B10.Q mice, despite marked demyelination.
T54287	27599-27988	Sentence	denotes	In these experiments, we found that wild-type B10.Q mice developed significant demyelination, a dramatic decrease in the frequency of large axons in the spinal cord, and significant neurological dysfunction, as measured by rotarod performance, but that large axon frequency and neurological function were relatively preserved in perforin-deficient B10.Q mice, despite marked demyelination.
TextSentencer_T141	27989-28179	Sentence	denotes	Fas is a member of the tumor necrosis factor (TNF) receptor superfamily that is expressed on target cells as a receptor for the Fas ligand (FasL) present on the surface of cytotoxic T-cells.
TextSentencer_T141	27989-28179	Sentence	denotes	Fas is a member of the tumor necrosis factor (TNF) receptor superfamily that is expressed on target cells as a receptor for the Fas ligand (FasL) present on the surface of cytotoxic T-cells.
T2913	27989-28179	Sentence	denotes	Fas is a member of the tumor necrosis factor (TNF) receptor superfamily that is expressed on target cells as a receptor for the Fas ligand (FasL) present on the surface of cytotoxic T-cells.
TextSentencer_T142	28180-28285	Sentence	denotes	The intracellular domain of Fas contains a death domain (DD) region necessary for induction of apoptosis.
TextSentencer_T142	28180-28285	Sentence	denotes	The intracellular domain of Fas contains a death domain (DD) region necessary for induction of apoptosis.
T26885	28180-28285	Sentence	denotes	The intracellular domain of Fas contains a death domain (DD) region necessary for induction of apoptosis.
TextSentencer_T143	28286-28422	Sentence	denotes	Upon binding of FasL to Fas on a target cell, the DD is induced to recruit an adaptor protein called Fas-associated death domain (FADD).
TextSentencer_T143	28286-28422	Sentence	denotes	Upon binding of FasL to Fas on a target cell, the DD is induced to recruit an adaptor protein called Fas-associated death domain (FADD).
T54346	28286-28422	Sentence	denotes	Upon binding of FasL to Fas on a target cell, the DD is induced to recruit an adaptor protein called Fas-associated death domain (FADD).
TextSentencer_T144	28423-28581	Sentence	denotes	FADD bears both a death domain, via which it binds to Fas, and a death effector domain, forin-deficient C57BL/6 H-2 b mice results in extensive demyelination.
TextSentencer_T144	28423-28581	Sentence	denotes	FADD bears both a death domain, via which it binds to Fas, and a death effector domain, forin-deficient C57BL/6 H-2 b mice results in extensive demyelination.
T59580	28423-28581	Sentence	denotes	FADD bears both a death domain, via which it binds to Fas, and a death effector domain, forin-deficient C57BL/6 H-2 b mice results in extensive demyelination.
TextSentencer_T145	28582-28693	Sentence	denotes	Despite such widespread demyelination, however, these animals do not exhibit significant functional impairment.
TextSentencer_T145	28582-28693	Sentence	denotes	Despite such widespread demyelination, however, these animals do not exhibit significant functional impairment.
T21585	28582-28693	Sentence	denotes	Despite such widespread demyelination, however, these animals do not exhibit significant functional impairment.
TextSentencer_T146	28694-28841	Sentence	denotes	This finding suggests that perforin-mediated killing by CD8 + T-cells is required for axon loss and functional deficits, but not for demyelination.
TextSentencer_T146	28694-28841	Sentence	denotes	This finding suggests that perforin-mediated killing by CD8 + T-cells is required for axon loss and functional deficits, but not for demyelination.
T89166	28694-28841	Sentence	denotes	This finding suggests that perforin-mediated killing by CD8 + T-cells is required for axon loss and functional deficits, but not for demyelination.
TextSentencer_T147	28842-28889	Sentence	denotes	through which it associates with pro-caspase-8.
TextSentencer_T147	28842-28889	Sentence	denotes	through which it associates with pro-caspase-8.
T82611	28842-28889	Sentence	denotes	through which it associates with pro-caspase-8.
TextSentencer_T148	28890-29004	Sentence	denotes	Thus, a death-inducing complex, called the death-inducing signaling complex (DISC), is formed at the Fas receptor.
TextSentencer_T148	28890-29004	Sentence	denotes	Thus, a death-inducing complex, called the death-inducing signaling complex (DISC), is formed at the Fas receptor.
T6232	28890-29004	Sentence	denotes	Thus, a death-inducing complex, called the death-inducing signaling complex (DISC), is formed at the Fas receptor.
TextSentencer_T149	29005-29205	Sentence	denotes	Pro-caspase-8 recruitment to the DISC results in autocleavage and activation of caspase-8, which then goes on to activate effector caspases such as caspase-3, resulting in apoptosis (Thorburn, 2004) .
TextSentencer_T149	29005-29205	Sentence	denotes	Pro-caspase-8 recruitment to the DISC results in autocleavage and activation of caspase-8, which then goes on to activate effector caspases such as caspase-3, resulting in apoptosis (Thorburn, 2004) .
T45811	29005-29205	Sentence	denotes	Pro-caspase-8 recruitment to the DISC results in autocleavage and activation of caspase-8, which then goes on to activate effector caspases such as caspase-3, resulting in apoptosis (Thorburn, 2004) .
TextSentencer_T150	29206-29364	Sentence	denotes	The Fas/FasL pathway is active in essentially all cytotoxic cells, but is apparently most important for CD4 + cells of the T H 1 phenotype (Ju et al., 1994) .
TextSentencer_T150	29206-29364	Sentence	denotes	The Fas/FasL pathway is active in essentially all cytotoxic cells, but is apparently most important for CD4 + cells of the T H 1 phenotype (Ju et al., 1994) .
T26886	29206-29364	Sentence	denotes	The Fas/FasL pathway is active in essentially all cytotoxic cells, but is apparently most important for CD4 + cells of the T H 1 phenotype (Ju et al., 1994) .
TextSentencer_T151	29365-29706	Sentence	denotes	Although cultured CD4 + and CD8 + T-cells can engage both the perforin and the Fas/FasL pathways, in vivo experiments suggest that MHC class I-dependent killing is dominated by the perforin pathway, whereas MHC class II-dependent elimination is almost entirely mediated by Fas/FasL interactions (Graubert et al., 1997; Schulz et al., 1995) .
TextSentencer_T151	29365-29706	Sentence	denotes	Although cultured CD4 + and CD8 + T-cells can engage both the perforin and the Fas/FasL pathways, in vivo experiments suggest that MHC class I-dependent killing is dominated by the perforin pathway, whereas MHC class II-dependent elimination is almost entirely mediated by Fas/FasL interactions (Graubert et al., 1997; Schulz et al., 1995) .
T61652	29365-29706	Sentence	denotes	Although cultured CD4 + and CD8 + T-cells can engage both the perforin and the Fas/FasL pathways, in vivo experiments suggest that MHC class I-dependent killing is dominated by the perforin pathway, whereas MHC class II-dependent elimination is almost entirely mediated by Fas/FasL interactions (Graubert et al., 1997; Schulz et al., 1995) .
TextSentencer_T152	29707-29918	Sentence	denotes	Thus, a comparison between the relative role of perforin and Fas/FasL in demyelination and neurological deficit associated with Theiler's virus infection is a reasonable approach to address the CD8 + hypothesis.
TextSentencer_T152	29707-29918	Sentence	denotes	Thus, a comparison between the relative role of perforin and Fas/FasL in demyelination and neurological deficit associated with Theiler's virus infection is a reasonable approach to address the CD8 + hypothesis.
T49512	29707-29918	Sentence	denotes	Thus, a comparison between the relative role of perforin and Fas/FasL in demyelination and neurological deficit associated with Theiler's virus infection is a reasonable approach to address the CD8 + hypothesis.
TextSentencer_T153	29919-30115	Sentence	denotes	Indeed, in support of the CD8 + hypothesis, and in contrast to the findings for perforin, the Fas/FasL system appears to play a minimal role in determining resistance to Theiler's virus infection.
TextSentencer_T153	29919-30115	Sentence	denotes	Indeed, in support of the CD8 + hypothesis, and in contrast to the findings for perforin, the Fas/FasL system appears to play a minimal role in determining resistance to Theiler's virus infection.
T86408	29919-30115	Sentence	denotes	Indeed, in support of the CD8 + hypothesis, and in contrast to the findings for perforin, the Fas/FasL system appears to play a minimal role in determining resistance to Theiler's virus infection.
TextSentencer_T154	30116-30317	Sentence	denotes	Neither the lpr mutant, deficient in Fas, nor the gld mutant, defective in FasL binding, developed demyelination or neurological deficit in response to Theiler's virus infection (Murray et al., 1998) .
TextSentencer_T154	30116-30317	Sentence	denotes	Neither the lpr mutant, deficient in Fas, nor the gld mutant, defective in FasL binding, developed demyelination or neurological deficit in response to Theiler's virus infection (Murray et al., 1998) .
T35260	30116-30317	Sentence	denotes	Neither the lpr mutant, deficient in Fas, nor the gld mutant, defective in FasL binding, developed demyelination or neurological deficit in response to Theiler's virus infection (Murray et al., 1998) .
TextSentencer_T155	30318-30518	Sentence	denotes	Moreover, Rensing-Ehl and colleagues have reported that neurons express only low levels of Fas, even after cytokine stimulation, and are resistant to FasL-mediated killing (Rensing-Ehl et al., 1996) .
TextSentencer_T155	30318-30518	Sentence	denotes	Moreover, Rensing-Ehl and colleagues have reported that neurons express only low levels of Fas, even after cytokine stimulation, and are resistant to FasL-mediated killing (Rensing-Ehl et al., 1996) .
T23763	30318-30518	Sentence	denotes	Moreover, Rensing-Ehl and colleagues have reported that neurons express only low levels of Fas, even after cytokine stimulation, and are resistant to FasL-mediated killing (Rensing-Ehl et al., 1996) .
TextSentencer_T156	30519-30769	Sentence	denotes	In contrast, other investigators have suggested that in certain situations, MHC class I-restricted killing of neurons by virus-specific CD8 + T-lymphocytes is mediated through the Fas/FasL pathway, but not the perforin pathway (Medana et al., 2000) .
TextSentencer_T156	30519-30769	Sentence	denotes	In contrast, other investigators have suggested that in certain situations, MHC class I-restricted killing of neurons by virus-specific CD8 + T-lymphocytes is mediated through the Fas/FasL pathway, but not the perforin pathway (Medana et al., 2000) .
T66599	30519-30769	Sentence	denotes	In contrast, other investigators have suggested that in certain situations, MHC class I-restricted killing of neurons by virus-specific CD8 + T-lymphocytes is mediated through the Fas/FasL pathway, but not the perforin pathway (Medana et al., 2000) .
TextSentencer_T157	30770-30861	Sentence	denotes	Likewise, the role of Fas/FasL in human MS is less clear than in the Theiler's virus model.
TextSentencer_T157	30770-30861	Sentence	denotes	Likewise, the role of Fas/FasL in human MS is less clear than in the Theiler's virus model.
T70462	30770-30861	Sentence	denotes	Likewise, the role of Fas/FasL in human MS is less clear than in the Theiler's virus model.
TextSentencer_T158	30862-31112	Sentence	denotes	Although one report indicates that Fas is irrelevant to oligodendrocyte loss in MS lesions (Bonetti and Raine, 1997) , another provides evidence, at least in vitro, that Fas-mediated signaling contributes to a nonapoptotic injury of oligodendrocytes.
TextSentencer_T158	30862-31112	Sentence	denotes	Although one report indicates that Fas is irrelevant to oligodendrocyte loss in MS lesions (Bonetti and Raine, 1997) , another provides evidence, at least in vitro, that Fas-mediated signaling contributes to a nonapoptotic injury of oligodendrocytes.
T49516	30862-31112	Sentence	denotes	Although one report indicates that Fas is irrelevant to oligodendrocyte loss in MS lesions (Bonetti and Raine, 1997) , another provides evidence, at least in vitro, that Fas-mediated signaling contributes to a nonapoptotic injury of oligodendrocytes.
TextSentencer_T159	31113-31411	Sentence	denotes	Of particular interest, FasL has been shown to protect neurons against perforin-mediated cytotoxicity (Medana et al., 2001) , raising the possibility that both these mechanisms of neuronal killing may interact with one another in as yet uncharacterized, and potentially extremely complicated, ways.
TextSentencer_T159	31113-31411	Sentence	denotes	Of particular interest, FasL has been shown to protect neurons against perforin-mediated cytotoxicity (Medana et al., 2001) , raising the possibility that both these mechanisms of neuronal killing may interact with one another in as yet uncharacterized, and potentially extremely complicated, ways.
T42859	31113-31411	Sentence	denotes	Of particular interest, FasL has been shown to protect neurons against perforin-mediated cytotoxicity (Medana et al., 2001) , raising the possibility that both these mechanisms of neuronal killing may interact with one another in as yet uncharacterized, and potentially extremely complicated, ways.
TextSentencer_T160	31412-31518	Sentence	denotes	Interferon γ (IFNγ) is another important molecule involved in the effector functions of cytotoxic T-cells.
TextSentencer_T160	31412-31518	Sentence	denotes	Interferon γ (IFNγ) is another important molecule involved in the effector functions of cytotoxic T-cells.
T87063	31412-31518	Sentence	denotes	Interferon γ (IFNγ) is another important molecule involved in the effector functions of cytotoxic T-cells.
TextSentencer_T161	31519-31644	Sentence	denotes	IFNγ is a T H 1 antiviral and immunomodulatory cytokine that is critically involved in host resistance to multiple pathogens.
TextSentencer_T161	31519-31644	Sentence	denotes	IFNγ is a T H 1 antiviral and immunomodulatory cytokine that is critically involved in host resistance to multiple pathogens.
T14609	31519-31644	Sentence	denotes	IFNγ is a T H 1 antiviral and immunomodulatory cytokine that is critically involved in host resistance to multiple pathogens.
TextSentencer_T162	31645-31903	Sentence	denotes	IFNγ induces a wide range of effects on CNS cells, including macrophage activation, enhancement of leukocyte adhe-sion, release of TNF-α and other cytokines, and upregulation of MHC expression on microglia and macrophages (Munoz-Fernandez and Fresno, 1998) .
TextSentencer_T162	31645-31903	Sentence	denotes	IFNγ induces a wide range of effects on CNS cells, including macrophage activation, enhancement of leukocyte adhe-sion, release of TNF-α and other cytokines, and upregulation of MHC expression on microglia and macrophages (Munoz-Fernandez and Fresno, 1998) .
T15337	31645-31903	Sentence	denotes	IFNγ induces a wide range of effects on CNS cells, including macrophage activation, enhancement of leukocyte adhe-sion, release of TNF-α and other cytokines, and upregulation of MHC expression on microglia and macrophages (Munoz-Fernandez and Fresno, 1998) .
TextSentencer_T163	31904-32019	Sentence	denotes	We evaluated the role of IFNγ in protecting neurons from virus-induced injury after infection with Theiler's virus.
TextSentencer_T163	31904-32019	Sentence	denotes	We evaluated the role of IFNγ in protecting neurons from virus-induced injury after infection with Theiler's virus.
T48815	31904-32019	Sentence	denotes	We evaluated the role of IFNγ in protecting neurons from virus-induced injury after infection with Theiler's virus.
TextSentencer_T164	32020-32252	Sentence	denotes	During viral infections, IFNγ is produced by natural killer (NK) cells, CD4 + , and CD8 + T-cells; however, the proportion of lymphocyte subsets responding to virus infection influences the contributions to IFNγ-mediated protection.
TextSentencer_T164	32020-32252	Sentence	denotes	During viral infections, IFNγ is produced by natural killer (NK) cells, CD4 + , and CD8 + T-cells; however, the proportion of lymphocyte subsets responding to virus infection influences the contributions to IFNγ-mediated protection.
T30646	32020-32252	Sentence	denotes	During viral infections, IFNγ is produced by natural killer (NK) cells, CD4 + , and CD8 + T-cells; however, the proportion of lymphocyte subsets responding to virus infection influences the contributions to IFNγ-mediated protection.
TextSentencer_T165	32253-32442	Sentence	denotes	To determine the lymphocyte subsets that produce IFNγ to maintain resistance, we used adoptive transfer strategies to generate mice with lymphocyte-specific deficiencies in IFNγ production.
TextSentencer_T165	32253-32442	Sentence	denotes	To determine the lymphocyte subsets that produce IFNγ to maintain resistance, we used adoptive transfer strategies to generate mice with lymphocyte-specific deficiencies in IFNγ production.
T81439	32253-32442	Sentence	denotes	To determine the lymphocyte subsets that produce IFNγ to maintain resistance, we used adoptive transfer strategies to generate mice with lymphocyte-specific deficiencies in IFNγ production.
TextSentencer_T166	32443-32692	Sentence	denotes	We demonstrated that IFNγ production by both CD4 + and CD8 + T-cell subsets is critical for resistance to Theiler's virus-induced demyelination and neurological disease, and that CD4 + T-cells make a greater contribution to IFNγ-mediated protection.
TextSentencer_T166	32443-32692	Sentence	denotes	We demonstrated that IFNγ production by both CD4 + and CD8 + T-cell subsets is critical for resistance to Theiler's virus-induced demyelination and neurological disease, and that CD4 + T-cells make a greater contribution to IFNγ-mediated protection.
T33107	32443-32692	Sentence	denotes	We demonstrated that IFNγ production by both CD4 + and CD8 + T-cell subsets is critical for resistance to Theiler's virus-induced demyelination and neurological disease, and that CD4 + T-cells make a greater contribution to IFNγ-mediated protection.
TextSentencer_T167	32693-32922	Sentence	denotes	To determine the cellular targets of IFNγmediated responses, we used adoptive transfer studies and bone marrow chimerism to generate mice in which either hematopoietic or somatic cells lacked the ability to express IFNγ receptor.
TextSentencer_T167	32693-32922	Sentence	denotes	To determine the cellular targets of IFNγmediated responses, we used adoptive transfer studies and bone marrow chimerism to generate mice in which either hematopoietic or somatic cells lacked the ability to express IFNγ receptor.

TextSentencer_T1

0-32

Sentence

denotes

Remyelination as Neuroprotection

TextSentencer_T1

0-32

Sentence

denotes

Remyelination as Neuroprotection

T69746

0-32

Sentence

denotes

Remyelination as Neuroprotection

TextSentencer_T2

34-42

Sentence

denotes

Abstract

TextSentencer_T2

34-42

Sentence

denotes

Abstract

T51567

34-42

Sentence

denotes

Abstract

TextSentencer_T3

45-179

Sentence

denotes

A major area of investigation in the neurosciences is directed at understanding the factors that participate in neurological deficits.

TextSentencer_T3

45-179

Sentence

denotes

A major area of investigation in the neurosciences is directed at understanding the factors that participate in neurological deficits.

T99813

45-179

Sentence

denotes

A major area of investigation in the neurosciences is directed at understanding the factors that participate in neurological deficits.

TextSentencer_T4

180-327

Sentence

denotes

In demyelinating diseases of the central nervous system (CNS), it has been assumed that demyelination by itself contributes to functional deficits.

TextSentencer_T4

180-327

Sentence

denotes

In demyelinating diseases of the central nervous system (CNS), it has been assumed that demyelination by itself contributes to functional deficits.

T11175

180-327

Sentence

denotes

In demyelinating diseases of the central nervous system (CNS), it has been assumed that demyelination by itself contributes to functional deficits.

TextSentencer_T5

328-484

Sentence

denotes

Previous physiological studies demonstrated that demyelination in the CNS can result in conduction slowing and conduction block (McDonald and Sears, 1969) .

TextSentencer_T5

328-484

Sentence

denotes

Previous physiological studies demonstrated that demyelination in the CNS can result in conduction slowing and conduction block (McDonald and Sears, 1969) .

T24544

328-484

Sentence

denotes

Previous physiological studies demonstrated that demyelination in the CNS can result in conduction slowing and conduction block (McDonald and Sears, 1969) .

TextSentencer_T6

485-623

Sentence

denotes

Such observations appeared sufficient to explain the majority of deficits in demyelinating human diseases such as multiple sclerosis (MS).

TextSentencer_T6

485-623

Sentence

denotes

Such observations appeared sufficient to explain the majority of deficits in demyelinating human diseases such as multiple sclerosis (MS).

T35322

485-623

Sentence

denotes

Such observations appeared sufficient to explain the majority of deficits in demyelinating human diseases such as multiple sclerosis (MS).

TextSentencer_T7

624-713

Sentence

denotes

However, clinical and basic science observations have begun to challenge this hypothesis.

TextSentencer_T7

624-713

Sentence

denotes

However, clinical and basic science observations have begun to challenge this hypothesis.

T7964

624-713

Sentence

denotes

However, clinical and basic science observations have begun to challenge this hypothesis.

TextSentencer_T8

714-924

Sentence

denotes

MS is one of the most frequent neurological diseases of early adulthood, affecting as many as 400,000 patients in the United States, 85% of whom are between the ages of 20 and 50 years old (Mayr et al., 2003) .

TextSentencer_T8

714-924

Sentence

denotes

MS is one of the most frequent neurological diseases of early adulthood, affecting as many as 400,000 patients in the United States, 85% of whom are between the ages of 20 and 50 years old (Mayr et al., 2003) .

T13283

714-924

Sentence

denotes

MS is one of the most frequent neurological diseases of early adulthood, affecting as many as 400,000 patients in the United States, 85% of whom are between the ages of 20 and 50 years old (Mayr et al., 2003) .

TextSentencer_T9

925-1189

Sentence

denotes

Clinically, this disease is most often marked by a relapsing and remitting pattern of neurological dysfunction, frequently leading over time to a secondary progressive disease pattern marked by accumulative loss of neurological function (Noseworthy et al., 2000) .

TextSentencer_T9

925-1189

Sentence

denotes

Clinically, this disease is most often marked by a relapsing and remitting pattern of neurological dysfunction, frequently leading over time to a secondary progressive disease pattern marked by accumulative loss of neurological function (Noseworthy et al., 2000) .

T60915

925-1189

Sentence

denotes

Clinically, this disease is most often marked by a relapsing and remitting pattern of neurological dysfunction, frequently leading over time to a secondary progressive disease pattern marked by accumulative loss of neurological function (Noseworthy et al., 2000) .

TextSentencer_T10

1190-1463

Sentence

denotes

The relapsing-remitting phase is characterized by clinical symptoms such as loss of visual acuity, weakness, ataxia, fatigue, and clumsiness that develop over a period of several days, stabilize, and then resolve over the course of several weeks (Noseworthy et al., 2000) .

TextSentencer_T10

1190-1463

Sentence

denotes

The relapsing-remitting phase is characterized by clinical symptoms such as loss of visual acuity, weakness, ataxia, fatigue, and clumsiness that develop over a period of several days, stabilize, and then resolve over the course of several weeks (Noseworthy et al., 2000) .

T18666

1190-1463

Sentence

denotes

The relapsing-remitting phase is characterized by clinical symptoms such as loss of visual acuity, weakness, ataxia, fatigue, and clumsiness that develop over a period of several days, stabilize, and then resolve over the course of several weeks (Noseworthy et al., 2000) .

TextSentencer_T11

1464-1563

Sentence

denotes

At least early in the disease, corticosteroid treatment accelerates recovery from clinical deficit.

TextSentencer_T11

1464-1563

Sentence

denotes

At least early in the disease, corticosteroid treatment accelerates recovery from clinical deficit.

T14006

1464-1563

Sentence

denotes

At least early in the disease, corticosteroid treatment accelerates recovery from clinical deficit.

TextSentencer_T12

1564-1782

Sentence

denotes

Frequently, some dysfunction may persist after relapse, and an accumulation of such persistant clinical deficit ultimately results in a progressive impairment termed secondary progressive MS (Noseworthy et al., 2000) .

TextSentencer_T12

1564-1782

Sentence

denotes

Frequently, some dysfunction may persist after relapse, and an accumulation of such persistant clinical deficit ultimately results in a progressive impairment termed secondary progressive MS (Noseworthy et al., 2000) .

T33108

1564-1782

Sentence

denotes

Frequently, some dysfunction may persist after relapse, and an accumulation of such persistant clinical deficit ultimately results in a progressive impairment termed secondary progressive MS (Noseworthy et al., 2000) .

TextSentencer_T13

1783-2040

Sentence

denotes

Although clinically characterized by pathological and functional hallmarks such as focally demyelinated lesions and gadolinium enhancement, as detected by magnetic resonance imaging (MRI), the cellular and molecular locus of MS is distinctly heterogeneous .

TextSentencer_T13

1783-2040

Sentence

denotes

Although clinically characterized by pathological and functional hallmarks such as focally demyelinated lesions and gadolinium enhancement, as detected by magnetic resonance imaging (MRI), the cellular and molecular locus of MS is distinctly heterogeneous .

T6992

1783-2040

Sentence

denotes

Although clinically characterized by pathological and functional hallmarks such as focally demyelinated lesions and gadolinium enhancement, as detected by magnetic resonance imaging (MRI), the cellular and molecular locus of MS is distinctly heterogeneous .

TextSentencer_T14

2041-2224

Sentence

denotes

Although all lesions contain an inflammatory infiltration of T-cells and macrophages, further analysis suggests that four distinct patterns of pathology are present in active lesions.

TextSentencer_T14

2041-2224

Sentence

denotes

Although all lesions contain an inflammatory infiltration of T-cells and macrophages, further analysis suggests that four distinct patterns of pathology are present in active lesions.

T20474

2041-2224

Sentence

denotes

Although all lesions contain an inflammatory infiltration of T-cells and macrophages, further analysis suggests that four distinct patterns of pathology are present in active lesions.

TextSentencer_T15

2225-2532

Sentence

denotes

The first two patterns are marked by well-delineated perivascular demyelination and simultaneous loss of immunoreactivity for all myelin proteins within the lesion, but relative sparing of oligodendrocytes and active repopulation of demyelinated lesions with oligodendrocytes during remyelination (Fig. 1) .

TextSentencer_T15

2225-2532

Sentence

denotes

The first two patterns are marked by well-delineated perivascular demyelination and simultaneous loss of immunoreactivity for all myelin proteins within the lesion, but relative sparing of oligodendrocytes and active repopulation of demyelinated lesions with oligodendrocytes during remyelination (Fig. 1) .

T79878

2225-2532

Sentence

denotes

The first two patterns are marked by well-delineated perivascular demyelination and simultaneous loss of immunoreactivity for all myelin proteins within the lesion, but relative sparing of oligodendrocytes and active repopulation of demyelinated lesions with oligodendrocytes during remyelination (Fig. 1) .

TextSentencer_T16

2533-2730

Sentence

denotes

This is consistent with previous reports show- 390 Remyelination as Neuroprotection ing abortive attempts at remyelination in MS lesions (Prineas and Connell, 1979; Prineas et al., 1989) (Fig. 2) .

TextSentencer_T16

2533-2730

Sentence

denotes

This is consistent with previous reports show- 390 Remyelination as Neuroprotection ing abortive attempts at remyelination in MS lesions (Prineas and Connell, 1979; Prineas et al., 1989) (Fig. 2) .

T49204

2533-2730

Sentence

denotes

This is consistent with previous reports show- 390 Remyelination as Neuroprotection ing abortive attempts at remyelination in MS lesions (Prineas and Connell, 1979; Prineas et al., 1989) (Fig. 2) .

TextSentencer_T17

2731-2869

Sentence

denotes

The second pattern is unique in that actively degenerating myelin is associated with pronounced immunoglobulin and complement reactivity .

TextSentencer_T17

2731-2869

Sentence

denotes

The second pattern is unique in that actively degenerating myelin is associated with pronounced immunoglobulin and complement reactivity .

T70532

2731-2869

Sentence

denotes

The second pattern is unique in that actively degenerating myelin is associated with pronounced immunoglobulin and complement reactivity .

TextSentencer_T18

2870-3000

Sentence

denotes

The third and fourth patterns do not exhibit perivascular localization, and the borders of active lesions are only poorly defined.

TextSentencer_T18

2870-3000

Sentence

denotes

The third and fourth patterns do not exhibit perivascular localization, and the borders of active lesions are only poorly defined.

T94439

2870-3000

Sentence

denotes

The third and fourth patterns do not exhibit perivascular localization, and the borders of active lesions are only poorly defined.

TextSentencer_T19

3001-3077

Sentence

denotes

Oligodendrocytes are not spared and repopulation of lesions is not observed.

TextSentencer_T19

3001-3077

Sentence

denotes

Oligodendrocytes are not spared and repopulation of lesions is not observed.

T68175

3001-3077

Sentence

denotes

Oligodendrocytes are not spared and repopulation of lesions is not observed.

TextSentencer_T20

3078-3225

Sentence

denotes

Finally, the third pattern is uniquely associated with greater loss of myelin-associated glycoprotein immunoreactivity than other myelin proteins .

TextSentencer_T20

3078-3225

Sentence

denotes

Finally, the third pattern is uniquely associated with greater loss of myelin-associated glycoprotein immunoreactivity than other myelin proteins .

T88632

3078-3225

Sentence

denotes

Finally, the third pattern is uniquely associated with greater loss of myelin-associated glycoprotein immunoreactivity than other myelin proteins .

TextSentencer_T21

3226-3362

Sentence

denotes

This pattern is consistent with the concept of "dying-back oligodendrogliopathy," in which the primary injury is to the oligodendrocyte.

TextSentencer_T21

3226-3362

Sentence

denotes

This pattern is consistent with the concept of "dying-back oligodendrogliopathy," in which the primary injury is to the oligodendrocyte.

T92740

3226-3362

Sentence

denotes

This pattern is consistent with the concept of "dying-back oligodendrogliopathy," in which the primary injury is to the oligodendrocyte.

TextSentencer_T22

3363-3569

Sentence

denotes

The earliest morphological manifestation of this pattern is degeneration of the inner myelin sheath and oligodendroglial loops, the most distal extensions of the oligodendrocyte (Rodriguez, 2003) (Fig. 3) .

TextSentencer_T22

3363-3569

Sentence

denotes

The earliest morphological manifestation of this pattern is degeneration of the inner myelin sheath and oligodendroglial loops, the most distal extensions of the oligodendrocyte (Rodriguez, 2003) (Fig. 3) .

T51407

3363-3569

Sentence

denotes

The earliest morphological manifestation of this pattern is degeneration of the inner myelin sheath and oligodendroglial loops, the most distal extensions of the oligodendrocyte (Rodriguez, 2003) (Fig. 3) .

TextSentencer_T23

3570-3650

Sentence

denotes

Of importance, heterogeneity is found among patients but not within individuals.

TextSentencer_T23

3570-3650

Sentence

denotes

Of importance, heterogeneity is found among patients but not within individuals.

T13220

3570-3650

Sentence

denotes

Of importance, heterogeneity is found among patients but not within individuals.

TextSentencer_T24

3651-3815

Sentence

denotes

All lesions of any given patient are of the same phenotype, suggesting a single pathogenic mechanism within a patient but multiple mechanisms across the population.

TextSentencer_T24

3651-3815

Sentence

denotes

All lesions of any given patient are of the same phenotype, suggesting a single pathogenic mechanism within a patient but multiple mechanisms across the population.

T95611

3651-3815

Sentence

denotes

All lesions of any given patient are of the same phenotype, suggesting a single pathogenic mechanism within a patient but multiple mechanisms across the population.

TextSentencer_T25

3816-3904

Sentence

denotes

The heterogeneity observed in patients with MS is also reflected in animal models of MS.

TextSentencer_T25

3816-3904

Sentence

denotes

The heterogeneity observed in patients with MS is also reflected in animal models of MS.

T50257

3816-3904

Sentence

denotes

The heterogeneity observed in patients with MS is also reflected in animal models of MS.

TextSentencer_T26

3905-4058

Sentence

denotes

The two best studied models of human MS are immune-mediated encephalo-myelitis induced by immunization with CNS antigens and viral-induced demyelination.

TextSentencer_T26

3905-4058

Sentence

denotes

The two best studied models of human MS are immune-mediated encephalo-myelitis induced by immunization with CNS antigens and viral-induced demyelination.

T51372

3905-4058

Sentence

denotes

The two best studied models of human MS are immune-mediated encephalo-myelitis induced by immunization with CNS antigens and viral-induced demyelination.

TextSentencer_T27

4059-4240

Sentence

denotes

Lesions commonly found in patients with the first and second pattern of MS pathology are similar to those observed in T-cell-mediated and antibody-mediated autoimmune demyelination.

TextSentencer_T27

4059-4240

Sentence

denotes

Lesions commonly found in patients with the first and second pattern of MS pathology are similar to those observed in T-cell-mediated and antibody-mediated autoimmune demyelination.

T5626

4059-4240

Sentence

denotes

Lesions commonly found in patients with the first and second pattern of MS pathology are similar to those observed in T-cell-mediated and antibody-mediated autoimmune demyelination.

TextSentencer_T28

4241-4448

Sentence

denotes

Likewise, lesions observed in the third and fourth patterns of human MS are typical of the oligodendrogliopathy and demyelination induced by viral infection Paz Soldan and Rodriguez, 2002; Rodriguez, 1985) .

TextSentencer_T28

4241-4448

Sentence

denotes

Likewise, lesions observed in the third and fourth patterns of human MS are typical of the oligodendrogliopathy and demyelination induced by viral infection Paz Soldan and Rodriguez, 2002; Rodriguez, 1985) .

T16426

4241-4448

Sentence

denotes

Likewise, lesions observed in the third and fourth patterns of human MS are typical of the oligodendrogliopathy and demyelination induced by viral infection Paz Soldan and Rodriguez, 2002; Rodriguez, 1985) .

TextSentencer_T29

4449-4601

Sentence

denotes

The functional correlate of any of the patterns described previously is generally considered to be loss of axon conduction resulting from demyelination.

TextSentencer_T29

4449-4601

Sentence

denotes

The functional correlate of any of the patterns described previously is generally considered to be loss of axon conduction resulting from demyelination.

T47363

4449-4601

Sentence

denotes

The functional correlate of any of the patterns described previously is generally considered to be loss of axon conduction resulting from demyelination.

TextSentencer_T30

4602-4775

Sentence

denotes

During the relapsing-remitting phase of MS, the regression of symptoms is likely due to resolution of inflammation and remyelination, resulting in a return of axon function.

TextSentencer_T30

4602-4775

Sentence

denotes

During the relapsing-remitting phase of MS, the regression of symptoms is likely due to resolution of inflammation and remyelination, resulting in a return of axon function.

T57350

4602-4775

Sentence

denotes

During the relapsing-remitting phase of MS, the regression of symptoms is likely due to resolution of inflammation and remyelination, resulting in a return of axon function.

TextSentencer_T31

4776-4952

Sentence

denotes

However, as the disease progresses and as each round of repair accumulates demyelination that is not resolved, axonal function deteriorates (Noseworthy et al., 2000) (Fig. 4 ).

TextSentencer_T31

4776-4952

Sentence

denotes

However, as the disease progresses and as each round of repair accumulates demyelination that is not resolved, axonal function deteriorates (Noseworthy et al., 2000) (Fig. 4 ).

T16969

4776-4952

Sentence

denotes

However, as the disease progresses and as each round of repair accumulates demyelination that is not resolved, axonal function deteriorates (Noseworthy et al., 2000) (Fig. 4 ).

TextSentencer_T32

4953-5139

Sentence

denotes

This is marked by redistribution of sodium channels along demyelinated axon segments, and eventually by loss of the axon altogether (Rivera-Quinones et al., 1998) (see Chapters 7 and 8).

TextSentencer_T32

4953-5139

Sentence

denotes

This is marked by redistribution of sodium channels along demyelinated axon segments, and eventually by loss of the axon altogether (Rivera-Quinones et al., 1998) (see Chapters 7 and 8).

T10364

4953-5139

Sentence

denotes

This is marked by redistribution of sodium channels along demyelinated axon segments, and eventually by loss of the axon altogether (Rivera-Quinones et al., 1998) (see Chapters 7 and 8).

TextSentencer_T33

5140-5338

Sentence

denotes

Because axons are the absolute locus of neuronal function and transmission, it is likely that understanding and reversing axon failure and loss will be required for any rational therapeutic program.

TextSentencer_T33

5140-5338

Sentence

denotes

Because axons are the absolute locus of neuronal function and transmission, it is likely that understanding and reversing axon failure and loss will be required for any rational therapeutic program.

T15260

5140-5338

Sentence

denotes

Because axons are the absolute locus of neuronal function and transmission, it is likely that understanding and reversing axon failure and loss will be required for any rational therapeutic program.

TextSentencer_T34

5339-5508

Sentence

denotes

Magnetic resonance imaging (MRI) studies in patients with MS have demonstrated only a weak correlation between lesion load and clinical deficits (Stevens et al., 1986) .

TextSentencer_T34

5339-5508

Sentence

denotes

Magnetic resonance imaging (MRI) studies in patients with MS have demonstrated only a weak correlation between lesion load and clinical deficits (Stevens et al., 1986) .

T23329

5339-5508

Sentence

denotes

Magnetic resonance imaging (MRI) studies in patients with MS have demonstrated only a weak correlation between lesion load and clinical deficits (Stevens et al., 1986) .

TextSentencer_T35

5509-5737

Sentence

denotes

Moreover, pathological studies have demonstrated that some lesions observed by MRI are indeed demyelinated and frequently involve areas of CNS that should have resulted in neurological deficits, but do not (Bruck et al., 1997) .

TextSentencer_T35

5509-5737

Sentence

denotes

Moreover, pathological studies have demonstrated that some lesions observed by MRI are indeed demyelinated and frequently involve areas of CNS that should have resulted in neurological deficits, but do not (Bruck et al., 1997) .

T49460

5509-5737

Sentence

denotes

Moreover, pathological studies have demonstrated that some lesions observed by MRI are indeed demyelinated and frequently involve areas of CNS that should have resulted in neurological deficits, but do not (Bruck et al., 1997) .

TextSentencer_T36

5738-5964

Sentence

denotes

Likewise, autopsy analysis has demonstrated that demyelination, sufficient to make the pathological diagnosis of MS, can be observed in individuals who during life remained normal in neurological function (Mews et al., 1998) .

TextSentencer_T36

5738-5964

Sentence

denotes

Likewise, autopsy analysis has demonstrated that demyelination, sufficient to make the pathological diagnosis of MS, can be observed in individuals who during life remained normal in neurological function (Mews et al., 1998) .

T69035

5738-5964

Sentence

denotes

Likewise, autopsy analysis has demonstrated that demyelination, sufficient to make the pathological diagnosis of MS, can be observed in individuals who during life remained normal in neurological function (Mews et al., 1998) .

TextSentencer_T37

5965-6108

Sentence

denotes

These observations have suggested that demyelination may be required but not sufficient for the development of permanent neurological deficits.

TextSentencer_T37

5965-6108

Sentence

denotes

These observations have suggested that demyelination may be required but not sufficient for the development of permanent neurological deficits.

T82056

5965-6108

Sentence

denotes

These observations have suggested that demyelination may be required but not sufficient for the development of permanent neurological deficits.

TextSentencer_T38

6109-6324

Sentence

denotes

Further challenge to the demyelination hypothesis is provided by studies that use magnetic resonance spectroscopy to sensitively and quantitatively measure axon-specific metabolites such as N-acetyl aspartate (NAA).

TextSentencer_T38

6109-6324

Sentence

denotes

Further challenge to the demyelination hypothesis is provided by studies that use magnetic resonance spectroscopy to sensitively and quantitatively measure axon-specific metabolites such as N-acetyl aspartate (NAA).

T41892

6109-6324

Sentence

denotes

Further challenge to the demyelination hypothesis is provided by studies that use magnetic resonance spectroscopy to sensitively and quantitatively measure axon-specific metabolites such as N-acetyl aspartate (NAA).

TextSentencer_T39

6325-6601

Sentence

denotes

These studies found that active lesions are significantly reduced in NAA, and that as the disease progresses from the relapsing-remitting phase to the chronic-progressive phase, a reduction in NAA can be measured even in normal-appearing white matter (Matthews et al., 1996) .

TextSentencer_T39

6325-6601

Sentence

denotes

These studies found that active lesions are significantly reduced in NAA, and that as the disease progresses from the relapsing-remitting phase to the chronic-progressive phase, a reduction in NAA can be measured even in normal-appearing white matter (Matthews et al., 1996) .

T29824

6325-6601

Sentence

denotes

These studies found that active lesions are significantly reduced in NAA, and that as the disease progresses from the relapsing-remitting phase to the chronic-progressive phase, a reduction in NAA can be measured even in normal-appearing white matter (Matthews et al., 1996) .

TextSentencer_T40

6602-6885

Sentence

denotes

This finding suggests that a reduction in NAA may reflect both acute, but potentially reversible, axonal dysfunction associated with temporary demyelination, as well as chronic, irreversible loss of axons as a result of degeneration beyond the scope of any given demyelinated lesion.

TextSentencer_T40

6602-6885

Sentence

denotes

This finding suggests that a reduction in NAA may reflect both acute, but potentially reversible, axonal dysfunction associated with temporary demyelination, as well as chronic, irreversible loss of axons as a result of degeneration beyond the scope of any given demyelinated lesion.

T81958

6602-6885

Sentence

denotes

This finding suggests that a reduction in NAA may reflect both acute, but potentially reversible, axonal dysfunction associated with temporary demyelination, as well as chronic, irreversible loss of axons as a result of degeneration beyond the scope of any given demyelinated lesion.

TextSentencer_T41

6886-7206

Sentence

denotes

The mechanisms by which demyelination induces axon dysfunction and axon degeneration remain unclear (Trapp et al., 1998) , but a number of recent studies suggest that multiple factors may be involved, ranging from increased accessibility of inflammatory mediators and immune effector cells, to a loss of trophic support.

TextSentencer_T41

6886-7206

Sentence

denotes

The mechanisms by which demyelination induces axon dysfunction and axon degeneration remain unclear (Trapp et al., 1998) , but a number of recent studies suggest that multiple factors may be involved, ranging from increased accessibility of inflammatory mediators and immune effector cells, to a loss of trophic support.

T87035

6886-7206

Sentence

denotes

The mechanisms by which demyelination induces axon dysfunction and axon degeneration remain unclear (Trapp et al., 1998) , but a number of recent studies suggest that multiple factors may be involved, ranging from increased accessibility of inflammatory mediators and immune effector cells, to a loss of trophic support.

TextSentencer_T42

7207-7473

Sentence

denotes

For example, CD8 + cytotoxic T-cells have been observed in contact with demyelinated axons in active MS lesions (Neumann et al., 2002) , and the terminal swellings of transected axons have been found to be engulfed by macrophages and microglia (Trapp et al., 1998) .

TextSentencer_T42

7207-7473

Sentence

denotes

For example, CD8 + cytotoxic T-cells have been observed in contact with demyelinated axons in active MS lesions (Neumann et al., 2002) , and the terminal swellings of transected axons have been found to be engulfed by macrophages and microglia (Trapp et al., 1998) .

T41402

7207-7473

Sentence

denotes

For example, CD8 + cytotoxic T-cells have been observed in contact with demyelinated axons in active MS lesions (Neumann et al., 2002) , and the terminal swellings of transected axons have been found to be engulfed by macrophages and microglia (Trapp et al., 1998) .

TextSentencer_T43

7474-7675

Sentence

denotes

Likewise, myelination is known to provide trophic and maintenance cues to axons, controlling axon caliber, and neurofilament phosphorylation and spacing (Sanchez et al., 1996; Windebank et al., 1985) .

TextSentencer_T43

7474-7675

Sentence

denotes

Likewise, myelination is known to provide trophic and maintenance cues to axons, controlling axon caliber, and neurofilament phosphorylation and spacing (Sanchez et al., 1996; Windebank et al., 1985) .

T89708

7474-7675

Sentence

denotes

Likewise, myelination is known to provide trophic and maintenance cues to axons, controlling axon caliber, and neurofilament phosphorylation and spacing (Sanchez et al., 1996; Windebank et al., 1985) .

TextSentencer_T44

7676-7965

Sentence

denotes

Finally, changes in NAA associated with MS may reflect defects or dysregulation of axonal energy-storage mechanisms, as NAA-derived metabolic products such as acetyl coenzyme A may function to meet the high energy demands of axonal electrochemical conduction (Mehta and Namboodiri, 1995) .

TextSentencer_T44

7676-7965

Sentence

denotes

Finally, changes in NAA associated with MS may reflect defects or dysregulation of axonal energy-storage mechanisms, as NAA-derived metabolic products such as acetyl coenzyme A may function to meet the high energy demands of axonal electrochemical conduction (Mehta and Namboodiri, 1995) .

T47562

7676-7965

Sentence

denotes

Finally, changes in NAA associated with MS may reflect defects or dysregulation of axonal energy-storage mechanisms, as NAA-derived metabolic products such as acetyl coenzyme A may function to meet the high energy demands of axonal electrochemical conduction (Mehta and Namboodiri, 1995) .

TextSentencer_T45

7966-7991

Sentence

denotes

This idea is particularly

TextSentencer_T45

7966-7991

Sentence

denotes

This idea is particularly

T56362

7966-7991

Sentence

denotes

This idea is particularly

TextSentencer_T46

7992-8084

Sentence

denotes

Remyelination as Neuroprotection B A Figure 3 Evidence of "dying-back" oligodendrogliopathy.

TextSentencer_T46

7992-8084

Sentence

denotes

Remyelination as Neuroprotection B A Figure 3 Evidence of "dying-back" oligodendrogliopathy.

T17153

7992-8084

Sentence

denotes

Remyelination as Neuroprotection B A Figure 3 Evidence of "dying-back" oligodendrogliopathy.

TextSentencer_T47

8085-8184

Sentence

denotes

Note the degeneration of the inner myelin sheath, presenting an "inside-out" type of myelin damage.

TextSentencer_T47

8085-8184

Sentence

denotes

Note the degeneration of the inner myelin sheath, presenting an "inside-out" type of myelin damage.

T1220

8085-8184

Sentence

denotes

Note the degeneration of the inner myelin sheath, presenting an "inside-out" type of myelin damage.

TextSentencer_T48

8185-8315

Sentence

denotes

This type of pathology is present in Pattern III MS lesions in which the attack is primarily directed against the oligodendrocyte.

TextSentencer_T48

8185-8315

Sentence

denotes

This type of pathology is present in Pattern III MS lesions in which the attack is primarily directed against the oligodendrocyte.

T39276

8185-8315

Sentence

denotes

This type of pathology is present in Pattern III MS lesions in which the attack is primarily directed against the oligodendrocyte.

TextSentencer_T49

8316-8394

Sentence

denotes

The most distal extension of the oligodendrocyte is the inner myelin lamellae.

TextSentencer_T49

8316-8394

Sentence

denotes

The most distal extension of the oligodendrocyte is the inner myelin lamellae.

T88463

8316-8394

Sentence

denotes

The most distal extension of the oligodendrocyte is the inner myelin lamellae.

TextSentencer_T50

8395-8794

Sentence

denotes

Therefore, injury to the inner sheath with relative preservation of the other myelin lamellae is indicative of primary injury to the myelin-producing cell. virus-induced demyelinating disease resembled human MS (Lipton, 1975; Lipton and Dal Canto, 1976a; 1976b; , and numerous investigators have extended our understanding of MS using a variety of TMEV strains (Brahic 2002; Monteyne et al., 1997) .

TextSentencer_T50

8395-8794

Sentence

denotes

Therefore, injury to the inner sheath with relative preservation of the other myelin lamellae is indicative of primary injury to the myelin-producing cell. virus-induced demyelinating disease resembled human MS (Lipton, 1975; Lipton and Dal Canto, 1976a; 1976b; , and numerous investigators have extended our understanding of MS using a variety of TMEV strains (Brahic 2002; Monteyne et al., 1997) .

T28603

8395-8794

Sentence

denotes

Therefore, injury to the inner sheath with relative preservation of the other myelin lamellae is indicative of primary injury to the myelin-producing cell. virus-induced demyelinating disease resembled human MS (Lipton, 1975; Lipton and Dal Canto, 1976a; 1976b; , and numerous investigators have extended our understanding of MS using a variety of TMEV strains (Brahic 2002; Monteyne et al., 1997) .

TextSentencer_T51

8795-9090

Sentence

denotes

After intracerebral injection of Theiler's virus, and during the first 10 to 12 days of infection, the virus replicates primarily in neurons of the hippocampus (Fig. 5) , striatum, cortex, and anterior horn of the spinal cord, and then is rapidly cleared from the brain (Drescher et al., 1999) .

TextSentencer_T51

8795-9090

Sentence

denotes

After intracerebral injection of Theiler's virus, and during the first 10 to 12 days of infection, the virus replicates primarily in neurons of the hippocampus (Fig. 5) , striatum, cortex, and anterior horn of the spinal cord, and then is rapidly cleared from the brain (Drescher et al., 1999) .

T90121

8795-9090

Sentence

denotes

After intracerebral injection of Theiler's virus, and during the first 10 to 12 days of infection, the virus replicates primarily in neurons of the hippocampus (Fig. 5) , striatum, cortex, and anterior horn of the spinal cord, and then is rapidly cleared from the brain (Drescher et al., 1999) .

TextSentencer_T52

9091-9172

Sentence

denotes

Oligodendrocytes and macrophages are also infected early (Njenga et al., 1997a) .

TextSentencer_T52

9091-9172

Sentence

denotes

Oligodendrocytes and macrophages are also infected early (Njenga et al., 1997a) .

T96098

9091-9172

Sentence

denotes

Oligodendrocytes and macrophages are also infected early (Njenga et al., 1997a) .

TextSentencer_T53

9173-9306

Sentence

denotes

In mice of resistant major histocompatibility complex (MHC) haplotypes (H-2 b,d,k ) , no demyelination or viral persistence develops.

TextSentencer_T53

9173-9306

Sentence

denotes

In mice of resistant major histocompatibility complex (MHC) haplotypes (H-2 b,d,k ) , no demyelination or viral persistence develops.

T12360

9173-9306

Sentence

denotes

In mice of resistant major histocompatibility complex (MHC) haplotypes (H-2 b,d,k ) , no demyelination or viral persistence develops.

TextSentencer_T54

9307-9638

Sentence

denotes

However, in animals of susceptible MHC haplotypes (H-2 s,q,r,v,f,p ), the virus is cleared from neurons in the brain but persists in glial cells (Brahic et al., 1981; Rodriguez et al., 1983) and macrophages (Dal Canto and Lipton, 1982; Levy et al., 1992; Rossi et al., 1997) of the spinal cord white matter and brainstem (Fig. 6 ).

TextSentencer_T54

9307-9638

Sentence

denotes

However, in animals of susceptible MHC haplotypes (H-2 s,q,r,v,f,p ), the virus is cleared from neurons in the brain but persists in glial cells (Brahic et al., 1981; Rodriguez et al., 1983) and macrophages (Dal Canto and Lipton, 1982; Levy et al., 1992; Rossi et al., 1997) of the spinal cord white matter and brainstem (Fig. 6 ).

T86444

9307-9638

Sentence

denotes

However, in animals of susceptible MHC haplotypes (H-2 s,q,r,v,f,p ), the virus is cleared from neurons in the brain but persists in glial cells (Brahic et al., 1981; Rodriguez et al., 1983) and macrophages (Dal Canto and Lipton, 1982; Levy et al., 1992; Rossi et al., 1997) of the spinal cord white matter and brainstem (Fig. 6 ).

TextSentencer_T55

9639-9859

Sentence

denotes

This viral persistence is associated with chronic demyelination and stereotypical neurological impairment and paralysis due to the loss of axons (Drescher et al., 1997; Lipton 1975; Rodriguez and Miller, 1994) (Fig. 7) .

TextSentencer_T55

9639-9859

Sentence

denotes

This viral persistence is associated with chronic demyelination and stereotypical neurological impairment and paralysis due to the loss of axons (Drescher et al., 1997; Lipton 1975; Rodriguez and Miller, 1994) (Fig. 7) .

T79191

9639-9859

Sentence

denotes

This viral persistence is associated with chronic demyelination and stereotypical neurological impairment and paralysis due to the loss of axons (Drescher et al., 1997; Lipton 1975; Rodriguez and Miller, 1994) (Fig. 7) .

TextSentencer_T56

9860-10069

Sentence

denotes

Demyelination in this model is in part mediated by a "dying-back" oligoden- drogliopathy (Ludwin and Johnson, 1981) manifested by injury to the most distal extensions of the oligodendrocyte (Rodriguez, 1985) .

TextSentencer_T56

9860-10069

Sentence

denotes

Demyelination in this model is in part mediated by a "dying-back" oligoden- drogliopathy (Ludwin and Johnson, 1981) manifested by injury to the most distal extensions of the oligodendrocyte (Rodriguez, 1985) .

T67871

9860-10069

Sentence

denotes

Demyelination in this model is in part mediated by a "dying-back" oligoden- drogliopathy (Ludwin and Johnson, 1981) manifested by injury to the most distal extensions of the oligodendrocyte (Rodriguez, 1985) .

TextSentencer_T57

10070-10168

Sentence

denotes

Of the H-2 genes, it is the D locus that is of major importance for resistance vs. susceptibility.

TextSentencer_T57

10070-10168

Sentence

denotes

Of the H-2 genes, it is the D locus that is of major importance for resistance vs. susceptibility.

T56444

10070-10168

Sentence

denotes

Of the H-2 genes, it is the D locus that is of major importance for resistance vs. susceptibility.

TextSentencer_T58

10169-10356

Sentence

denotes

Resistance is a dominant trait that maps to H-2D, and genetic deletion or mutation of the D locus results in viral persistance and chronic demyelinating disease (Rodriguez et al., 1986) .

TextSentencer_T58

10169-10356

Sentence

denotes

Resistance is a dominant trait that maps to H-2D, and genetic deletion or mutation of the D locus results in viral persistance and chronic demyelinating disease (Rodriguez et al., 1986) .

T85127

10169-10356

Sentence

denotes

Resistance is a dominant trait that maps to H-2D, and genetic deletion or mutation of the D locus results in viral persistance and chronic demyelinating disease (Rodriguez et al., 1986) .

TextSentencer_T59

10357-10527

Sentence

denotes

Specific introduction of H-2D b or H-2D d genes into normally susceptible mice results in the acquisition of resistance to viral persistence (Rodriguez and David, 1995) .

TextSentencer_T59

10357-10527

Sentence

denotes

Specific introduction of H-2D b or H-2D d genes into normally susceptible mice results in the acquisition of resistance to viral persistence (Rodriguez and David, 1995) .

T1083

10357-10527

Sentence

denotes

Specific introduction of H-2D b or H-2D d genes into normally susceptible mice results in the acquisition of resistance to viral persistence (Rodriguez and David, 1995) .

TextSentencer_T60

10528-10898

Sentence

denotes

This resistance is associated with a robust antiviral cytotoxic Tcell response that develops in the gray matter of infected C57BL6 mice (Pena Rossi et al., 1991) , and immunological depletion of CD8 + T-cells or the genetic deletion of CD8 + T cells observed in β2-microglobulin knock-out mice results in viral persistence within otherwise resistant genetic backgrounds.

TextSentencer_T60

10528-10898

Sentence

denotes

This resistance is associated with a robust antiviral cytotoxic Tcell response that develops in the gray matter of infected C57BL6 mice (Pena Rossi et al., 1991) , and immunological depletion of CD8 + T-cells or the genetic deletion of CD8 + T cells observed in β2-microglobulin knock-out mice results in viral persistence within otherwise resistant genetic backgrounds.

T44052

10528-10898

Sentence

denotes

This resistance is associated with a robust antiviral cytotoxic Tcell response that develops in the gray matter of infected C57BL6 mice (Pena Rossi et al., 1991) , and immunological depletion of CD8 + T-cells or the genetic deletion of CD8 + T cells observed in β2-microglobulin knock-out mice results in viral persistence within otherwise resistant genetic backgrounds.

TextSentencer_T61

10899-11090

Sentence

denotes

Consistent with the genetics of resistance discussed previously, the cytotoxic T-cell response observed during the acute phase of Theiler's virus infection is restricted to the D b molecule .

TextSentencer_T61

10899-11090

Sentence

denotes

Consistent with the genetics of resistance discussed previously, the cytotoxic T-cell response observed during the acute phase of Theiler's virus infection is restricted to the D b molecule .

T86865

10899-11090

Sentence

denotes

Consistent with the genetics of resistance discussed previously, the cytotoxic T-cell response observed during the acute phase of Theiler's virus infection is restricted to the D b molecule .

TextSentencer_T62

11091-11373

Sentence

denotes

Moreover, after Theiler's virus infection of resistant mice of the H-2 b haplotype, we have identified an immunodominant cytotoxic T-cell population within the CNS that is specific for the VP2 121-130 viral capsid peptide presented within the context of D b (Johnson et al., 1999) .

TextSentencer_T62

11091-11373

Sentence

denotes

Moreover, after Theiler's virus infection of resistant mice of the H-2 b haplotype, we have identified an immunodominant cytotoxic T-cell population within the CNS that is specific for the VP2 121-130 viral capsid peptide presented within the context of D b (Johnson et al., 1999) .

T87045

11091-11373

Sentence

denotes

Moreover, after Theiler's virus infection of resistant mice of the H-2 b haplotype, we have identified an immunodominant cytotoxic T-cell population within the CNS that is specific for the VP2 121-130 viral capsid peptide presented within the context of D b (Johnson et al., 1999) .

TextSentencer_T63

11374-11670

Sentence

denotes

We have also previously demonstrated that cytotoxic T-cells appear to play a critical role in the injury of neurons and axons in both the acute (Howe and Rodriguez, unpublished observations) and chronic phases of Theiler's virus infection (Rivera-Quinones et al., 1998; Ure and Rodriguez, 2000; .

TextSentencer_T63

11374-11670

Sentence

denotes

We have also previously demonstrated that cytotoxic T-cells appear to play a critical role in the injury of neurons and axons in both the acute (Howe and Rodriguez, unpublished observations) and chronic phases of Theiler's virus infection (Rivera-Quinones et al., 1998; Ure and Rodriguez, 2000; .

T90913

11374-11670

Sentence

denotes

We have also previously demonstrated that cytotoxic T-cells appear to play a critical role in the injury of neurons and axons in both the acute (Howe and Rodriguez, unpublished observations) and chronic phases of Theiler's virus infection (Rivera-Quinones et al., 1998; Ure and Rodriguez, 2000; .

TextSentencer_T64

11671-11929

Sentence

denotes

Experimental allergic (or autoimmune) encephalomyelitis (EAE) has been a central model of inflammatory demyelinating disease since Rivers and Schwentker induced myelin destruction in monkeys immunized with brain tissue in 1935 (Rivers and Schwentker, 1935) .

TextSentencer_T64

11671-11929

Sentence

denotes

Experimental allergic (or autoimmune) encephalomyelitis (EAE) has been a central model of inflammatory demyelinating disease since Rivers and Schwentker induced myelin destruction in monkeys immunized with brain tissue in 1935 (Rivers and Schwentker, 1935) .

T36212

11671-11929

Sentence

denotes

Experimental allergic (or autoimmune) encephalomyelitis (EAE) has been a central model of inflammatory demyelinating disease since Rivers and Schwentker induced myelin destruction in monkeys immunized with brain tissue in 1935 (Rivers and Schwentker, 1935) .

TextSentencer_T65

11930-12108

Sentence

denotes

Since that time, it has become clear that EAE can be induced in essentially all mammals, from rodents to humans (Lassmann and Wekerle, 1998; Raine and Bornstein, 1970) (Fig. 8) .

TextSentencer_T65

11930-12108

Sentence

denotes

Since that time, it has become clear that EAE can be induced in essentially all mammals, from rodents to humans (Lassmann and Wekerle, 1998; Raine and Bornstein, 1970) (Fig. 8) .

T82055

11930-12108

Sentence

denotes

Since that time, it has become clear that EAE can be induced in essentially all mammals, from rodents to humans (Lassmann and Wekerle, 1998; Raine and Bornstein, 1970) (Fig. 8) .

TextSentencer_T66

12109-12291

Sentence

denotes

CNS proteinreactive T-cells are required for induction of EAE, and adoptive transfer of T-cells from immunized animals into naïve animals can elicit autoimmune-mediated inflammation.

TextSentencer_T66

12109-12291

Sentence

denotes

CNS proteinreactive T-cells are required for induction of EAE, and adoptive transfer of T-cells from immunized animals into naïve animals can elicit autoimmune-mediated inflammation.

T61122

12109-12291

Sentence

denotes

CNS proteinreactive T-cells are required for induction of EAE, and adoptive transfer of T-cells from immunized animals into naïve animals can elicit autoimmune-mediated inflammation.

TextSentencer_T67

12292-12494

Sentence

denotes

In contrast to Theiler's virus-mediated demyelination, EAErelated encephalitogenic T-cells are almost entirely CD4 + , recognizing CNS antigens only within the context of MHC class II (Swanborg, 2001) .

TextSentencer_T67

12292-12494

Sentence

denotes

In contrast to Theiler's virus-mediated demyelination, EAErelated encephalitogenic T-cells are almost entirely CD4 + , recognizing CNS antigens only within the context of MHC class II (Swanborg, 2001) .

T65698

12292-12494

Sentence

denotes

In contrast to Theiler's virus-mediated demyelination, EAErelated encephalitogenic T-cells are almost entirely CD4 + , recognizing CNS antigens only within the context of MHC class II (Swanborg, 2001) .

TextSentencer_T68

12495-12694

Sentence

denotes

While some evidence suggests that CD8 + and γδ-T cells may play a regulatory role in EAE (Segal, 2003) , CD4 + T-cells are considered to be the primary mediators of autoimmune-mediated demyelination.

TextSentencer_T68

12495-12694

Sentence

denotes

While some evidence suggests that CD8 + and γδ-T cells may play a regulatory role in EAE (Segal, 2003) , CD4 + T-cells are considered to be the primary mediators of autoimmune-mediated demyelination.

T11279

12495-12694

Sentence

denotes

While some evidence suggests that CD8 + and γδ-T cells may play a regulatory role in EAE (Segal, 2003) , CD4 + T-cells are considered to be the primary mediators of autoimmune-mediated demyelination.

TextSentencer_T69

12695-12800

Sentence

denotes

This is an important distinction, as well as an important difference between human MS and EAE in animals.

TextSentencer_T69

12695-12800

Sentence

denotes

This is an important distinction, as well as an important difference between human MS and EAE in animals.

T37138

12695-12800

Sentence

denotes

This is an important distinction, as well as an important difference between human MS and EAE in animals.

TextSentencer_T70

12801-13139

Sentence

denotes

Remyelination as Neuroprotection Axon damage is also associated with EAE (Ahmed et al., 2002; Kornek et al., 2000 Kornek et al., , 2001 Linker et al., 2002; Madrid and Wisniewski, 1977; Mancardi et al., 2001; Mead et al., 2002; Petzold et al., 2003; Pluchino et al., 2003; Raine and Cross, 1989; Raine et al., 1984; Storch et al., 2002) .

TextSentencer_T70

12801-13139

Sentence

denotes

Remyelination as Neuroprotection Axon damage is also associated with EAE (Ahmed et al., 2002; Kornek et al., 2000 Kornek et al., , 2001 Linker et al., 2002; Madrid and Wisniewski, 1977; Mancardi et al., 2001; Mead et al., 2002; Petzold et al., 2003; Pluchino et al., 2003; Raine and Cross, 1989; Raine et al., 1984; Storch et al., 2002) .

T36155

12801-13139

Sentence

denotes

Remyelination as Neuroprotection Axon damage is also associated with EAE (Ahmed et al., 2002; Kornek et al., 2000 Kornek et al., , 2001 Linker et al., 2002; Madrid and Wisniewski, 1977; Mancardi et al., 2001; Mead et al., 2002; Petzold et al., 2003; Pluchino et al., 2003; Raine and Cross, 1989; Raine et al., 1984; Storch et al., 2002) .

TextSentencer_T71

13140-13331

Sentence

denotes

Both acute axonal damage within actively demyelinating lesions, and chronic axonal injury within inactive lesions and normal-appearing white matter are observed in EAE (Kornek et al., 2000) .

TextSentencer_T71

13140-13331

Sentence

denotes

Both acute axonal damage within actively demyelinating lesions, and chronic axonal injury within inactive lesions and normal-appearing white matter are observed in EAE (Kornek et al., 2000) .

T1961

13140-13331

Sentence

denotes

Both acute axonal damage within actively demyelinating lesions, and chronic axonal injury within inactive lesions and normal-appearing white matter are observed in EAE (Kornek et al., 2000) .

TextSentencer_T72

13332-13595

Sentence

denotes

However, the mechanisms responsible for this axon damage are unclear, and, in contrast to the Theiler's virus model of MS, no study to date has identified a specific effector cell or process that is indispensable for axon injury but dispensable for demyelination.

TextSentencer_T72

13332-13595

Sentence

denotes

However, the mechanisms responsible for this axon damage are unclear, and, in contrast to the Theiler's virus model of MS, no study to date has identified a specific effector cell or process that is indispensable for axon injury but dispensable for demyelination.

T6065

13332-13595

Sentence

denotes

However, the mechanisms responsible for this axon damage are unclear, and, in contrast to the Theiler's virus model of MS, no study to date has identified a specific effector cell or process that is indispensable for axon injury but dispensable for demyelination.

TextSentencer_T73

13596-13781

Sentence

denotes

A variety of toxins, when injected into the spinal cord, rapidly induce demyelinating lesions without significant impact on cells other than oligodendrocytes van Engelen et al., 1997) .

TextSentencer_T73

13596-13781

Sentence

denotes

A variety of toxins, when injected into the spinal cord, rapidly induce demyelinating lesions without significant impact on cells other than oligodendrocytes van Engelen et al., 1997) .

T84695

13596-13781

Sentence

denotes

A variety of toxins, when injected into the spinal cord, rapidly induce demyelinating lesions without significant impact on cells other than oligodendrocytes van Engelen et al., 1997) .

TextSentencer_T74

13782-13905

Sentence

denotes

These include lysolecithin (lysophosphatidylcholine), an activator of phospholipase A 2 , and cuprizone, a copper chelator.

TextSentencer_T74

13782-13905

Sentence

denotes

These include lysolecithin (lysophosphatidylcholine), an activator of phospholipase A 2 , and cuprizone, a copper chelator.

T14715

13782-13905

Sentence

denotes

These include lysolecithin (lysophosphatidylcholine), an activator of phospholipase A 2 , and cuprizone, a copper chelator.

TextSentencer_T75

13906-14160

Sentence

denotes

Although a significant amount of evidence supports the role of the immune system in mediating and repairing the myelin damage induced by these two toxins, very little evidence is available regarding the extent of axon damage associated with these models.

TextSentencer_T75

13906-14160

Sentence

denotes

Although a significant amount of evidence supports the role of the immune system in mediating and repairing the myelin damage induced by these two toxins, very little evidence is available regarding the extent of axon damage associated with these models.

T87300

13906-14160

Sentence

denotes

Although a significant amount of evidence supports the role of the immune system in mediating and repairing the myelin damage induced by these two toxins, very little evidence is available regarding the extent of axon damage associated with these models.

TextSentencer_T76

14161-14417

Sentence

denotes

That said, Redford et al. (1997) showed that lysolecithin-induced demyelination sensitizes axons to conduction blockade induced by nitric oxide donors, suggesting that naked axons are more susceptible to soluble effector molecules released by immune cells.

TextSentencer_T76

14161-14417

Sentence

denotes

That said, Redford et al. (1997) showed that lysolecithin-induced demyelination sensitizes axons to conduction blockade induced by nitric oxide donors, suggesting that naked axons are more susceptible to soluble effector molecules released by immune cells.

T28081

14161-14417

Sentence

denotes

That said, Redford et al. (1997) showed that lysolecithin-induced demyelination sensitizes axons to conduction blockade induced by nitric oxide donors, suggesting that naked axons are more susceptible to soluble effector molecules released by immune cells.

TextSentencer_T77

14418-14683

Sentence

denotes

Likewise, Jean et al. (2002) have described a dramatic reduction in neurofilament staining of axons within lysolecithin-damaged areas, and have shown that acceleration of remyelination with plateletderived growth factor ameliorates this loss of axon immunolabeling.

TextSentencer_T77

14418-14683

Sentence

denotes

Likewise, Jean et al. (2002) have described a dramatic reduction in neurofilament staining of axons within lysolecithin-damaged areas, and have shown that acceleration of remyelination with plateletderived growth factor ameliorates this loss of axon immunolabeling.

T65746

14418-14683

Sentence

denotes

Likewise, Jean et al. (2002) have described a dramatic reduction in neurofilament staining of axons within lysolecithin-damaged areas, and have shown that acceleration of remyelination with plateletderived growth factor ameliorates this loss of axon immunolabeling.

TextSentencer_T78

14684-14735

Sentence

denotes

Finally, a subtantial reduction in axon caliber was

TextSentencer_T78

14684-14735

Sentence

denotes

Finally, a subtantial reduction in axon caliber was

T10318

14684-14735

Sentence

denotes

Finally, a subtantial reduction in axon caliber was

TextSentencer_T79

14736-14922

Sentence

denotes

Remyelination as Neuroprotection associated with chronic demyelination induced by cuprizone treatment, with axon diameter being reduced to 60% of normal after 16 weeks of demyelination .

TextSentencer_T79

14736-14922

Sentence

denotes

Remyelination as Neuroprotection associated with chronic demyelination induced by cuprizone treatment, with axon diameter being reduced to 60% of normal after 16 weeks of demyelination .

T49121

14736-14922

Sentence

denotes

Remyelination as Neuroprotection associated with chronic demyelination induced by cuprizone treatment, with axon diameter being reduced to 60% of normal after 16 weeks of demyelination .

TextSentencer_T80

14923-15010

Sentence

denotes

Thus, every major animal model of demyelinating disease is associated with axon damage.

TextSentencer_T80

14923-15010

Sentence

denotes

Thus, every major animal model of demyelinating disease is associated with axon damage.

T31539

14923-15010

Sentence

denotes

Thus, every major animal model of demyelinating disease is associated with axon damage.

TextSentencer_T81

15011-15317

Sentence

denotes

Because the methods used to induce demyelination in these models are extremely disparate, and because the cellular effectors of demyelination are variable across each of these models, it seems that axon failure, rather than mechanism of demyelination, is the critical feature of MS and animal models of MS.

TextSentencer_T81

15011-15317

Sentence

denotes

Because the methods used to induce demyelination in these models are extremely disparate, and because the cellular effectors of demyelination are variable across each of these models, it seems that axon failure, rather than mechanism of demyelination, is the critical feature of MS and animal models of MS.

T18046

15011-15317

Sentence

denotes

Because the methods used to induce demyelination in these models are extremely disparate, and because the cellular effectors of demyelination are variable across each of these models, it seems that axon failure, rather than mechanism of demyelination, is the critical feature of MS and animal models of MS.

TextSentencer_T82

15318-15550

Sentence

denotes

Therefore, from the perspective of controlling and reversing the neurological dysfunction associated with MS, it is important to understand the cellular mechanisms and the cellular effectors involved in axon damage and axon dropout.

TextSentencer_T82

15318-15550

Sentence

denotes

Therefore, from the perspective of controlling and reversing the neurological dysfunction associated with MS, it is important to understand the cellular mechanisms and the cellular effectors involved in axon damage and axon dropout.

T20250

15318-15550

Sentence

denotes

Therefore, from the perspective of controlling and reversing the neurological dysfunction associated with MS, it is important to understand the cellular mechanisms and the cellular effectors involved in axon damage and axon dropout.

TextSentencer_T83

15551-15677

Sentence

denotes

Experiments carried out by our group suggest that at least one important cellular effector of axon damage is the CD8 + T-cell.

TextSentencer_T83

15551-15677

Sentence

denotes

Experiments carried out by our group suggest that at least one important cellular effector of axon damage is the CD8 + T-cell.

T73093

15551-15677

Sentence

denotes

Experiments carried out by our group suggest that at least one important cellular effector of axon damage is the CD8 + T-cell.

TextSentencer_T84

15678-15867

Sentence

denotes

Using the Theiler's virus model of MS, we have investigated the role of MHC class I and class II in the progression of demyelination and the development of functional neurological deficits.

TextSentencer_T84

15678-15867

Sentence

denotes

Using the Theiler's virus model of MS, we have investigated the role of MHC class I and class II in the progression of demyelination and the development of functional neurological deficits.

T87122

15678-15867

Sentence

denotes

Using the Theiler's virus model of MS, we have investigated the role of MHC class I and class II in the progression of demyelination and the development of functional neurological deficits.

TextSentencer_T85

15868-16017

Sentence

denotes

We found that C57BL/6 × 129/J mice (H-2 b haplotype) were resistant to demyelination induced by Theiler's virus and never developed clinical disease.

TextSentencer_T85

15868-16017

Sentence

denotes

We found that C57BL/6 × 129/J mice (H-2 b haplotype) were resistant to demyelination induced by Theiler's virus and never developed clinical disease.

T60910

15868-16017

Sentence

denotes

We found that C57BL/6 × 129/J mice (H-2 b haplotype) were resistant to demyelination induced by Theiler's virus and never developed clinical disease.

TextSentencer_T86

16018-16198

Sentence

denotes

In contrast, mice of the identical haplotype that were deficient in expression of MHC class I (C57BL/6 × 129/J β 2 -microglobulin −/− ) developed extensive demyelination (Fig. 9 ).

TextSentencer_T86

16018-16198

Sentence

denotes

In contrast, mice of the identical haplotype that were deficient in expression of MHC class I (C57BL/6 × 129/J β 2 -microglobulin −/− ) developed extensive demyelination (Fig. 9 ).

T4100

16018-16198

Sentence

denotes

In contrast, mice of the identical haplotype that were deficient in expression of MHC class I (C57BL/6 × 129/J β 2 -microglobulin −/− ) developed extensive demyelination (Fig. 9 ).

TextSentencer_T87

16199-16559

Sentence

denotes

These animals failed to develop significant clinical signs of functional deficit as measured by hind-limb motor-evoked potentials, spontaneous vertical and horizontal movement assessment, rotarod performance, and activity wheel behavior (Fiette et al., 1993; Pullen et al., 1993; Rivera-Quinones et al., 1998; Rodriguez et al., 1993; Ure and Rodriguez, 2002) .

TextSentencer_T87

16199-16559

Sentence

denotes

These animals failed to develop significant clinical signs of functional deficit as measured by hind-limb motor-evoked potentials, spontaneous vertical and horizontal movement assessment, rotarod performance, and activity wheel behavior (Fiette et al., 1993; Pullen et al., 1993; Rivera-Quinones et al., 1998; Rodriguez et al., 1993; Ure and Rodriguez, 2002) .

T31356

16199-16559

Sentence

denotes

These animals failed to develop significant clinical signs of functional deficit as measured by hind-limb motor-evoked potentials, spontaneous vertical and horizontal movement assessment, rotarod performance, and activity wheel behavior (Fiette et al., 1993; Pullen et al., 1993; Rivera-Quinones et al., 1998; Rodriguez et al., 1993; Ure and Rodriguez, 2002) .

TextSentencer_T88

16560-16882

Sentence

denotes

On the other hand, mice of the same haplotype that were deficient in expression of MHC class II (C57BL/6 × 129/J Ab 0 ) developed not only extensive demyelination but also severe neurological impairment, and were, in fact, frequently moribund by 120 days postinfection (Njenga et al., 1996; Rivera-Quinones et al., 1998) .

TextSentencer_T88

16560-16882

Sentence

denotes

On the other hand, mice of the same haplotype that were deficient in expression of MHC class II (C57BL/6 × 129/J Ab 0 ) developed not only extensive demyelination but also severe neurological impairment, and were, in fact, frequently moribund by 120 days postinfection (Njenga et al., 1996; Rivera-Quinones et al., 1998) .

T91706

16560-16882

Sentence

denotes

On the other hand, mice of the same haplotype that were deficient in expression of MHC class II (C57BL/6 × 129/J Ab 0 ) developed not only extensive demyelination but also severe neurological impairment, and were, in fact, frequently moribund by 120 days postinfection (Njenga et al., 1996; Rivera-Quinones et al., 1998) .

TextSentencer_T89

16883-17047

Sentence

denotes

Our findings indicate that physiological function was likely preserved secondary to the upregulation and redistribution of sodium channels along demyelinated axons.

TextSentencer_T89

16883-17047

Sentence

denotes

Our findings indicate that physiological function was likely preserved secondary to the upregulation and redistribution of sodium channels along demyelinated axons.

T60739

16883-17047

Sentence

denotes

Our findings indicate that physiological function was likely preserved secondary to the upregulation and redistribution of sodium channels along demyelinated axons.

TextSentencer_T90

17048-17494

Sentence

denotes

In fact, whereas chronically infected mice of a susceptible haplotype (SJL/J mice) showed a severe loss of sodium channel density and intensity along axons, chronically infected β 2 -microglobulin −/− mice showed a dramatic upregulation and redistribution of axonal sodium channels, even though overall levels of myelin loss and distribution of demyelinated lesions were similiar between the two strains (Rivera-Quinones et al., 1998) (Fig. 10) .

TextSentencer_T90

17048-17494

Sentence

denotes

In fact, whereas chronically infected mice of a susceptible haplotype (SJL/J mice) showed a severe loss of sodium channel density and intensity along axons, chronically infected β 2 -microglobulin −/− mice showed a dramatic upregulation and redistribution of axonal sodium channels, even though overall levels of myelin loss and distribution of demyelinated lesions were similiar between the two strains (Rivera-Quinones et al., 1998) (Fig. 10) .

T10912

17048-17494

Sentence

denotes

In fact, whereas chronically infected mice of a susceptible haplotype (SJL/J mice) showed a severe loss of sodium channel density and intensity along axons, chronically infected β 2 -microglobulin −/− mice showed a dramatic upregulation and redistribution of axonal sodium channels, even though overall levels of myelin loss and distribution of demyelinated lesions were similiar between the two strains (Rivera-Quinones et al., 1998) (Fig. 10) .

TextSentencer_T91

17495-17736

Sentence

denotes

Furthermore, axons, as marked by either Bielschowski staining or antineurofilament staining, were preserved in chronically infected β 2 -microglobulin −/− mice, even in regions of significant cellular infiltrate and demyelination (Fig. 11 ).

TextSentencer_T91

17495-17736

Sentence

denotes

Furthermore, axons, as marked by either Bielschowski staining or antineurofilament staining, were preserved in chronically infected β 2 -microglobulin −/− mice, even in regions of significant cellular infiltrate and demyelination (Fig. 11 ).

T44165

17495-17736

Sentence

denotes

Furthermore, axons, as marked by either Bielschowski staining or antineurofilament staining, were preserved in chronically infected β 2 -microglobulin −/− mice, even in regions of significant cellular infiltrate and demyelination (Fig. 11 ).

TextSentencer_T92

17737-17876

Sentence

denotes

In contrast, there was significant disruption and degeneration of axons in chronically infected SJL/J mice (Rivera-Quinones et al., 1998) .

TextSentencer_T92

17737-17876

Sentence

denotes

In contrast, there was significant disruption and degeneration of axons in chronically infected SJL/J mice (Rivera-Quinones et al., 1998) .

T87461

17737-17876

Sentence

denotes

In contrast, there was significant disruption and degeneration of axons in chronically infected SJL/J mice (Rivera-Quinones et al., 1998) .

TextSentencer_T93

17877-18124

Sentence

denotes

These findings indicate Infected β2m +/+ mice do not exhibit demyelination, whereas the extent and distribution of demyelinated lesions is qualitatively similar in class I-deficient mice (β2m −/− ), SJL/J mice, and class II-deficient mice (Ab 0 ).

TextSentencer_T93

17877-18124

Sentence

denotes

These findings indicate Infected β2m +/+ mice do not exhibit demyelination, whereas the extent and distribution of demyelinated lesions is qualitatively similar in class I-deficient mice (β2m −/− ), SJL/J mice, and class II-deficient mice (Ab 0 ).

T44062

17877-18124

Sentence

denotes

These findings indicate Infected β2m +/+ mice do not exhibit demyelination, whereas the extent and distribution of demyelinated lesions is qualitatively similar in class I-deficient mice (β2m −/− ), SJL/J mice, and class II-deficient mice (Ab 0 ).

TextSentencer_T94

18125-18330

Sentence

denotes

For each pair of reconstructions, the left profile shows gray matter (green) with an overlay of demyelinated areas (red); the right profile shows normal white matter (white) and demyelinated lesions (red).

TextSentencer_T94

18125-18330

Sentence

denotes

For each pair of reconstructions, the left profile shows gray matter (green) with an overlay of demyelinated areas (red); the right profile shows normal white matter (white) and demyelinated lesions (red).

T66873

18125-18330

Sentence

denotes

For each pair of reconstructions, the left profile shows gray matter (green) with an overlay of demyelinated areas (red); the right profile shows normal white matter (white) and demyelinated lesions (red).

TextSentencer_T95

18331-18497

Sentence

denotes

that MHC class I-restricted CD8 + T-cells are likely to be critical mediators of axon damage associated with demyelination in susceptible strains of mice ( Fig. 12 ).

TextSentencer_T95

18331-18497

Sentence

denotes

that MHC class I-restricted CD8 + T-cells are likely to be critical mediators of axon damage associated with demyelination in susceptible strains of mice ( Fig. 12 ).

T17976

18331-18497

Sentence

denotes

that MHC class I-restricted CD8 + T-cells are likely to be critical mediators of axon damage associated with demyelination in susceptible strains of mice ( Fig. 12 ).

TextSentencer_T96

18498-18646

Sentence

denotes

Further evidence in support of this CD8 + T-cell hypothesis is provided by our recent studies assessing axon transport in chronically infected mice.

TextSentencer_T96

18498-18646

Sentence

denotes

Further evidence in support of this CD8 + T-cell hypothesis is provided by our recent studies assessing axon transport in chronically infected mice.

T27532

18498-18646

Sentence

denotes

Further evidence in support of this CD8 + T-cell hypothesis is provided by our recent studies assessing axon transport in chronically infected mice.

TextSentencer_T97

18647-18844

Sentence

denotes

Using retrograde labeling of spinal axon tracts, we have demonstrated a failure of retrograde axon transport in mice with demyelination and functional deficits (Ure and Rodriguez, 2000) (Fig. 13 ).

TextSentencer_T97

18647-18844

Sentence

denotes

Using retrograde labeling of spinal axon tracts, we have demonstrated a failure of retrograde axon transport in mice with demyelination and functional deficits (Ure and Rodriguez, 2000) (Fig. 13 ).

T6621

18647-18844

Sentence

denotes

Using retrograde labeling of spinal axon tracts, we have demonstrated a failure of retrograde axon transport in mice with demyelination and functional deficits (Ure and Rodriguez, 2000) (Fig. 13 ).

TextSentencer_T98

18845-19139

Sentence

denotes

However, we found that retrograde axonal transport was preserved in demyelinated mice with deletion of MHC class I (Ure and Rodriguez, 2002) , suggesting that the lack of CD8 + cytotoxic T-cells protected axonal integrity while not affecting demyelinated lesion load (Ure and Rodriguez, 2002) .

TextSentencer_T98

18845-19139

Sentence

denotes

However, we found that retrograde axonal transport was preserved in demyelinated mice with deletion of MHC class I (Ure and Rodriguez, 2002) , suggesting that the lack of CD8 + cytotoxic T-cells protected axonal integrity while not affecting demyelinated lesion load (Ure and Rodriguez, 2002) .

T76450

18845-19139

Sentence

denotes

However, we found that retrograde axonal transport was preserved in demyelinated mice with deletion of MHC class I (Ure and Rodriguez, 2002) , suggesting that the lack of CD8 + cytotoxic T-cells protected axonal integrity while not affecting demyelinated lesion load (Ure and Rodriguez, 2002) .

TextSentencer_T99

19140-19437

Sentence

denotes

A specific CD8+ T-cell-mediated response is further supported by our experiments showing that depletion of antigen-specific cytotoxic T-cells restricted to a viral peptide (VP2 121-130 ) resulted in preservation of neurological function, as measured by rotarod performance (Johnson et al., 2001) .

TextSentencer_T99

19140-19437

Sentence

denotes

A specific CD8+ T-cell-mediated response is further supported by our experiments showing that depletion of antigen-specific cytotoxic T-cells restricted to a viral peptide (VP2 121-130 ) resulted in preservation of neurological function, as measured by rotarod performance (Johnson et al., 2001) .

T18711

19140-19437

Sentence

denotes

A specific CD8+ T-cell-mediated response is further supported by our experiments showing that depletion of antigen-specific cytotoxic T-cells restricted to a viral peptide (VP2 121-130 ) resulted in preservation of neurological function, as measured by rotarod performance (Johnson et al., 2001) .

TextSentencer_T100

19438-19779

Sentence

denotes

Therefore, specific presentation of a Theiler's viral epitope within the context of H-2D b is necessary for at least a component of the neurological dysfunction associated with infection, although VP2 peptide depletion has no effect on the extent of viral infection or the level of demyelination induced by infection (Johnson et al., 2001) .

TextSentencer_T100

19438-19779

Sentence

denotes

Therefore, specific presentation of a Theiler's viral epitope within the context of H-2D b is necessary for at least a component of the neurological dysfunction associated with infection, although VP2 peptide depletion has no effect on the extent of viral infection or the level of demyelination induced by infection (Johnson et al., 2001) .

T16835

19438-19779

Sentence

denotes

Therefore, specific presentation of a Theiler's viral epitope within the context of H-2D b is necessary for at least a component of the neurological dysfunction associated with infection, although VP2 peptide depletion has no effect on the extent of viral infection or the level of demyelination induced by infection (Johnson et al., 2001) .

TextSentencer_T101

19780-20039

Sentence

denotes

Finally, ongoing experiments in our laboratory indicate that VP2 peptide depletion of the MHC class I cytotoxic T-cell response to Theiler's virus infection preserves spinal axons, as measured by neurofilament staining, axon counting, and retrograde labeling.

TextSentencer_T101

19780-20039

Sentence

denotes

Finally, ongoing experiments in our laboratory indicate that VP2 peptide depletion of the MHC class I cytotoxic T-cell response to Theiler's virus infection preserves spinal axons, as measured by neurofilament staining, axon counting, and retrograde labeling.

T87816

19780-20039

Sentence

denotes

Finally, ongoing experiments in our laboratory indicate that VP2 peptide depletion of the MHC class I cytotoxic T-cell response to Theiler's virus infection preserves spinal axons, as measured by neurofilament staining, axon counting, and retrograde labeling.

TextSentencer_T102

20040-20241

Sentence

denotes

Thus, antiviral CD8 + cytotoxic T-cells are clearly important for the loss of axons and development of neurological dysfunction associated with chronic demyelination in the Theiler's virus model of MS.

TextSentencer_T102

20040-20241

Sentence

denotes

Thus, antiviral CD8 + cytotoxic T-cells are clearly important for the loss of axons and development of neurological dysfunction associated with chronic demyelination in the Theiler's virus model of MS.

T86103

20040-20241

Sentence

denotes

Thus, antiviral CD8 + cytotoxic T-cells are clearly important for the loss of axons and development of neurological dysfunction associated with chronic demyelination in the Theiler's virus model of MS.

TextSentencer_T103

20242-20394

Sentence

denotes

The hypothesis that CD8 + T-cells are critical in the pathogenesis of Theiler's virus infection is relevant specifically to mice of the H-2 b haplotype.

TextSentencer_T103

20242-20394

Sentence

denotes

The hypothesis that CD8 + T-cells are critical in the pathogenesis of Theiler's virus infection is relevant specifically to mice of the H-2 b haplotype.

T50307

20242-20394

Sentence

denotes

The hypothesis that CD8 + T-cells are critical in the pathogenesis of Theiler's virus infection is relevant specifically to mice of the H-2 b haplotype.

TextSentencer_T104

20395-20727

Sentence

denotes

Observations regarding the role of MHC class I in resistance vs. susceptibility to viral persistance and demyelination were made in recombinant inbred strains of the C57BL background (Rodriguez and David, 1985; Rodriguez et al., 1986) , and the immunodominant VP2 121-130 peptide response was observed only in H-2 b mice (Fig. 14) .

TextSentencer_T104

20395-20727

Sentence

denotes

Observations regarding the role of MHC class I in resistance vs. susceptibility to viral persistance and demyelination were made in recombinant inbred strains of the C57BL background (Rodriguez and David, 1985; Rodriguez et al., 1986) , and the immunodominant VP2 121-130 peptide response was observed only in H-2 b mice (Fig. 14) .

T80880

20395-20727

Sentence

denotes

Observations regarding the role of MHC class I in resistance vs. susceptibility to viral persistance and demyelination were made in recombinant inbred strains of the C57BL background (Rodriguez and David, 1985; Rodriguez et al., 1986) , and the immunodominant VP2 121-130 peptide response was observed only in H-2 b mice (Fig. 14) .

TextSentencer_T105

20728-20885

Sentence

denotes

The hypothesis probably does not explain the mechanism of demyelination and neurological deficit in susceptible strains such as SJL/J mice (H-2 s haplotype).

TextSentencer_T105

20728-20885

Sentence

denotes

The hypothesis probably does not explain the mechanism of demyelination and neurological deficit in susceptible strains such as SJL/J mice (H-2 s haplotype).

T91490

20728-20885

Sentence

denotes

The hypothesis probably does not explain the mechanism of demyelination and neurological deficit in susceptible strains such as SJL/J mice (H-2 s haplotype).

TextSentencer_T106

20886-21337

Sentence

denotes

For example, disruption of MHC class I function by deletion of β 2 -microglobulin in SJL/J mice results in more demyelination and increased neurological deficit (Begolka et al., 2001) , and in the SJL/J strain it has been suggested that MHC class II-restricted T-cell response (Miller et al., 1987) , and epitope-spreading to myelin antigens may be the mechanism of demyelination and neurological deficit (Croxford et al., 2002; Miller et al., 1997) .

TextSentencer_T106

20886-21337

Sentence

denotes

For example, disruption of MHC class I function by deletion of β 2 -microglobulin in SJL/J mice results in more demyelination and increased neurological deficit (Begolka et al., 2001) , and in the SJL/J strain it has been suggested that MHC class II-restricted T-cell response (Miller et al., 1987) , and epitope-spreading to myelin antigens may be the mechanism of demyelination and neurological deficit (Croxford et al., 2002; Miller et al., 1997) .

T46970

20886-21337

Sentence

denotes

For example, disruption of MHC class I function by deletion of β 2 -microglobulin in SJL/J mice results in more demyelination and increased neurological deficit (Begolka et al., 2001) , and in the SJL/J strain it has been suggested that MHC class II-restricted T-cell response (Miller et al., 1987) , and epitope-spreading to myelin antigens may be the mechanism of demyelination and neurological deficit (Croxford et al., 2002; Miller et al., 1997) .

TextSentencer_T107

21338-21595

Sentence

denotes

However, CD8 + MHC class I-restricted cytotoxic T-cells have definitely been implicated in human MS, and it is likely that demyelination and neurological dysfunction in humans are a combination of both CD8 + -and CD4 + -mediated mechanisms (Neumann, 2003) .

TextSentencer_T107

21338-21595

Sentence

denotes

However, CD8 + MHC class I-restricted cytotoxic T-cells have definitely been implicated in human MS, and it is likely that demyelination and neurological dysfunction in humans are a combination of both CD8 + -and CD4 + -mediated mechanisms (Neumann, 2003) .

T95181

21338-21595

Sentence

denotes

However, CD8 + MHC class I-restricted cytotoxic T-cells have definitely been implicated in human MS, and it is likely that demyelination and neurological dysfunction in humans are a combination of both CD8 + -and CD4 + -mediated mechanisms (Neumann, 2003) .

TextSentencer_T108

21596-21782

Sentence

denotes

Recent pathological studies have shown that CD8 + T-cells may be the most common subset of T-cells in the MS brain and appear to be clonally expanded in MS lesions (Babbe et al., 2000) .

TextSentencer_T108

21596-21782

Sentence

denotes

Recent pathological studies have shown that CD8 + T-cells may be the most common subset of T-cells in the MS brain and appear to be clonally expanded in MS lesions (Babbe et al., 2000) .

T44800

21596-21782

Sentence

denotes

Recent pathological studies have shown that CD8 + T-cells may be the most common subset of T-cells in the MS brain and appear to be clonally expanded in MS lesions (Babbe et al., 2000) .

TextSentencer_T109

21783-22121

Sentence

denotes

Recent experiments in collaboration with Hans Lassmann have demonstrated intense expression of MHC class I in oligodendrocytes, neurons, axons, and astrocytes in the MS lesion (Hoftberger et al., 2003) , and autopsy studies have demonstrated that CD8 + T-cells are statistically associated with axonal injury in MS (Bitsch et al., 2000) .

TextSentencer_T109

21783-22121

Sentence

denotes

Recent experiments in collaboration with Hans Lassmann have demonstrated intense expression of MHC class I in oligodendrocytes, neurons, axons, and astrocytes in the MS lesion (Hoftberger et al., 2003) , and autopsy studies have demonstrated that CD8 + T-cells are statistically associated with axonal injury in MS (Bitsch et al., 2000) .

T29420

21783-22121

Sentence

denotes

Recent experiments in collaboration with Hans Lassmann have demonstrated intense expression of MHC class I in oligodendrocytes, neurons, axons, and astrocytes in the MS lesion (Hoftberger et al., 2003) , and autopsy studies have demonstrated that CD8 + T-cells are statistically associated with axonal injury in MS (Bitsch et al., 2000) .

TextSentencer_T110

22122-22428

Sentence

denotes

In addition, CD8 + T-cells have been shown to injure neurons and transect axons in vitro (Medana et al., 2000 (Medana et al., , 2001 , and imaging studies have indicated that axonal loss in MS is a direct correlate for disability (Narayanan et al., 1997; Truyen et al., 1996; van Waesberghe et al., 1999) .

TextSentencer_T110

22122-22428

Sentence

denotes

In addition, CD8 + T-cells have been shown to injure neurons and transect axons in vitro (Medana et al., 2000 (Medana et al., , 2001 , and imaging studies have indicated that axonal loss in MS is a direct correlate for disability (Narayanan et al., 1997; Truyen et al., 1996; van Waesberghe et al., 1999) .

T42580

22122-22428

Sentence

denotes

In addition, CD8 + T-cells have been shown to injure neurons and transect axons in vitro (Medana et al., 2000 (Medana et al., , 2001 , and imaging studies have indicated that axonal loss in MS is a direct correlate for disability (Narayanan et al., 1997; Truyen et al., 1996; van Waesberghe et al., 1999) .

TextSentencer_T111

22429-22549

Sentence

denotes

These studies suggest that CD8 + T-cells may be the primary effectors for axonal injury and neurological deficits in MS.

TextSentencer_T111

22429-22549

Sentence

denotes

These studies suggest that CD8 + T-cells may be the primary effectors for axonal injury and neurological deficits in MS.

T78951

22429-22549

Sentence

denotes

These studies suggest that CD8 + T-cells may be the primary effectors for axonal injury and neurological deficits in MS.

TextSentencer_T112

22550-22642

Sentence

denotes

Cytotoxic T-cell-induced cytotoxicity is mediated predominantly by two independent pathways.

TextSentencer_T112

22550-22642

Sentence

denotes

Cytotoxic T-cell-induced cytotoxicity is mediated predominantly by two independent pathways.

T39472

22550-22642

Sentence

denotes

Cytotoxic T-cell-induced cytotoxicity is mediated predominantly by two independent pathways.

TextSentencer_T113

22643-22657

Sentence

denotes

The first is a

TextSentencer_T113

22643-22657

Sentence

denotes

The first is a

T97038

22643-22657

Sentence

denotes

The first is a

TextSentencer_T114

22658-22775

Sentence

denotes

Remyelination as Neuroprotection granule-mediated process involving the pore-forming molecule perforin and granzymes.

TextSentencer_T114

22658-22775

Sentence

denotes

Remyelination as Neuroprotection granule-mediated process involving the pore-forming molecule perforin and granzymes.

T44319

22658-22775

Sentence

denotes

Remyelination as Neuroprotection granule-mediated process involving the pore-forming molecule perforin and granzymes.

TextSentencer_T115

22776-22944

Sentence

denotes

The second is a receptor ligand interaction that induces apoptosis through Fas (CD95/Apo-1) on the target and Fas ligand (FasL/CD95L/ Apo-1ligand) on the effector cell.

TextSentencer_T115

22776-22944

Sentence

denotes

The second is a receptor ligand interaction that induces apoptosis through Fas (CD95/Apo-1) on the target and Fas ligand (FasL/CD95L/ Apo-1ligand) on the effector cell.

T73866

22776-22944

Sentence

denotes

The second is a receptor ligand interaction that induces apoptosis through Fas (CD95/Apo-1) on the target and Fas ligand (FasL/CD95L/ Apo-1ligand) on the effector cell.

TextSentencer_T116

22945-23074

Sentence

denotes

Both mechanisms are implicated in neurological injury, and both require contact between the target cell and the cytotoxic T-cell.

TextSentencer_T116

22945-23074

Sentence

denotes

Both mechanisms are implicated in neurological injury, and both require contact between the target cell and the cytotoxic T-cell.

T29427

22945-23074

Sentence

denotes

Both mechanisms are implicated in neurological injury, and both require contact between the target cell and the cytotoxic T-cell.

TextSentencer_T117

23075-23345

Sentence

denotes

At least one means of such physical contact is the generation of an "immune synapse," formed when the T-cell receptor complex of a cytotoxic T-cell encounters and binds to an MHC class I molecule presenting an appropriate peptide epitope on the surface of a target cell.

TextSentencer_T117

23075-23345

Sentence

denotes

At least one means of such physical contact is the generation of an "immune synapse," formed when the T-cell receptor complex of a cytotoxic T-cell encounters and binds to an MHC class I molecule presenting an appropriate peptide epitope on the surface of a target cell.

T80920

23075-23345

Sentence

denotes

At least one means of such physical contact is the generation of an "immune synapse," formed when the T-cell receptor complex of a cytotoxic T-cell encounters and binds to an MHC class I molecule presenting an appropriate peptide epitope on the surface of a target cell.

TextSentencer_T118

23346-23479

Sentence

denotes

It was assumed previously that neurons escape immune surveillance through their inability to express MHC class I on the cell surface.

TextSentencer_T118

23346-23479

Sentence

denotes

It was assumed previously that neurons escape immune surveillance through their inability to express MHC class I on the cell surface.

T40220

23346-23479

Sentence

denotes

It was assumed previously that neurons escape immune surveillance through their inability to express MHC class I on the cell surface.

TextSentencer_T119

23480-23630

Sentence

denotes

However, it has been shown in vivo that during pathological processes, the expression of MHC class I on the surface of neurons is rapidly upregulated.

TextSentencer_T119

23480-23630

Sentence

denotes

However, it has been shown in vivo that during pathological processes, the expression of MHC class I on the surface of neurons is rapidly upregulated.

T80294

23480-23630

Sentence

denotes

However, it has been shown in vivo that during pathological processes, the expression of MHC class I on the surface of neurons is rapidly upregulated.

TextSentencer_T120

23631-23797

Sentence

denotes

For example, after Theiler's virus infection, MHC class I is rapidly upregulated in most CNS cells, including neurons (Altintas et al., 1993; Lindsley et al., 1991) .

TextSentencer_T120

23631-23797

Sentence

denotes

For example, after Theiler's virus infection, MHC class I is rapidly upregulated in most CNS cells, including neurons (Altintas et al., 1993; Lindsley et al., 1991) .

T48409

23631-23797

Sentence

denotes

For example, after Theiler's virus infection, MHC class I is rapidly upregulated in most CNS cells, including neurons (Altintas et al., 1993; Lindsley et al., 1991) .

TextSentencer_T121

23798-23951

Sentence

denotes

Therefore, after viral infection, axons and neurons become suitable targets for cytotoxic T-cells that are specific for CD8 + -restricted viral epitopes.

TextSentencer_T121

23798-23951

Sentence

denotes

Therefore, after viral infection, axons and neurons become suitable targets for cytotoxic T-cells that are specific for CD8 + -restricted viral epitopes.

T68522

23798-23951

Sentence

denotes

Therefore, after viral infection, axons and neurons become suitable targets for cytotoxic T-cells that are specific for CD8 + -restricted viral epitopes.

TextSentencer_T122

23952-24141

Sentence

denotes

In addition, soluble factors such as interferon-α/β (IFN-α/β), released as a result of infection, appear to be involved in the induction of MHC class I on CNS cells (Njenga et al., 1997b) .

TextSentencer_T122

23952-24141

Sentence

denotes

In addition, soluble factors such as interferon-α/β (IFN-α/β), released as a result of infection, appear to be involved in the induction of MHC class I on CNS cells (Njenga et al., 1997b) .

T44899

23952-24141

Sentence

denotes

In addition, soluble factors such as interferon-α/β (IFN-α/β), released as a result of infection, appear to be involved in the induction of MHC class I on CNS cells (Njenga et al., 1997b) .

TextSentencer_T123

24142-24301

Sentence

denotes

Of interest, electrically silent neurons upregulate MHC class I molecules on their surface (Neumann et al., 1995) , thus predisposing them to cytotoxic attack.

TextSentencer_T123

24142-24301

Sentence

denotes

Of interest, electrically silent neurons upregulate MHC class I molecules on their surface (Neumann et al., 1995) , thus predisposing them to cytotoxic attack.

T80470

24142-24301

Sentence

denotes

Of interest, electrically silent neurons upregulate MHC class I molecules on their surface (Neumann et al., 1995) , thus predisposing them to cytotoxic attack.

TextSentencer_T124

24302-24483

Sentence

denotes

This suggests that pathological processes such as demyelination that lead to conduction block may cause axons to become particularly vulnerable to cytotoxic T-cell-mediated killing.

TextSentencer_T124

24302-24483

Sentence

denotes

This suggests that pathological processes such as demyelination that lead to conduction block may cause axons to become particularly vulnerable to cytotoxic T-cell-mediated killing.

T27214

24302-24483

Sentence

denotes

This suggests that pathological processes such as demyelination that lead to conduction block may cause axons to become particularly vulnerable to cytotoxic T-cell-mediated killing.

TextSentencer_T125

24484-24763

Sentence

denotes

The dominant mechanism for cytotoxic CD8 + T-cellmediated viral clearance and killing of virally infected cells is the release of cytolytic granules containing the pore-forming protein perforin, the proteoglycan serglycin, and a family of serine proteases known as the granzymes.

TextSentencer_T125

24484-24763

Sentence

denotes

The dominant mechanism for cytotoxic CD8 + T-cellmediated viral clearance and killing of virally infected cells is the release of cytolytic granules containing the pore-forming protein perforin, the proteoglycan serglycin, and a family of serine proteases known as the granzymes.

T28754

24484-24763

Sentence

denotes

The dominant mechanism for cytotoxic CD8 + T-cellmediated viral clearance and killing of virally infected cells is the release of cytolytic granules containing the pore-forming protein perforin, the proteoglycan serglycin, and a family of serine proteases known as the granzymes.

TextSentencer_T126

24764-24897

Sentence

denotes

Granzymes A and B are the most abundant granzymes in cytolytic granules, and granzyme B is a mediator of caspase-dependent apoptosis.

TextSentencer_T126

24764-24897

Sentence

denotes

Granzymes A and B are the most abundant granzymes in cytolytic granules, and granzyme B is a mediator of caspase-dependent apoptosis.

T13767

24764-24897

Sentence

denotes

Granzymes A and B are the most abundant granzymes in cytolytic granules, and granzyme B is a mediator of caspase-dependent apoptosis.

TextSentencer_T127

24898-24985

Sentence

denotes

Granzymes appear to be packaged within the cytolytic granule in complex with serglycin.

TextSentencer_T127

24898-24985

Sentence

denotes

Granzymes appear to be packaged within the cytolytic granule in complex with serglycin.

T61168

24898-24985

Sentence

denotes

Granzymes appear to be packaged within the cytolytic granule in complex with serglycin.

TextSentencer_T128

24986-25148

Sentence

denotes

Approximately 30 to 50 granzyme molecules bind to each molecule of serglycin, forming a large granzyme particle that ranges in size from 40 to 200 nm in diameter.

TextSentencer_T128

24986-25148

Sentence

denotes

Approximately 30 to 50 granzyme molecules bind to each molecule of serglycin, forming a large granzyme particle that ranges in size from 40 to 200 nm in diameter.

T27012

24986-25148

Sentence

denotes

Approximately 30 to 50 granzyme molecules bind to each molecule of serglycin, forming a large granzyme particle that ranges in size from 40 to 200 nm in diameter.

TextSentencer_T129

25149-25389

Sentence

denotes

After T-cell receptor recognition of the appropriate peptide/MHC class I complex on target cells and the formation of the immune synapse, the granzyme/serglycin complex and perforin are exocytosed by the cytotoxic T-cell (Lieberman, 2003) .

TextSentencer_T129

25149-25389

Sentence

denotes

After T-cell receptor recognition of the appropriate peptide/MHC class I complex on target cells and the formation of the immune synapse, the granzyme/serglycin complex and perforin are exocytosed by the cytotoxic T-cell (Lieberman, 2003) .

T11465

25149-25389

Sentence

denotes

After T-cell receptor recognition of the appropriate peptide/MHC class I complex on target cells and the formation of the immune synapse, the granzyme/serglycin complex and perforin are exocytosed by the cytotoxic T-cell (Lieberman, 2003) .

TextSentencer_T130

25390-25658

Sentence

denotes

Some confusion currently exists regarding the role of perforin in the steps subsequent to cytolytic granule exocytosis, but the current model suggests that granzymes, either free or in complex with serglycin, bind to the surface of the target cell and are endocytosed.

TextSentencer_T130

25390-25658

Sentence

denotes

Some confusion currently exists regarding the role of perforin in the steps subsequent to cytolytic granule exocytosis, but the current model suggests that granzymes, either free or in complex with serglycin, bind to the surface of the target cell and are endocytosed.

T71423

25390-25658

Sentence

denotes

Some confusion currently exists regarding the role of perforin in the steps subsequent to cytolytic granule exocytosis, but the current model suggests that granzymes, either free or in complex with serglycin, bind to the surface of the target cell and are endocytosed.

TextSentencer_T131

25659-25780

Sentence

denotes

This event appears to occur in the absence of perforin (Froelich et al., 1996; Pinkoski et al., 1998; Shi et al., 1997) .

TextSentencer_T131

25659-25780

Sentence

denotes

This event appears to occur in the absence of perforin (Froelich et al., 1996; Pinkoski et al., 1998; Shi et al., 1997) .

T27645

25659-25780

Sentence

denotes

This event appears to occur in the absence of perforin (Froelich et al., 1996; Pinkoski et al., 1998; Shi et al., 1997) .

TextSentencer_T132

25781-26048

Sentence

denotes

Once endocytosed, however, perforin may function to facilitate the transfer of granzymes from target cell endosomes to the cytosol via endosomolysis, apparently without plasma membrane pore formation (Browne et al., 1999; Froelich et al., 1996; Metkar et al., 2002) .

TextSentencer_T132

25781-26048

Sentence

denotes

Once endocytosed, however, perforin may function to facilitate the transfer of granzymes from target cell endosomes to the cytosol via endosomolysis, apparently without plasma membrane pore formation (Browne et al., 1999; Froelich et al., 1996; Metkar et al., 2002) .

T8087

25781-26048

Sentence

denotes

Once endocytosed, however, perforin may function to facilitate the transfer of granzymes from target cell endosomes to the cytosol via endosomolysis, apparently without plasma membrane pore formation (Browne et al., 1999; Froelich et al., 1996; Metkar et al., 2002) .

TextSentencer_T133

26049-26268

Sentence

denotes

Regardless of the precise mechanism of action, perforin is clearly required for the full killing function of cytotoxic T-cells, and it was therefore logical to assess the role of perforin in Tcell-mediated axon killing.

TextSentencer_T133

26049-26268

Sentence

denotes

Regardless of the precise mechanism of action, perforin is clearly required for the full killing function of cytotoxic T-cells, and it was therefore logical to assess the role of perforin in Tcell-mediated axon killing.

T68535

26049-26268

Sentence

denotes

Regardless of the precise mechanism of action, perforin is clearly required for the full killing function of cytotoxic T-cells, and it was therefore logical to assess the role of perforin in Tcell-mediated axon killing.

TextSentencer_T134

26269-26498

Sentence

denotes

Our laboratory has demonstrated, using Theiler's virus infection of C57BL/6 H-2 b mice, that perforin may be a critical component in the induction of neurological deficits once demyelination is established (Murray et al., 1998) .

TextSentencer_T134

26269-26498

Sentence

denotes

Our laboratory has demonstrated, using Theiler's virus infection of C57BL/6 H-2 b mice, that perforin may be a critical component in the induction of neurological deficits once demyelination is established (Murray et al., 1998) .

T53261

26269-26498

Sentence

denotes

Our laboratory has demonstrated, using Theiler's virus infection of C57BL/6 H-2 b mice, that perforin may be a critical component in the induction of neurological deficits once demyelination is established (Murray et al., 1998) .

TextSentencer_T135

26499-26628

Sentence

denotes

We found that perforin deficiency broke viral resistance, resulting in viral persistence and consequent demyelination (Fig. 15 ).

TextSentencer_T135

26499-26628

Sentence

denotes

We found that perforin deficiency broke viral resistance, resulting in viral persistence and consequent demyelination (Fig. 15 ).

T42218

26499-26628

Sentence

denotes

We found that perforin deficiency broke viral resistance, resulting in viral persistence and consequent demyelination (Fig. 15 ).

TextSentencer_T136

26629-26853

Sentence

denotes

Despite significant demyelination throughout the spinal cord, however, perforin-deficient C57BL/6 H-2 b mice failed to develop the significant functional deficits associated with demyelination in susceptible strains of mice.

TextSentencer_T136

26629-26853

Sentence

denotes

Despite significant demyelination throughout the spinal cord, however, perforin-deficient C57BL/6 H-2 b mice failed to develop the significant functional deficits associated with demyelination in susceptible strains of mice.

T84842

26629-26853

Sentence

denotes

Despite significant demyelination throughout the spinal cord, however, perforin-deficient C57BL/6 H-2 b mice failed to develop the significant functional deficits associated with demyelination in susceptible strains of mice.

TextSentencer_T137

26854-27193

Sentence

denotes

Perforin-deficient mice did not acquire hind-limb paralysis, did not show a decrease in spontaneous activity, and did not develop signficant changes in hind-limb stride, suggesting that neurological deficits associated with demyelination are dependent on perforin, and, by extension, on functional cytotoxic T-cells (Murray et al., 1998) .

TextSentencer_T137

26854-27193

Sentence

denotes

Perforin-deficient mice did not acquire hind-limb paralysis, did not show a decrease in spontaneous activity, and did not develop signficant changes in hind-limb stride, suggesting that neurological deficits associated with demyelination are dependent on perforin, and, by extension, on functional cytotoxic T-cells (Murray et al., 1998) .

T64719

26854-27193

Sentence

denotes

Perforin-deficient mice did not acquire hind-limb paralysis, did not show a decrease in spontaneous activity, and did not develop signficant changes in hind-limb stride, suggesting that neurological deficits associated with demyelination are dependent on perforin, and, by extension, on functional cytotoxic T-cells (Murray et al., 1998) .

TextSentencer_T138

27194-27493

Sentence

denotes

Furthermore, we have recently observed that the number of large axons in the spinal cord does not differ between infected wild-type C57BL/6 mice and perforin-deficient C57BL/6 mice, strengthening the argument that neurological function in these animals is preserved as a result of axon preservation.

TextSentencer_T138

27194-27493

Sentence

denotes

Furthermore, we have recently observed that the number of large axons in the spinal cord does not differ between infected wild-type C57BL/6 mice and perforin-deficient C57BL/6 mice, strengthening the argument that neurological function in these animals is preserved as a result of axon preservation.

T67656

27194-27493

Sentence

denotes

Furthermore, we have recently observed that the number of large axons in the spinal cord does not differ between infected wild-type C57BL/6 mice and perforin-deficient C57BL/6 mice, strengthening the argument that neurological function in these animals is preserved as a result of axon preservation.

TextSentencer_T139

27494-27598

Sentence

denotes

Likewise, perforin contributes to neurological deficit and axon dropout in susceptible B10.Q H-2 q mice.

TextSentencer_T139

27494-27598

Sentence

denotes

Likewise, perforin contributes to neurological deficit and axon dropout in susceptible B10.Q H-2 q mice.

T45404

27494-27598

Sentence

denotes

Likewise, perforin contributes to neurological deficit and axon dropout in susceptible B10.Q H-2 q mice.

TextSentencer_T140

27599-27988

Sentence

denotes

In these experiments, we found that wild-type B10.Q mice developed significant demyelination, a dramatic decrease in the frequency of large axons in the spinal cord, and significant neurological dysfunction, as measured by rotarod performance, but that large axon frequency and neurological function were relatively preserved in perforin-deficient B10.Q mice, despite marked demyelination.

TextSentencer_T140

27599-27988

Sentence

denotes

In these experiments, we found that wild-type B10.Q mice developed significant demyelination, a dramatic decrease in the frequency of large axons in the spinal cord, and significant neurological dysfunction, as measured by rotarod performance, but that large axon frequency and neurological function were relatively preserved in perforin-deficient B10.Q mice, despite marked demyelination.

T54287

27599-27988

Sentence

denotes

In these experiments, we found that wild-type B10.Q mice developed significant demyelination, a dramatic decrease in the frequency of large axons in the spinal cord, and significant neurological dysfunction, as measured by rotarod performance, but that large axon frequency and neurological function were relatively preserved in perforin-deficient B10.Q mice, despite marked demyelination.

TextSentencer_T141

27989-28179

Sentence

denotes

Fas is a member of the tumor necrosis factor (TNF) receptor superfamily that is expressed on target cells as a receptor for the Fas ligand (FasL) present on the surface of cytotoxic T-cells.

TextSentencer_T141

27989-28179

Sentence

denotes

Fas is a member of the tumor necrosis factor (TNF) receptor superfamily that is expressed on target cells as a receptor for the Fas ligand (FasL) present on the surface of cytotoxic T-cells.

T2913

27989-28179

Sentence

denotes

Fas is a member of the tumor necrosis factor (TNF) receptor superfamily that is expressed on target cells as a receptor for the Fas ligand (FasL) present on the surface of cytotoxic T-cells.

TextSentencer_T142

28180-28285

Sentence

denotes

The intracellular domain of Fas contains a death domain (DD) region necessary for induction of apoptosis.

TextSentencer_T142

28180-28285

Sentence

denotes

The intracellular domain of Fas contains a death domain (DD) region necessary for induction of apoptosis.

T26885

28180-28285

Sentence

denotes

The intracellular domain of Fas contains a death domain (DD) region necessary for induction of apoptosis.

TextSentencer_T143

28286-28422

Sentence

denotes

Upon binding of FasL to Fas on a target cell, the DD is induced to recruit an adaptor protein called Fas-associated death domain (FADD).

TextSentencer_T143

28286-28422

Sentence

denotes

Upon binding of FasL to Fas on a target cell, the DD is induced to recruit an adaptor protein called Fas-associated death domain (FADD).

T54346

28286-28422

Sentence

denotes

Upon binding of FasL to Fas on a target cell, the DD is induced to recruit an adaptor protein called Fas-associated death domain (FADD).

TextSentencer_T144

28423-28581

Sentence

denotes

FADD bears both a death domain, via which it binds to Fas, and a death effector domain, forin-deficient C57BL/6 H-2 b mice results in extensive demyelination.

TextSentencer_T144

28423-28581

Sentence

denotes

FADD bears both a death domain, via which it binds to Fas, and a death effector domain, forin-deficient C57BL/6 H-2 b mice results in extensive demyelination.

T59580

28423-28581

Sentence

denotes

FADD bears both a death domain, via which it binds to Fas, and a death effector domain, forin-deficient C57BL/6 H-2 b mice results in extensive demyelination.

TextSentencer_T145

28582-28693

Sentence

denotes

Despite such widespread demyelination, however, these animals do not exhibit significant functional impairment.

TextSentencer_T145

28582-28693

Sentence

denotes

Despite such widespread demyelination, however, these animals do not exhibit significant functional impairment.

T21585

28582-28693

Sentence

denotes

Despite such widespread demyelination, however, these animals do not exhibit significant functional impairment.

TextSentencer_T146

28694-28841

Sentence

denotes

This finding suggests that perforin-mediated killing by CD8 + T-cells is required for axon loss and functional deficits, but not for demyelination.

TextSentencer_T146

28694-28841

Sentence

denotes

This finding suggests that perforin-mediated killing by CD8 + T-cells is required for axon loss and functional deficits, but not for demyelination.

T89166

28694-28841

Sentence

denotes

This finding suggests that perforin-mediated killing by CD8 + T-cells is required for axon loss and functional deficits, but not for demyelination.

TextSentencer_T147

28842-28889

Sentence

denotes

through which it associates with pro-caspase-8.

TextSentencer_T147

28842-28889

Sentence

denotes

through which it associates with pro-caspase-8.

T82611

28842-28889

Sentence

denotes

through which it associates with pro-caspase-8.

TextSentencer_T148

28890-29004

Sentence

denotes

Thus, a death-inducing complex, called the death-inducing signaling complex (DISC), is formed at the Fas receptor.

TextSentencer_T148

28890-29004

Sentence

denotes

Thus, a death-inducing complex, called the death-inducing signaling complex (DISC), is formed at the Fas receptor.

T6232

28890-29004

Sentence

denotes

Thus, a death-inducing complex, called the death-inducing signaling complex (DISC), is formed at the Fas receptor.

TextSentencer_T149

29005-29205

Sentence

denotes

Pro-caspase-8 recruitment to the DISC results in autocleavage and activation of caspase-8, which then goes on to activate effector caspases such as caspase-3, resulting in apoptosis (Thorburn, 2004) .

TextSentencer_T149

29005-29205

Sentence

denotes

Pro-caspase-8 recruitment to the DISC results in autocleavage and activation of caspase-8, which then goes on to activate effector caspases such as caspase-3, resulting in apoptosis (Thorburn, 2004) .

T45811

29005-29205

Sentence

denotes

Pro-caspase-8 recruitment to the DISC results in autocleavage and activation of caspase-8, which then goes on to activate effector caspases such as caspase-3, resulting in apoptosis (Thorburn, 2004) .

TextSentencer_T150

29206-29364

Sentence

denotes

The Fas/FasL pathway is active in essentially all cytotoxic cells, but is apparently most important for CD4 + cells of the T H 1 phenotype (Ju et al., 1994) .

TextSentencer_T150

29206-29364

Sentence

denotes

The Fas/FasL pathway is active in essentially all cytotoxic cells, but is apparently most important for CD4 + cells of the T H 1 phenotype (Ju et al., 1994) .

T26886

29206-29364

Sentence

denotes

The Fas/FasL pathway is active in essentially all cytotoxic cells, but is apparently most important for CD4 + cells of the T H 1 phenotype (Ju et al., 1994) .

TextSentencer_T151

29365-29706

Sentence

denotes

Although cultured CD4 + and CD8 + T-cells can engage both the perforin and the Fas/FasL pathways, in vivo experiments suggest that MHC class I-dependent killing is dominated by the perforin pathway, whereas MHC class II-dependent elimination is almost entirely mediated by Fas/FasL interactions (Graubert et al., 1997; Schulz et al., 1995) .

TextSentencer_T151

29365-29706

Sentence

denotes

Although cultured CD4 + and CD8 + T-cells can engage both the perforin and the Fas/FasL pathways, in vivo experiments suggest that MHC class I-dependent killing is dominated by the perforin pathway, whereas MHC class II-dependent elimination is almost entirely mediated by Fas/FasL interactions (Graubert et al., 1997; Schulz et al., 1995) .

T61652

29365-29706

Sentence

denotes

Although cultured CD4 + and CD8 + T-cells can engage both the perforin and the Fas/FasL pathways, in vivo experiments suggest that MHC class I-dependent killing is dominated by the perforin pathway, whereas MHC class II-dependent elimination is almost entirely mediated by Fas/FasL interactions (Graubert et al., 1997; Schulz et al., 1995) .

TextSentencer_T152

29707-29918

Sentence

denotes

Thus, a comparison between the relative role of perforin and Fas/FasL in demyelination and neurological deficit associated with Theiler's virus infection is a reasonable approach to address the CD8 + hypothesis.

TextSentencer_T152

29707-29918

Sentence

denotes

Thus, a comparison between the relative role of perforin and Fas/FasL in demyelination and neurological deficit associated with Theiler's virus infection is a reasonable approach to address the CD8 + hypothesis.

T49512

29707-29918

Sentence

denotes

Thus, a comparison between the relative role of perforin and Fas/FasL in demyelination and neurological deficit associated with Theiler's virus infection is a reasonable approach to address the CD8 + hypothesis.

TextSentencer_T153

29919-30115

Sentence

denotes

Indeed, in support of the CD8 + hypothesis, and in contrast to the findings for perforin, the Fas/FasL system appears to play a minimal role in determining resistance to Theiler's virus infection.

TextSentencer_T153

29919-30115

Sentence

denotes

Indeed, in support of the CD8 + hypothesis, and in contrast to the findings for perforin, the Fas/FasL system appears to play a minimal role in determining resistance to Theiler's virus infection.

T86408

29919-30115

Sentence

denotes

Indeed, in support of the CD8 + hypothesis, and in contrast to the findings for perforin, the Fas/FasL system appears to play a minimal role in determining resistance to Theiler's virus infection.

TextSentencer_T154

30116-30317

Sentence

denotes

Neither the lpr mutant, deficient in Fas, nor the gld mutant, defective in FasL binding, developed demyelination or neurological deficit in response to Theiler's virus infection (Murray et al., 1998) .

TextSentencer_T154

30116-30317

Sentence

denotes

Neither the lpr mutant, deficient in Fas, nor the gld mutant, defective in FasL binding, developed demyelination or neurological deficit in response to Theiler's virus infection (Murray et al., 1998) .

T35260

30116-30317

Sentence

denotes

Neither the lpr mutant, deficient in Fas, nor the gld mutant, defective in FasL binding, developed demyelination or neurological deficit in response to Theiler's virus infection (Murray et al., 1998) .

TextSentencer_T155

30318-30518

Sentence

denotes

Moreover, Rensing-Ehl and colleagues have reported that neurons express only low levels of Fas, even after cytokine stimulation, and are resistant to FasL-mediated killing (Rensing-Ehl et al., 1996) .

TextSentencer_T155

30318-30518

Sentence

denotes

Moreover, Rensing-Ehl and colleagues have reported that neurons express only low levels of Fas, even after cytokine stimulation, and are resistant to FasL-mediated killing (Rensing-Ehl et al., 1996) .

T23763

30318-30518

Sentence

denotes

Moreover, Rensing-Ehl and colleagues have reported that neurons express only low levels of Fas, even after cytokine stimulation, and are resistant to FasL-mediated killing (Rensing-Ehl et al., 1996) .

TextSentencer_T156

30519-30769

Sentence

denotes

In contrast, other investigators have suggested that in certain situations, MHC class I-restricted killing of neurons by virus-specific CD8 + T-lymphocytes is mediated through the Fas/FasL pathway, but not the perforin pathway (Medana et al., 2000) .

TextSentencer_T156

30519-30769

Sentence

denotes

In contrast, other investigators have suggested that in certain situations, MHC class I-restricted killing of neurons by virus-specific CD8 + T-lymphocytes is mediated through the Fas/FasL pathway, but not the perforin pathway (Medana et al., 2000) .

T66599

30519-30769

Sentence

denotes

In contrast, other investigators have suggested that in certain situations, MHC class I-restricted killing of neurons by virus-specific CD8 + T-lymphocytes is mediated through the Fas/FasL pathway, but not the perforin pathway (Medana et al., 2000) .

TextSentencer_T157

30770-30861

Sentence

denotes

Likewise, the role of Fas/FasL in human MS is less clear than in the Theiler's virus model.

TextSentencer_T157

30770-30861

Sentence

denotes

Likewise, the role of Fas/FasL in human MS is less clear than in the Theiler's virus model.

T70462

30770-30861

Sentence

denotes

Likewise, the role of Fas/FasL in human MS is less clear than in the Theiler's virus model.

TextSentencer_T158

30862-31112

Sentence

denotes

Although one report indicates that Fas is irrelevant to oligodendrocyte loss in MS lesions (Bonetti and Raine, 1997) , another provides evidence, at least in vitro, that Fas-mediated signaling contributes to a nonapoptotic injury of oligodendrocytes.

TextSentencer_T158

30862-31112

Sentence

denotes

Although one report indicates that Fas is irrelevant to oligodendrocyte loss in MS lesions (Bonetti and Raine, 1997) , another provides evidence, at least in vitro, that Fas-mediated signaling contributes to a nonapoptotic injury of oligodendrocytes.

T49516

30862-31112

Sentence

denotes

Although one report indicates that Fas is irrelevant to oligodendrocyte loss in MS lesions (Bonetti and Raine, 1997) , another provides evidence, at least in vitro, that Fas-mediated signaling contributes to a nonapoptotic injury of oligodendrocytes.

TextSentencer_T159

31113-31411

Sentence

denotes

Of particular interest, FasL has been shown to protect neurons against perforin-mediated cytotoxicity (Medana et al., 2001) , raising the possibility that both these mechanisms of neuronal killing may interact with one another in as yet uncharacterized, and potentially extremely complicated, ways.

TextSentencer_T159

31113-31411

Sentence

denotes

Of particular interest, FasL has been shown to protect neurons against perforin-mediated cytotoxicity (Medana et al., 2001) , raising the possibility that both these mechanisms of neuronal killing may interact with one another in as yet uncharacterized, and potentially extremely complicated, ways.

T42859

31113-31411

Sentence

denotes

Of particular interest, FasL has been shown to protect neurons against perforin-mediated cytotoxicity (Medana et al., 2001) , raising the possibility that both these mechanisms of neuronal killing may interact with one another in as yet uncharacterized, and potentially extremely complicated, ways.

TextSentencer_T160

31412-31518

Sentence

denotes

Interferon γ (IFNγ) is another important molecule involved in the effector functions of cytotoxic T-cells.

TextSentencer_T160

31412-31518

Sentence

denotes

Interferon γ (IFNγ) is another important molecule involved in the effector functions of cytotoxic T-cells.

T87063

31412-31518

Sentence

denotes

Interferon γ (IFNγ) is another important molecule involved in the effector functions of cytotoxic T-cells.

TextSentencer_T161

31519-31644

Sentence

denotes

IFNγ is a T H 1 antiviral and immunomodulatory cytokine that is critically involved in host resistance to multiple pathogens.

TextSentencer_T161

31519-31644

Sentence

denotes

IFNγ is a T H 1 antiviral and immunomodulatory cytokine that is critically involved in host resistance to multiple pathogens.

T14609

31519-31644

Sentence

denotes

IFNγ is a T H 1 antiviral and immunomodulatory cytokine that is critically involved in host resistance to multiple pathogens.

TextSentencer_T162

31645-31903

Sentence

denotes

IFNγ induces a wide range of effects on CNS cells, including macrophage activation, enhancement of leukocyte adhe-sion, release of TNF-α and other cytokines, and upregulation of MHC expression on microglia and macrophages (Munoz-Fernandez and Fresno, 1998) .

TextSentencer_T162

31645-31903

Sentence

denotes

IFNγ induces a wide range of effects on CNS cells, including macrophage activation, enhancement of leukocyte adhe-sion, release of TNF-α and other cytokines, and upregulation of MHC expression on microglia and macrophages (Munoz-Fernandez and Fresno, 1998) .

T15337

31645-31903

Sentence

denotes

IFNγ induces a wide range of effects on CNS cells, including macrophage activation, enhancement of leukocyte adhe-sion, release of TNF-α and other cytokines, and upregulation of MHC expression on microglia and macrophages (Munoz-Fernandez and Fresno, 1998) .

TextSentencer_T163

31904-32019

Sentence

denotes

We evaluated the role of IFNγ in protecting neurons from virus-induced injury after infection with Theiler's virus.

TextSentencer_T163

31904-32019

Sentence

denotes

We evaluated the role of IFNγ in protecting neurons from virus-induced injury after infection with Theiler's virus.

T48815

31904-32019

Sentence

denotes

We evaluated the role of IFNγ in protecting neurons from virus-induced injury after infection with Theiler's virus.

TextSentencer_T164

32020-32252

Sentence

denotes

During viral infections, IFNγ is produced by natural killer (NK) cells, CD4 + , and CD8 + T-cells; however, the proportion of lymphocyte subsets responding to virus infection influences the contributions to IFNγ-mediated protection.

TextSentencer_T164

32020-32252

Sentence

denotes

During viral infections, IFNγ is produced by natural killer (NK) cells, CD4 + , and CD8 + T-cells; however, the proportion of lymphocyte subsets responding to virus infection influences the contributions to IFNγ-mediated protection.

T30646

32020-32252

Sentence

denotes

During viral infections, IFNγ is produced by natural killer (NK) cells, CD4 + , and CD8 + T-cells; however, the proportion of lymphocyte subsets responding to virus infection influences the contributions to IFNγ-mediated protection.

TextSentencer_T165

32253-32442

Sentence

denotes

To determine the lymphocyte subsets that produce IFNγ to maintain resistance, we used adoptive transfer strategies to generate mice with lymphocyte-specific deficiencies in IFNγ production.

TextSentencer_T165

32253-32442

Sentence

denotes

To determine the lymphocyte subsets that produce IFNγ to maintain resistance, we used adoptive transfer strategies to generate mice with lymphocyte-specific deficiencies in IFNγ production.

T81439

32253-32442

Sentence

denotes

To determine the lymphocyte subsets that produce IFNγ to maintain resistance, we used adoptive transfer strategies to generate mice with lymphocyte-specific deficiencies in IFNγ production.

TextSentencer_T166

32443-32692

Sentence

denotes

We demonstrated that IFNγ production by both CD4 + and CD8 + T-cell subsets is critical for resistance to Theiler's virus-induced demyelination and neurological disease, and that CD4 + T-cells make a greater contribution to IFNγ-mediated protection.

TextSentencer_T166

32443-32692

Sentence

denotes

We demonstrated that IFNγ production by both CD4 + and CD8 + T-cell subsets is critical for resistance to Theiler's virus-induced demyelination and neurological disease, and that CD4 + T-cells make a greater contribution to IFNγ-mediated protection.

T33107

32443-32692

Sentence

denotes

We demonstrated that IFNγ production by both CD4 + and CD8 + T-cell subsets is critical for resistance to Theiler's virus-induced demyelination and neurological disease, and that CD4 + T-cells make a greater contribution to IFNγ-mediated protection.

TextSentencer_T167

32693-32922

Sentence

denotes

To determine the cellular targets of IFNγmediated responses, we used adoptive transfer studies and bone marrow chimerism to generate mice in which either hematopoietic or somatic cells lacked the ability to express IFNγ receptor.

TextSentencer_T167

32693-32922

Sentence

denotes

To determine the cellular targets of IFNγmediated responses, we used adoptive transfer studies and bone marrow chimerism to generate mice in which either hematopoietic or somatic cells lacked the ability to express IFNγ receptor.

T42692

32693-32922

Sentence

denotes

To determine the cellular targets of IFNγmediated responses, we used adoptive transfer studies and bone marrow chimerism to generate mice in which either hematopoietic or somatic cells lacked the ability to express IFNγ receptor.

TextSentencer_T168

32923-33123

Sentence

denotes

We demonstrated that IFNγ receptor must be present on CNS glia, but not bone marrow-derived lymphocytes, in order to maintain resistance to Theiler's virusinduced demyelination (Murray et al., 2002) .

TextSentencer_T168

32923-33123

Sentence

denotes

We demonstrated that IFNγ receptor must be present on CNS glia, but not bone marrow-derived lymphocytes, in order to maintain resistance to Theiler's virusinduced demyelination (Murray et al., 2002) .

T75319

32923-33123

Sentence

denotes

We demonstrated that IFNγ receptor must be present on CNS glia, but not bone marrow-derived lymphocytes, in order to maintain resistance to Theiler's virusinduced demyelination (Murray et al., 2002) .

TextSentencer_T169

33124-33493

Sentence

denotes

In addition, we found that both IFNγ −/− and IFNγ +/+ mice of resistant MHC H-2 b haplotype cleared Theiler's virus infection from spinal motor neurons, but whereas IFNγ +/+ H-2 b mice eventually cleared virus from the spinal cord white matter, IFNγ −/− H-2 b mice developed viral persistence in glial cells of the white matter and consequent spinal cord demyelination.

TextSentencer_T169

33124-33493

Sentence

denotes

In addition, we found that both IFNγ −/− and IFNγ +/+ mice of resistant MHC H-2 b haplotype cleared Theiler's virus infection from spinal motor neurons, but whereas IFNγ +/+ H-2 b mice eventually cleared virus from the spinal cord white matter, IFNγ −/− H-2 b mice developed viral persistence in glial cells of the white matter and consequent spinal cord demyelination.

T47572

33124-33493

Sentence

denotes

In addition, we found that both IFNγ −/− and IFNγ +/+ mice of resistant MHC H-2 b haplotype cleared Theiler's virus infection from spinal motor neurons, but whereas IFNγ +/+ H-2 b mice eventually cleared virus from the spinal cord white matter, IFNγ −/− H-2 b mice developed viral persistence in glial cells of the white matter and consequent spinal cord demyelination.

TextSentencer_T170

33494-33767

Sentence

denotes

Moreover, infection of susceptible H-2 q haplotype IFNγ −/− mice resulted in frequent deaths and severe neurological deficits within 11 to 16 days of infection as compared to infected IFNγ +/− H-2 q littermate controls and parental IFNγ +/+ H-2 q B10.Q controls (Fig. 16) .

TextSentencer_T170

33494-33767

Sentence

denotes

Moreover, infection of susceptible H-2 q haplotype IFNγ −/− mice resulted in frequent deaths and severe neurological deficits within 11 to 16 days of infection as compared to infected IFNγ +/− H-2 q littermate controls and parental IFNγ +/+ H-2 q B10.Q controls (Fig. 16) .

T21960

33494-33767

Sentence

denotes

Moreover, infection of susceptible H-2 q haplotype IFNγ −/− mice resulted in frequent deaths and severe neurological deficits within 11 to 16 days of infection as compared to infected IFNγ +/− H-2 q littermate controls and parental IFNγ +/+ H-2 q B10.Q controls (Fig. 16) .

TextSentencer_T171

33768-33949

Sentence

denotes

Morphological analysis demonstrated severe injury to spinal cord neurons of IFNγ −/− H-2 q mice during early infection, with less than 20% of mice surviving 45 days after infection.

TextSentencer_T171

33768-33949

Sentence

denotes

Morphological analysis demonstrated severe injury to spinal cord neurons of IFNγ −/− H-2 q mice during early infection, with less than 20% of mice surviving 45 days after infection.

T64526

33768-33949

Sentence

denotes

Morphological analysis demonstrated severe injury to spinal cord neurons of IFNγ −/− H-2 q mice during early infection, with less than 20% of mice surviving 45 days after infection.

TextSentencer_T172

33950-34225

Sentence

denotes

More viral RNA was detected in the brain and spinal cord of IFNγ −/− H-2 q mice as compared to IFNγ +/− H-2 q or IFNγ +/+ H-2 q mice at 14 and 21 days after TMEV infection, and virus antigen was localized predominantly to spinal motor neurons in infected IFNγ −/− H-2 q mice.

TextSentencer_T172

33950-34225

Sentence

denotes

More viral RNA was detected in the brain and spinal cord of IFNγ −/− H-2 q mice as compared to IFNγ +/− H-2 q or IFNγ +/+ H-2 q mice at 14 and 21 days after TMEV infection, and virus antigen was localized predominantly to spinal motor neurons in infected IFNγ −/− H-2 q mice.

T59308

33950-34225

Sentence

denotes

More viral RNA was detected in the brain and spinal cord of IFNγ −/− H-2 q mice as compared to IFNγ +/− H-2 q or IFNγ +/+ H-2 q mice at 14 and 21 days after TMEV infection, and virus antigen was localized predominantly to spinal motor neurons in infected IFNγ −/− H-2 q mice.

TextSentencer_T173

34226-34314

Sentence

denotes

Virus antigen persisted in neurons in these mice for as long as 45 days after infection.

TextSentencer_T173

34226-34314

Sentence

denotes

Virus antigen persisted in neurons in these mice for as long as 45 days after infection.

T13928

34226-34314

Sentence

denotes

Virus antigen persisted in neurons in these mice for as long as 45 days after infection.

TextSentencer_T174

34315-34540

Sentence

denotes

IFNγ deletion did not affect the humoral response directed against the virus; however, there was less expression of CD4, CD8, MHC class I, and MHC class II in the CNS of IFNγ −/− H-2 q mice as compared to IFNγ +/+ H-2 q mice.

TextSentencer_T174

34315-34540

Sentence

denotes

IFNγ deletion did not affect the humoral response directed against the virus; however, there was less expression of CD4, CD8, MHC class I, and MHC class II in the CNS of IFNγ −/− H-2 q mice as compared to IFNγ +/+ H-2 q mice.

T90457

34315-34540

Sentence

denotes

IFNγ deletion did not affect the humoral response directed against the virus; however, there was less expression of CD4, CD8, MHC class I, and MHC class II in the CNS of IFNγ −/− H-2 q mice as compared to IFNγ +/+ H-2 q mice.

TextSentencer_T175

34541-34770

Sentence

denotes

Finally, in vitro analysis of virusinduced death of NSC-34 spinal motor neurons and primary spinal motor neurons showed that IFNγ exerted a neuroprotective effect in the absence of other aspects of the immune response (Fig. 16) .

TextSentencer_T175

34541-34770

Sentence

denotes

Finally, in vitro analysis of virusinduced death of NSC-34 spinal motor neurons and primary spinal motor neurons showed that IFNγ exerted a neuroprotective effect in the absence of other aspects of the immune response (Fig. 16) .

T74885

34541-34770

Sentence

denotes

Finally, in vitro analysis of virusinduced death of NSC-34 spinal motor neurons and primary spinal motor neurons showed that IFNγ exerted a neuroprotective effect in the absence of other aspects of the immune response (Fig. 16) .

TextSentencer_T176

34771-34998

Sentence

denotes

These findings suggest that IFNγ plays a critical role in protecting spinal cord neurons from persistent infection and death, and that the cells responsible for production of this protective IFNγ appear to be cytotoxic T-cells.

TextSentencer_T176

34771-34998

Sentence

denotes

These findings suggest that IFNγ plays a critical role in protecting spinal cord neurons from persistent infection and death, and that the cells responsible for production of this protective IFNγ appear to be cytotoxic T-cells.

T30780

34771-34998

Sentence

denotes

These findings suggest that IFNγ plays a critical role in protecting spinal cord neurons from persistent infection and death, and that the cells responsible for production of this protective IFNγ appear to be cytotoxic T-cells.

TextSentencer_T177

34999-35243

Sentence

denotes

Thus, a model in which CD8 + T-cells attack and kill axons and neurons via perforin must also include CD8 + and CD4 + T-cells that release potentially neuroprotective cytokines that accelerate viral clearance while sparing irreplacable neurons.

TextSentencer_T177

34999-35243

Sentence

denotes

Thus, a model in which CD8 + T-cells attack and kill axons and neurons via perforin must also include CD8 + and CD4 + T-cells that release potentially neuroprotective cytokines that accelerate viral clearance while sparing irreplacable neurons.

T34129

34999-35243

Sentence

denotes

Thus, a model in which CD8 + T-cells attack and kill axons and neurons via perforin must also include CD8 + and CD4 + T-cells that release potentially neuroprotective cytokines that accelerate viral clearance while sparing irreplacable neurons.

TextSentencer_T178

35244-35329

Sentence

denotes

In addition to IFNγ, other cytokines also display unexpected neuroprotective effects.

TextSentencer_T178

35244-35329

Sentence

denotes

In addition to IFNγ, other cytokines also display unexpected neuroprotective effects.

T90357

35244-35329

Sentence

denotes

In addition to IFNγ, other cytokines also display unexpected neuroprotective effects.

TextSentencer_T179

35330-35568

Sentence

denotes

For example, we have shown that interleukin-6 (IL-6) protects anterior horn neurons from death induced by Theiler's virus without altering the development of the normal antiviral humoral response or the development of normal viral titer .

TextSentencer_T179

35330-35568

Sentence

denotes

For example, we have shown that interleukin-6 (IL-6) protects anterior horn neurons from death induced by Theiler's virus without altering the development of the normal antiviral humoral response or the development of normal viral titer .

T61444

35330-35568

Sentence

denotes

For example, we have shown that interleukin-6 (IL-6) protects anterior horn neurons from death induced by Theiler's virus without altering the development of the normal antiviral humoral response or the development of normal viral titer .

TextSentencer_T180

35569-35774

Sentence

denotes

Instead, we found that IL-6 protects anterior horn neurons, as well as NSC-34 motor neurons (Cashman et al., 1992) , from death induced by viral infection via a direct neuroprotective mechanism (Fig. 16) .

TextSentencer_T180

35569-35774

Sentence

denotes

Instead, we found that IL-6 protects anterior horn neurons, as well as NSC-34 motor neurons (Cashman et al., 1992) , from death induced by viral infection via a direct neuroprotective mechanism (Fig. 16) .

T46703

35569-35774

Sentence

denotes

Instead, we found that IL-6 protects anterior horn neurons, as well as NSC-34 motor neurons (Cashman et al., 1992) , from death induced by viral infection via a direct neuroprotective mechanism (Fig. 16) .

TextSentencer_T181

35775-36025

Sentence

denotes

This finding is in agreement with other reports that IL-6 promotes neurite outgrowth and survival of cultured enteric neurons (Schafer et al., 1999) , and that IL-6 delays the progression of motor neuron disease in wobbler mice (Ikeda et al., 1996) .

TextSentencer_T181

35775-36025

Sentence

denotes

This finding is in agreement with other reports that IL-6 promotes neurite outgrowth and survival of cultured enteric neurons (Schafer et al., 1999) , and that IL-6 delays the progression of motor neuron disease in wobbler mice (Ikeda et al., 1996) .

T96989

35775-36025

Sentence

denotes

This finding is in agreement with other reports that IL-6 promotes neurite outgrowth and survival of cultured enteric neurons (Schafer et al., 1999) , and that IL-6 delays the progression of motor neuron disease in wobbler mice (Ikeda et al., 1996) .

TextSentencer_T182

36026-36240

Sentence

denotes

Infection with a neurotropic coronavirus activated astrocytes to produce IL-6 (Sun et al., 1995) , and we observed a similar upregulation in astrocytic expression of IL-6 after Theiler's virus infection (Fig. 16) .

TextSentencer_T182

36026-36240

Sentence

denotes

Infection with a neurotropic coronavirus activated astrocytes to produce IL-6 (Sun et al., 1995) , and we observed a similar upregulation in astrocytic expression of IL-6 after Theiler's virus infection (Fig. 16) .

T17562

36026-36240

Sentence

denotes

Infection with a neurotropic coronavirus activated astrocytes to produce IL-6 (Sun et al., 1995) , and we observed a similar upregulation in astrocytic expression of IL-6 after Theiler's virus infection (Fig. 16) .

TextSentencer_T183

36241-36402

Sentence

denotes

Therefore, we suggest that IL-6, normally considered to be an immune modulator during inflammation, signals to protect motor neurons from death, potentially in a

TextSentencer_T183

36241-36402

Sentence

denotes

Therefore, we suggest that IL-6, normally considered to be an immune modulator during inflammation, signals to protect motor neurons from death, potentially in a

T19489

36241-36402

Sentence

denotes

Therefore, we suggest that IL-6, normally considered to be an immune modulator during inflammation, signals to protect motor neurons from death, potentially in a

TextSentencer_T184

36403-36601

Sentence

denotes

Remyelination as Neuroprotection manner analogous to ciliary neurotrophic factor (CNTF), a neurotrophic factor that also uses the gp130 signal transduction module Ransohoff et al., 2002) (Fig. 16) .

TextSentencer_T184

36403-36601

Sentence

denotes

Remyelination as Neuroprotection manner analogous to ciliary neurotrophic factor (CNTF), a neurotrophic factor that also uses the gp130 signal transduction module Ransohoff et al., 2002) (Fig. 16) .

T52586

36403-36601

Sentence

denotes

Remyelination as Neuroprotection manner analogous to ciliary neurotrophic factor (CNTF), a neurotrophic factor that also uses the gp130 signal transduction module Ransohoff et al., 2002) (Fig. 16) .

TextSentencer_T185

36602-36949

Sentence

denotes

The relevance of IL-6-mediated neuroprotection to MS remains to be delineated, but the concentrations of IL-6 receptor components are altered in the cerebrospinal fluid and serum of patients with MS (Padberg et al., 1999) , suggesting that IL-6 signaling may be important to protect neurons during a demyelinating insult (Ransohoff et al., 2002) .

TextSentencer_T185

36602-36949

Sentence

denotes

The relevance of IL-6-mediated neuroprotection to MS remains to be delineated, but the concentrations of IL-6 receptor components are altered in the cerebrospinal fluid and serum of patients with MS (Padberg et al., 1999) , suggesting that IL-6 signaling may be important to protect neurons during a demyelinating insult (Ransohoff et al., 2002) .

T271

36602-36949

Sentence

denotes

The relevance of IL-6-mediated neuroprotection to MS remains to be delineated, but the concentrations of IL-6 receptor components are altered in the cerebrospinal fluid and serum of patients with MS (Padberg et al., 1999) , suggesting that IL-6 signaling may be important to protect neurons during a demyelinating insult (Ransohoff et al., 2002) .

TextSentencer_T186

36950-37399

Sentence

denotes

A variety of other cytokines are also implicated in MS and animal models of MS, including TNFα (Arnett et al., 2001 (Arnett et al., , 2003 Paya et al., 1990) , CNTF (Linker et al., 2002) , leukemia inhibitory factor (Butzkueven et al., 2002) , oncostatin M (Repovic et al., 2003) , IL-10 (Petereit et al., 2003) , and IL-4 (Hulshof et al., 2002) , and a number of these cytokines use the common gp130 signal transduction module described previously.

TextSentencer_T186

36950-37399

Sentence

denotes

A variety of other cytokines are also implicated in MS and animal models of MS, including TNFα (Arnett et al., 2001 (Arnett et al., , 2003 Paya et al., 1990) , CNTF (Linker et al., 2002) , leukemia inhibitory factor (Butzkueven et al., 2002) , oncostatin M (Repovic et al., 2003) , IL-10 (Petereit et al., 2003) , and IL-4 (Hulshof et al., 2002) , and a number of these cytokines use the common gp130 signal transduction module described previously.

T29854

36950-37399

Sentence

denotes

A variety of other cytokines are also implicated in MS and animal models of MS, including TNFα (Arnett et al., 2001 (Arnett et al., , 2003 Paya et al., 1990) , CNTF (Linker et al., 2002) , leukemia inhibitory factor (Butzkueven et al., 2002) , oncostatin M (Repovic et al., 2003) , IL-10 (Petereit et al., 2003) , and IL-4 (Hulshof et al., 2002) , and a number of these cytokines use the common gp130 signal transduction module described previously.

TextSentencer_T187

37400-37611

Sentence

denotes

However, the exact mechanism(s) via which these factors function in MS, and the role each may play in protection of axons and neurons from damage or death associated with demyelination, remains to be discovered.

TextSentencer_T187

37400-37611

Sentence

denotes

However, the exact mechanism(s) via which these factors function in MS, and the role each may play in protection of axons and neurons from damage or death associated with demyelination, remains to be discovered.

T20756

37400-37611

Sentence

denotes

However, the exact mechanism(s) via which these factors function in MS, and the role each may play in protection of axons and neurons from damage or death associated with demyelination, remains to be discovered.

TextSentencer_T188

37612-38242

Sentence

denotes

Likewise, numerous neurotrophic factors and cytokines are known to support the survival of neurons and axons, including nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4/5, glial cell line-derived neurotrophic factor, CNTF (Ransohoff et al., 2002; Sofroniew et al., 2001) , insulin-like growth factor-1 (Kaspar et al., 2003) , vascular endothelial growth factor (Lambrechts et al., 2003) , hepatocyte growth factor (Sun et al., 2002) , cardiotrophin-like cytokine/cytokine-like factor 1 (Forger et al., 2003; Ransohoff et al., 2002) , and other immune cell-derived factors (Yin et al., 2003) .

TextSentencer_T188

37612-38242

Sentence

denotes

Likewise, numerous neurotrophic factors and cytokines are known to support the survival of neurons and axons, including nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4/5, glial cell line-derived neurotrophic factor, CNTF (Ransohoff et al., 2002; Sofroniew et al., 2001) , insulin-like growth factor-1 (Kaspar et al., 2003) , vascular endothelial growth factor (Lambrechts et al., 2003) , hepatocyte growth factor (Sun et al., 2002) , cardiotrophin-like cytokine/cytokine-like factor 1 (Forger et al., 2003; Ransohoff et al., 2002) , and other immune cell-derived factors (Yin et al., 2003) .

T12178

37612-38242

Sentence

denotes

Likewise, numerous neurotrophic factors and cytokines are known to support the survival of neurons and axons, including nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4/5, glial cell line-derived neurotrophic factor, CNTF (Ransohoff et al., 2002; Sofroniew et al., 2001) , insulin-like growth factor-1 (Kaspar et al., 2003) , vascular endothelial growth factor (Lambrechts et al., 2003) , hepatocyte growth factor (Sun et al., 2002) , cardiotrophin-like cytokine/cytokine-like factor 1 (Forger et al., 2003; Ransohoff et al., 2002) , and other immune cell-derived factors (Yin et al., 2003) .

TextSentencer_T189

38243-38503

Sentence

denotes

The role of each of these factors in limiting neurological dysfunction in MS is unknown, but is likely to be important, both for understanding the pathophysiology of the disease and for designing appropriate therapeutic interventions (Ransohoff et al., 2002) .

TextSentencer_T189

38243-38503

Sentence

denotes

The role of each of these factors in limiting neurological dysfunction in MS is unknown, but is likely to be important, both for understanding the pathophysiology of the disease and for designing appropriate therapeutic interventions (Ransohoff et al., 2002) .

T28647

38243-38503

Sentence

denotes

The role of each of these factors in limiting neurological dysfunction in MS is unknown, but is likely to be important, both for understanding the pathophysiology of the disease and for designing appropriate therapeutic interventions (Ransohoff et al., 2002) .

TextSentencer_T190

38504-38679

Sentence

denotes

Moreover, the complexity of interactions possible between these factors and between elements of the immune system is certainly a critical consideration (Bonini et al., 2003) .

TextSentencer_T190

38504-38679

Sentence

denotes

Moreover, the complexity of interactions possible between these factors and between elements of the immune system is certainly a critical consideration (Bonini et al., 2003) .

T35184

38504-38679

Sentence

denotes

Moreover, the complexity of interactions possible between these factors and between elements of the immune system is certainly a critical consideration (Bonini et al., 2003) .

TextSentencer_T191

38680-38784

Sentence

denotes

Obviously, the most efficacious therapy will be one that displays exquisite sensitivity and specificity.

TextSentencer_T191

38680-38784

Sentence

denotes

Obviously, the most efficacious therapy will be one that displays exquisite sensitivity and specificity.

T28583

38680-38784

Sentence

denotes

Obviously, the most efficacious therapy will be one that displays exquisite sensitivity and specificity.

TextSentencer_T192

38785-38976

Sentence

denotes

We have proposed the use of growth factor-like natural autoantibodies to rapidly promote remyelination, and thereby protect axons from the deleterious effects of exposure to immune effectors.

TextSentencer_T192

38785-38976

Sentence

denotes

We have proposed the use of growth factor-like natural autoantibodies to rapidly promote remyelination, and thereby protect axons from the deleterious effects of exposure to immune effectors.

T2485

38785-38976

Sentence

denotes

We have proposed the use of growth factor-like natural autoantibodies to rapidly promote remyelination, and thereby protect axons from the deleterious effects of exposure to immune effectors.

TextSentencer_T193

38977-39215

Sentence

denotes

The existence of pathogenic autoantibodies is well established for several peripheral neurological syndromes including myasthenia gravis, Lambert-Eaton syndrome, Guillain-Barré syndrome, and acquired neuromyotonia (Vincent et al., 1999) .

TextSentencer_T193

38977-39215

Sentence

denotes

The existence of pathogenic autoantibodies is well established for several peripheral neurological syndromes including myasthenia gravis, Lambert-Eaton syndrome, Guillain-Barré syndrome, and acquired neuromyotonia (Vincent et al., 1999) .

T10152

38977-39215

Sentence

denotes

The existence of pathogenic autoantibodies is well established for several peripheral neurological syndromes including myasthenia gravis, Lambert-Eaton syndrome, Guillain-Barré syndrome, and acquired neuromyotonia (Vincent et al., 1999) .

TextSentencer_T194

39216-39354

Sentence

denotes

Involvement of pathogenic autoantibodies in a particular dis-ease has been defined by several lines of experimental and clinical evidence.

TextSentencer_T194

39216-39354

Sentence

denotes

Involvement of pathogenic autoantibodies in a particular dis-ease has been defined by several lines of experimental and clinical evidence.

T11998

39216-39354

Sentence

denotes

Involvement of pathogenic autoantibodies in a particular dis-ease has been defined by several lines of experimental and clinical evidence.

TextSentencer_T195

39355-39475

Sentence

denotes

For example, antibodies to a defined target should be present in the majority of patients that present with the disease.

TextSentencer_T195

39355-39475

Sentence

denotes

For example, antibodies to a defined target should be present in the majority of patients that present with the disease.

T15936

39355-39475

Sentence

denotes

For example, antibodies to a defined target should be present in the majority of patients that present with the disease.

TextSentencer_T196

39476-39619

Sentence

denotes

The presence of these antibodies is often demonstrated by using the purified antibodies to immunostain tissues that express the target antigen.

TextSentencer_T196

39476-39619

Sentence

denotes

The presence of these antibodies is often demonstrated by using the purified antibodies to immunostain tissues that express the target antigen.

T19609

39476-39619

Sentence

denotes

The presence of these antibodies is often demonstrated by using the purified antibodies to immunostain tissues that express the target antigen.

TextSentencer_T197

39620-39816

Sentence

denotes

Moreover, immunization with the target antigen, passive transfer of antibodies against the antigen, or transfer of antibodies from patients with the disease to naïve animals should induce disease.

TextSentencer_T197

39620-39816

Sentence

denotes

Moreover, immunization with the target antigen, passive transfer of antibodies against the antigen, or transfer of antibodies from patients with the disease to naïve animals should induce disease.

T9164

39620-39816

Sentence

denotes

Moreover, immunization with the target antigen, passive transfer of antibodies against the antigen, or transfer of antibodies from patients with the disease to naïve animals should induce disease.

TextSentencer_T198

39817-40036

Sentence

denotes

Finally, reduction of serum antibody levels, by plasma exchange or by immunosuppression, generally leads to clinical improvement in patients, whereas an increase in antibody levels induces a return of clinical symptoms.

TextSentencer_T198

39817-40036

Sentence

denotes

Finally, reduction of serum antibody levels, by plasma exchange or by immunosuppression, generally leads to clinical improvement in patients, whereas an increase in antibody levels induces a return of clinical symptoms.

T75066

39817-40036

Sentence

denotes

Finally, reduction of serum antibody levels, by plasma exchange or by immunosuppression, generally leads to clinical improvement in patients, whereas an increase in antibody levels induces a return of clinical symptoms.

TextSentencer_T199

40037-40079

Sentence

denotes

Autoantibodies may also play a role in MS.

TextSentencer_T199

40037-40079

Sentence

denotes

Autoantibodies may also play a role in MS.

T90006

40037-40079

Sentence

denotes

Autoantibodies may also play a role in MS.

TextSentencer_T200

40080-40349

Sentence

denotes

When antibodies to myelin oligodendrocyte glycoprotein (MOG) are injected after the induction of EAE, the severity of the disease is dramatically increased and large demyelinating lesions develop (Genain et al., 1995; Linington et al., 1992; Schluesener et al., 1987) .

TextSentencer_T200

40080-40349

Sentence

denotes

When antibodies to myelin oligodendrocyte glycoprotein (MOG) are injected after the induction of EAE, the severity of the disease is dramatically increased and large demyelinating lesions develop (Genain et al., 1995; Linington et al., 1992; Schluesener et al., 1987) .

T7124

40080-40349

Sentence

denotes

When antibodies to myelin oligodendrocyte glycoprotein (MOG) are injected after the induction of EAE, the severity of the disease is dramatically increased and large demyelinating lesions develop (Genain et al., 1995; Linington et al., 1992; Schluesener et al., 1987) .

TextSentencer_T201

40350-40522

Sentence

denotes

In addition, antibodies to MOG have been detected in association with disintegrating myelin in both human MS patients and in a marmoset model of EAE (Genain et al., 1999) .

TextSentencer_T201

40350-40522

Sentence

denotes

In addition, antibodies to MOG have been detected in association with disintegrating myelin in both human MS patients and in a marmoset model of EAE (Genain et al., 1999) .

T41814

40350-40522

Sentence

denotes

In addition, antibodies to MOG have been detected in association with disintegrating myelin in both human MS patients and in a marmoset model of EAE (Genain et al., 1999) .

TextSentencer_T202

40523-40709

Sentence

denotes

Likewise, EAE-like Type II MS lesions, responsible for 30% to 50% of lesions in patients, are characterized by the deposition of immunoglobulin and complement (Lucchinetti et al., 1998 .

TextSentencer_T202

40523-40709

Sentence

denotes

Likewise, EAE-like Type II MS lesions, responsible for 30% to 50% of lesions in patients, are characterized by the deposition of immunoglobulin and complement (Lucchinetti et al., 1998 .

T64070

40523-40709

Sentence

denotes

Likewise, EAE-like Type II MS lesions, responsible for 30% to 50% of lesions in patients, are characterized by the deposition of immunoglobulin and complement (Lucchinetti et al., 1998 .

TextSentencer_T203

40710-40929

Sentence

denotes

Finally, we have shown that plasma exchange is effective in approximately 40% of cases with fulminant MS exacerbations, suggesting the presence of pathogenic autoantibodies in these patients (Weinshenker et al., 1999) .

TextSentencer_T203

40710-40929

Sentence

denotes

Finally, we have shown that plasma exchange is effective in approximately 40% of cases with fulminant MS exacerbations, suggesting the presence of pathogenic autoantibodies in these patients (Weinshenker et al., 1999) .

T24732

40710-40929

Sentence

denotes

Finally, we have shown that plasma exchange is effective in approximately 40% of cases with fulminant MS exacerbations, suggesting the presence of pathogenic autoantibodies in these patients (Weinshenker et al., 1999) .

TextSentencer_T204

40930-41086

Sentence

denotes

In a novel application of many of the same criteria used to define pathogenic antibodies, we have tried to define autoantibodies that promote tissue repair.

TextSentencer_T204

40930-41086

Sentence

denotes

In a novel application of many of the same criteria used to define pathogenic antibodies, we have tried to define autoantibodies that promote tissue repair.

T52530

40930-41086

Sentence

denotes

In a novel application of many of the same criteria used to define pathogenic antibodies, we have tried to define autoantibodies that promote tissue repair.

TextSentencer_T205

41087-41295

Sentence

denotes

A direct demonstration that autoreactive antibodies can enhance endogenous myelin repair came from our studies using Theiler's virus to induce chronic demyelinating disease in mice (Rodriguez et al., 1987a) .

TextSentencer_T205

41087-41295

Sentence

denotes

A direct demonstration that autoreactive antibodies can enhance endogenous myelin repair came from our studies using Theiler's virus to induce chronic demyelinating disease in mice (Rodriguez et al., 1987a) .

T80867

41087-41295

Sentence

denotes

A direct demonstration that autoreactive antibodies can enhance endogenous myelin repair came from our studies using Theiler's virus to induce chronic demyelinating disease in mice (Rodriguez et al., 1987a) .

TextSentencer_T206

41296-41551

Sentence

denotes

As described previously, intracerebral infection of susceptible mice with Theiler's virus results in a disease course characterized by acute encephalitis that is resolved in 14 to 21 days, followed by chronic viral persistence in spinal cord white matter.

TextSentencer_T206

41296-41551

Sentence

denotes

As described previously, intracerebral infection of susceptible mice with Theiler's virus results in a disease course characterized by acute encephalitis that is resolved in 14 to 21 days, followed by chronic viral persistence in spinal cord white matter.

T93664

41296-41551

Sentence

denotes

As described previously, intracerebral infection of susceptible mice with Theiler's virus results in a disease course characterized by acute encephalitis that is resolved in 14 to 21 days, followed by chronic viral persistence in spinal cord white matter.

TextSentencer_T207

41552-41744

Sentence

denotes

Persistent Theiler's virus infection eventually leads to chronic demyelination and progressive loss of motor function, a clinical pattern similar to that observed for progressive MS in humans.

TextSentencer_T207

41552-41744

Sentence

denotes

Persistent Theiler's virus infection eventually leads to chronic demyelination and progressive loss of motor function, a clinical pattern similar to that observed for progressive MS in humans.

T83620

41552-41744

Sentence

denotes

Persistent Theiler's virus infection eventually leads to chronic demyelination and progressive loss of motor function, a clinical pattern similar to that observed for progressive MS in humans.

TextSentencer_T208

41745-41945

Sentence

denotes

Myelin pathology in Theiler's virus infected mice is immune-mediated, with chronically infected animals demonstrating a wide range of disease phenotypes depending on their specific genetic background.

TextSentencer_T208

41745-41945

Sentence

denotes

Myelin pathology in Theiler's virus infected mice is immune-mediated, with chronically infected animals demonstrating a wide range of disease phenotypes depending on their specific genetic background.

T22703

41745-41945

Sentence

denotes

Myelin pathology in Theiler's virus infected mice is immune-mediated, with chronically infected animals demonstrating a wide range of disease phenotypes depending on their specific genetic background.

TextSentencer_T209

41946-42189

Sentence

denotes

In the SJL strain, demyelination is evident within 30 days after infection and by 1 to 3 months the animals develop neurological deficits including spasticity and gait abnormalities, weakness of the lower extremities, and bladder incontinence.

TextSentencer_T209

41946-42189

Sentence

denotes

In the SJL strain, demyelination is evident within 30 days after infection and by 1 to 3 months the animals develop neurological deficits including spasticity and gait abnormalities, weakness of the lower extremities, and bladder incontinence.

T70127

41946-42189

Sentence

denotes

In the SJL strain, demyelination is evident within 30 days after infection and by 1 to 3 months the animals develop neurological deficits including spasticity and gait abnormalities, weakness of the lower extremities, and bladder incontinence.

TextSentencer_T210

42190-42251

Sentence

denotes

Paralysis eventually occurs by 6 to 9 months after infection.

TextSentencer_T210

42190-42251

Sentence

denotes

Paralysis eventually occurs by 6 to 9 months after infection.

T62031

42190-42251

Sentence

denotes

Paralysis eventually occurs by 6 to 9 months after infection.

TextSentencer_T211

42252-42415

Sentence

denotes

Spontaneous remyelination is common in many mouse strains, but is limited in the SJL strain; often less than 10% of the total demyelinated lesion area is repaired.

TextSentencer_T211

42252-42415

Sentence

denotes

Spontaneous remyelination is common in many mouse strains, but is limited in the SJL strain; often less than 10% of the total demyelinated lesion area is repaired.

T8777

42252-42415

Sentence

denotes

Spontaneous remyelination is common in many mouse strains, but is limited in the SJL strain; often less than 10% of the total demyelinated lesion area is repaired.

TextSentencer_T212

42416-42595

Sentence

denotes

The low background of spontaneous repair in these animals makes them an excellent model for the study of strategies to promote endogenous remyelination (Rodriguez et al., 1987b) .

TextSentencer_T212

42416-42595

Sentence

denotes

The low background of spontaneous repair in these animals makes them an excellent model for the study of strategies to promote endogenous remyelination (Rodriguez et al., 1987b) .

T4627

42416-42595

Sentence

denotes

The low background of spontaneous repair in these animals makes them an excellent model for the study of strategies to promote endogenous remyelination (Rodriguez et al., 1987b) .

TextSentencer_T213

42596-42870

Sentence

denotes

Our initial observation of a beneficial humoral immune response occurred when significant remyelination was demonstrated in SJL mice that were chronically infected with Theiler's virus and immunized with spinal cord homogenate (SCH) prepared in incomplete Freund's adjuvant.

TextSentencer_T213

42596-42870

Sentence

denotes

Our initial observation of a beneficial humoral immune response occurred when significant remyelination was demonstrated in SJL mice that were chronically infected with Theiler's virus and immunized with spinal cord homogenate (SCH) prepared in incomplete Freund's adjuvant.

T36508

42596-42870

Sentence

denotes

Our initial observation of a beneficial humoral immune response occurred when significant remyelination was demonstrated in SJL mice that were chronically infected with Theiler's virus and immunized with spinal cord homogenate (SCH) prepared in incomplete Freund's adjuvant.

TextSentencer_T214

42871-43005

Sentence

denotes

Histological examination of spinal cord lesions from immunized animals revealed substantial remyelination compared to control animals.

TextSentencer_T214

42871-43005

Sentence

denotes

Histological examination of spinal cord lesions from immunized animals revealed substantial remyelination compared to control animals.

T34510

42871-43005

Sentence

denotes

Histological examination of spinal cord lesions from immunized animals revealed substantial remyelination compared to control animals.

TextSentencer_T215

43006-43344

Sentence

denotes

Passive transfer of antiserum (Rodriguez et al., 1987a) or purified immunoglobulin (Rodriguez and Lennon, 1990 ) from uninfected animals that had been immunized with SCH also enhanced remyelination in infected SJL mice, directly demonstrating for the first time a beneficial role of the humoral immune response in promoting myelin repair.

TextSentencer_T215

43006-43344

Sentence

denotes

Passive transfer of antiserum (Rodriguez et al., 1987a) or purified immunoglobulin (Rodriguez and Lennon, 1990 ) from uninfected animals that had been immunized with SCH also enhanced remyelination in infected SJL mice, directly demonstrating for the first time a beneficial role of the humoral immune response in promoting myelin repair.

T58049

43006-43344

Sentence

denotes

Passive transfer of antiserum (Rodriguez et al., 1987a) or purified immunoglobulin (Rodriguez and Lennon, 1990 ) from uninfected animals that had been immunized with SCH also enhanced remyelination in infected SJL mice, directly demonstrating for the first time a beneficial role of the humoral immune response in promoting myelin repair.

TextSentencer_T216

43345-43517

Sentence

denotes

This enhancement of remyelination was associated with proliferation or preservation of mature oligodendrocytes (Ludwin and Bakker, 1988; Prayoonwiwat and Rodriguez, 1993) .

TextSentencer_T216

43345-43517

Sentence

denotes

This enhancement of remyelination was associated with proliferation or preservation of mature oligodendrocytes (Ludwin and Bakker, 1988; Prayoonwiwat and Rodriguez, 1993) .

T94983

43345-43517

Sentence

denotes

This enhancement of remyelination was associated with proliferation or preservation of mature oligodendrocytes (Ludwin and Bakker, 1988; Prayoonwiwat and Rodriguez, 1993) .

TextSentencer_T217

43518-43723

Sentence

denotes

To further explore the nature of this beneficial immune response, hybridomas were generated from SJL mice after SCH immunization, in an attempt to identify monoclonal antibodies that promote remyelination.

TextSentencer_T217

43518-43723

Sentence

denotes

To further explore the nature of this beneficial immune response, hybridomas were generated from SJL mice after SCH immunization, in an attempt to identify monoclonal antibodies that promote remyelination.

T68459

43518-43723

Sentence

denotes

To further explore the nature of this beneficial immune response, hybridomas were generated from SJL mice after SCH immunization, in an attempt to identify monoclonal antibodies that promote remyelination.

TextSentencer_T218

43724-43847

Sentence

denotes

Two mouse monoclonal antibodies that enhance remyelination were identified and designated SCH94.03 and SCH79.08 (Fig. 17) .

TextSentencer_T218

43724-43847

Sentence

denotes

Two mouse monoclonal antibodies that enhance remyelination were identified and designated SCH94.03 and SCH79.08 (Fig. 17) .

T23836

43724-43847

Sentence

denotes

Two mouse monoclonal antibodies that enhance remyelination were identified and designated SCH94.03 and SCH79.08 (Fig. 17) .

TextSentencer_T219

43848-44109

Sentence

denotes

Both of these monoclonal antibodies are polyreactive IgMs that bind to antigens on the surface of oligodendrocytes, suggesting that the activity of these monoclonal antibodies may involve direct stimulation of the myelin-producing cells (Asakura et al., 1996) .

TextSentencer_T219

43848-44109

Sentence

denotes

Both of these monoclonal antibodies are polyreactive IgMs that bind to antigens on the surface of oligodendrocytes, suggesting that the activity of these monoclonal antibodies may involve direct stimulation of the myelin-producing cells (Asakura et al., 1996) .

T62967

43848-44109

Sentence

denotes

Both of these monoclonal antibodies are polyreactive IgMs that bind to antigens on the surface of oligodendrocytes, suggesting that the activity of these monoclonal antibodies may involve direct stimulation of the myelin-producing cells (Asakura et al., 1996) .

TextSentencer_T220

44110-44362

Sentence

denotes

Four additional oligodendrocyte-specific mouse IgMs (O4, O1, A2B5, and HNK1) were also shown to promote CNS remyelination (Asakura et al., 1998) , suggesting that this phenomenon was a general principle rather than an isolated immunological aberration.

TextSentencer_T220

44110-44362

Sentence

denotes

Four additional oligodendrocyte-specific mouse IgMs (O4, O1, A2B5, and HNK1) were also shown to promote CNS remyelination (Asakura et al., 1998) , suggesting that this phenomenon was a general principle rather than an isolated immunological aberration.

T79360

44110-44362

Sentence

denotes

Four additional oligodendrocyte-specific mouse IgMs (O4, O1, A2B5, and HNK1) were also shown to promote CNS remyelination (Asakura et al., 1998) , suggesting that this phenomenon was a general principle rather than an isolated immunological aberration.

TextSentencer_T221

44363-44565

Sentence

denotes

Remyelination as Neuroprotection Using oligodendrocyte binding as a screening assay, we identified candidate human monoclonal antibodies that might also promote remyelination (Warrington et al., 2000) .

TextSentencer_T221

44363-44565

Sentence

denotes

Remyelination as Neuroprotection Using oligodendrocyte binding as a screening assay, we identified candidate human monoclonal antibodies that might also promote remyelination (Warrington et al., 2000) .

T75884

44363-44565

Sentence

denotes

Remyelination as Neuroprotection Using oligodendrocyte binding as a screening assay, we identified candidate human monoclonal antibodies that might also promote remyelination (Warrington et al., 2000) .

TextSentencer_T222

44566-44746

Sentence

denotes

Human monoclonal antibodies were isolated from patients with monoclonal gammopathy, a relatively common condition characterized by high concentrations of monoclonal serum antibody.

TextSentencer_T222

44566-44746

Sentence

denotes

Human monoclonal antibodies were isolated from patients with monoclonal gammopathy, a relatively common condition characterized by high concentrations of monoclonal serum antibody.

T37881

44566-44746

Sentence

denotes

Human monoclonal antibodies were isolated from patients with monoclonal gammopathy, a relatively common condition characterized by high concentrations of monoclonal serum antibody.

TextSentencer_T223

44747-44921

Sentence

denotes

A total of 52 serum-derived human monoclonal IgMs (sHIgMs) were screened, and six were found to bind to the surface of morphologically mature rat oligodendrocytes in culture.

TextSentencer_T223

44747-44921

Sentence

denotes

A total of 52 serum-derived human monoclonal IgMs (sHIgMs) were screened, and six were found to bind to the surface of morphologically mature rat oligodendrocytes in culture.

T75201

44747-44921

Sentence

denotes

A total of 52 serum-derived human monoclonal IgMs (sHIgMs) were screened, and six were found to bind to the surface of morphologically mature rat oligodendrocytes in culture.

TextSentencer_T224

44922-45019

Sentence

denotes

In contrast, none of the 50 serumderived human monoclonal IgGs (sHIgG) bound to oligodendrocytes.

TextSentencer_T224

44922-45019

Sentence

denotes

In contrast, none of the 50 serumderived human monoclonal IgGs (sHIgG) bound to oligodendrocytes.

T20611

44922-45019

Sentence

denotes

In contrast, none of the 50 serumderived human monoclonal IgGs (sHIgG) bound to oligodendrocytes.

TextSentencer_T225

45020-45206

Sentence

denotes

The six oligodendrocyte-binding sHIgMs were tested in vivo, and two, designated sHIgM22 and sHIgM46, were found to promote substantial remyelination (Warrington et al., 2000) (Fig. 17) .

TextSentencer_T225

45020-45206

Sentence

denotes

The six oligodendrocyte-binding sHIgMs were tested in vivo, and two, designated sHIgM22 and sHIgM46, were found to promote substantial remyelination (Warrington et al., 2000) (Fig. 17) .

T30984

45020-45206

Sentence

denotes

The six oligodendrocyte-binding sHIgMs were tested in vivo, and two, designated sHIgM22 and sHIgM46, were found to promote substantial remyelination (Warrington et al., 2000) (Fig. 17) .

TextSentencer_T226

45207-45451

Sentence

denotes

More recently, we have engineered a recombinant form of sHIgM22, designated rHIgM22, that exhibits the same pattern of oligodendrocyte binding (Fig. 18) and induces the same level of remyelination as sHIgM22 (Mitsunaga et al., 2002) (Fig. 17) .

TextSentencer_T226

45207-45451

Sentence

denotes

More recently, we have engineered a recombinant form of sHIgM22, designated rHIgM22, that exhibits the same pattern of oligodendrocyte binding (Fig. 18) and induces the same level of remyelination as sHIgM22 (Mitsunaga et al., 2002) (Fig. 17) .

T52474

45207-45451

Sentence

denotes

More recently, we have engineered a recombinant form of sHIgM22, designated rHIgM22, that exhibits the same pattern of oligodendrocyte binding (Fig. 18) and induces the same level of remyelination as sHIgM22 (Mitsunaga et al., 2002) (Fig. 17) .

TextSentencer_T227

45452-45781

Sentence

denotes

Generation of this recombinant monoclonal human IgM marked an important step forward in the production of a potential therapeutic agent aimed at ameliorating demyelination in patients with MS, as this antibody is available in essentially unlimited quantities and will not induce crossspecies reactivity if administered to humans.

TextSentencer_T227

45452-45781

Sentence

denotes

Generation of this recombinant monoclonal human IgM marked an important step forward in the production of a potential therapeutic agent aimed at ameliorating demyelination in patients with MS, as this antibody is available in essentially unlimited quantities and will not induce crossspecies reactivity if administered to humans.

T22751

45452-45781

Sentence

denotes

Generation of this recombinant monoclonal human IgM marked an important step forward in the production of a potential therapeutic agent aimed at ameliorating demyelination in patients with MS, as this antibody is available in essentially unlimited quantities and will not induce crossspecies reactivity if administered to humans.

TextSentencer_T228

45782-45886

Sentence

denotes

As outlined previously, there are several properties used to define autoantibodies as pathogenic agents.

TextSentencer_T228

45782-45886

Sentence

denotes

As outlined previously, there are several properties used to define autoantibodies as pathogenic agents.

T99776

45782-45886

Sentence

denotes

As outlined previously, there are several properties used to define autoantibodies as pathogenic agents.

TextSentencer_T229

45887-45972

Sentence

denotes

Similar criteria can be applied to autoreactive antibodies involved in tissue repair.

TextSentencer_T229

45887-45972

Sentence

denotes

Similar criteria can be applied to autoreactive antibodies involved in tissue repair.

T31646

45887-45972

Sentence

denotes

Similar criteria can be applied to autoreactive antibodies involved in tissue repair.

TextSentencer_T230

45973-46074

Sentence

denotes

For example, recognition of appropriate tissues or molecules is an important defining characteristic.

TextSentencer_T230

45973-46074

Sentence

denotes

For example, recognition of appropriate tissues or molecules is an important defining characteristic.

T28090

45973-46074

Sentence

denotes

For example, recognition of appropriate tissues or molecules is an important defining characteristic.

TextSentencer_T231

46075-46275

Sentence

denotes

All of the antibodies that promote remyelination bind to antigens on the surface of oligodendrocytes, suggesting that these antibodies function through direct stimulation of the myelinproducing cells.

TextSentencer_T231

46075-46275

Sentence

denotes

All of the antibodies that promote remyelination bind to antigens on the surface of oligodendrocytes, suggesting that these antibodies function through direct stimulation of the myelinproducing cells.

T61305

46075-46275

Sentence

denotes

All of the antibodies that promote remyelination bind to antigens on the surface of oligodendrocytes, suggesting that these antibodies function through direct stimulation of the myelinproducing cells.

TextSentencer_T232

46276-46520

Sentence

denotes

It is important to note that these antibodies are polyreactive, recognizing a variety of chemical haptens and proteins as measured by enzyme-linked immunosorbent assay, and also robustly recognizing intracellular proteins in permeablized cells.

TextSentencer_T232

46276-46520

Sentence

denotes

It is important to note that these antibodies are polyreactive, recognizing a variety of chemical haptens and proteins as measured by enzyme-linked immunosorbent assay, and also robustly recognizing intracellular proteins in permeablized cells.

T79220

46276-46520

Sentence

denotes

It is important to note that these antibodies are polyreactive, recognizing a variety of chemical haptens and proteins as measured by enzyme-linked immunosorbent assay, and also robustly recognizing intracellular proteins in permeablized cells.

TextSentencer_T233

46521-46683

Sentence

denotes

Despite this antigenic promiscuity, however, remyelination-promoting antibodies bind only to a limited number of antigens on the surface of live oligodendrocytes.

TextSentencer_T233

46521-46683

Sentence

denotes

Despite this antigenic promiscuity, however, remyelination-promoting antibodies bind only to a limited number of antigens on the surface of live oligodendrocytes.

T55472

46521-46683

Sentence

denotes

Despite this antigenic promiscuity, however, remyelination-promoting antibodies bind only to a limited number of antigens on the surface of live oligodendrocytes.

TextSentencer_T234

46684-46879

Sentence

denotes

The surface antigens bound by several of these monoclonal antibodies have been characterized and are generally lipid or carbohydrate in nature (Asakura et al., 1998; Sommer and Schachner, 1981) .

TextSentencer_T234

46684-46879

Sentence

denotes

The surface antigens bound by several of these monoclonal antibodies have been characterized and are generally lipid or carbohydrate in nature (Asakura et al., 1998; Sommer and Schachner, 1981) .

T42820

46684-46879

Sentence

denotes

The surface antigens bound by several of these monoclonal antibodies have been characterized and are generally lipid or carbohydrate in nature (Asakura et al., 1998; Sommer and Schachner, 1981) .

TextSentencer_T235

46880-46963

Sentence

denotes

Remyelination-promoting antibodies appear to be naturally occurring autoantibodies.

TextSentencer_T235

46880-46963

Sentence

denotes

Remyelination-promoting antibodies appear to be naturally occurring autoantibodies.

T88771

46880-46963

Sentence

denotes

Remyelination-promoting antibodies appear to be naturally occurring autoantibodies.

TextSentencer_T236

46964-47186

Sentence

denotes

Antibodies of this type are present in the serum of normal individuals and are often polyreactive IgMs capable of binding to a variety of structurally unrelated, self and non-self antigens (Lacroix-Desmazes et al., 1998) .

TextSentencer_T236

46964-47186

Sentence

denotes

Antibodies of this type are present in the serum of normal individuals and are often polyreactive IgMs capable of binding to a variety of structurally unrelated, self and non-self antigens (Lacroix-Desmazes et al., 1998) .

T99497

46964-47186

Sentence

denotes

Antibodies of this type are present in the serum of normal individuals and are often polyreactive IgMs capable of binding to a variety of structurally unrelated, self and non-self antigens (Lacroix-Desmazes et al., 1998) .

TextSentencer_T237

47187-47395

Sentence

denotes

Such antibodies may represent a primordial form of the immune system that evolved to perform largely physiological functions rather than classical immune functions (Bouvet and Dighiero, 1998; Stewart, 1992) .

TextSentencer_T237

47187-47395

Sentence

denotes

Such antibodies may represent a primordial form of the immune system that evolved to perform largely physiological functions rather than classical immune functions (Bouvet and Dighiero, 1998; Stewart, 1992) .

T28704

47187-47395

Sentence

denotes

Such antibodies may represent a primordial form of the immune system that evolved to perform largely physiological functions rather than classical immune functions (Bouvet and Dighiero, 1998; Stewart, 1992) .

TextSentencer_T238

47396-47555

Sentence

denotes

One of these nonimmunological functions may be to promote tissue repair, serving effectively as trophic factors for specific cell types (Bieber et al., 2001) .

TextSentencer_T238

47396-47555

Sentence

denotes

One of these nonimmunological functions may be to promote tissue repair, serving effectively as trophic factors for specific cell types (Bieber et al., 2001) .

T63891

47396-47555

Sentence

denotes

One of these nonimmunological functions may be to promote tissue repair, serving effectively as trophic factors for specific cell types (Bieber et al., 2001) .

TextSentencer_T239

47556-47754

Sentence

denotes

The concept of an endogenous antibody-mediated repair system is consistent with our initial observation of enhanced remyelination after SCH or myelin antigen immunization (Rodriguez et al., 1987a) .

TextSentencer_T239

47556-47754

Sentence

denotes

The concept of an endogenous antibody-mediated repair system is consistent with our initial observation of enhanced remyelination after SCH or myelin antigen immunization (Rodriguez et al., 1987a) .

T83949

47556-47754

Sentence

denotes

The concept of an endogenous antibody-mediated repair system is consistent with our initial observation of enhanced remyelination after SCH or myelin antigen immunization (Rodriguez et al., 1987a) .

TextSentencer_T240

47755-47898

Sentence

denotes

Immunization may mimic immune system exposure to CNS antigens that occurs after injury, resulting in an increased titer of anti-CNS antibodies.

TextSentencer_T240

47755-47898

Sentence

denotes

Immunization may mimic immune system exposure to CNS antigens that occurs after injury, resulting in an increased titer of anti-CNS antibodies.

T37060

47755-47898

Sentence

denotes

Immunization may mimic immune system exposure to CNS antigens that occurs after injury, resulting in an increased titer of anti-CNS antibodies.

TextSentencer_T241

47899-48145

Sentence

denotes

Human IgMs from patients with macroglobulinemia were found to bind at high frequency to myelin antigens, suggesting that anti-CNS antibodies are common in the serum of individuals with no history of neurological damage (Warrington et al., 2000) .

TextSentencer_T241

47899-48145

Sentence

denotes

Human IgMs from patients with macroglobulinemia were found to bind at high frequency to myelin antigens, suggesting that anti-CNS antibodies are common in the serum of individuals with no history of neurological damage (Warrington et al., 2000) .

T991

47899-48145

Sentence

denotes

Human IgMs from patients with macroglobulinemia were found to bind at high frequency to myelin antigens, suggesting that anti-CNS antibodies are common in the serum of individuals with no history of neurological damage (Warrington et al., 2000) .

TextSentencer_T242

48146-48314

Sentence

denotes

Therefore, increasing the serum concentration of specific anti-CNS monoclonal antibodies may be a novel therapeutic treatment for human neurological injury and disease.

TextSentencer_T242

48146-48314

Sentence

denotes

Therefore, increasing the serum concentration of specific anti-CNS monoclonal antibodies may be a novel therapeutic treatment for human neurological injury and disease.

T43074

48146-48314

Sentence

denotes

Therefore, increasing the serum concentration of specific anti-CNS monoclonal antibodies may be a novel therapeutic treatment for human neurological injury and disease.

TextSentencer_T243

48315-48518

Sentence

denotes

Because all of the remyelination-promoting monoclonal antibodies that we have identified so far bind to oligodendrocytes or myelin, it seems reasonable to suggest a direct effect on the recognized cells.

TextSentencer_T243

48315-48518

Sentence

denotes

Because all of the remyelination-promoting monoclonal antibodies that we have identified so far bind to oligodendrocytes or myelin, it seems reasonable to suggest a direct effect on the recognized cells.

T91491

48315-48518

Sentence

denotes

Because all of the remyelination-promoting monoclonal antibodies that we have identified so far bind to oligodendrocytes or myelin, it seems reasonable to suggest a direct effect on the recognized cells.

TextSentencer_T244

48519-48661

Sentence

denotes

Other laboratories have demonstrated that oligodendrocyte-specific antibodies can induce biochemical and morphological changes in glial cells.

TextSentencer_T244

48519-48661

Sentence

denotes

Other laboratories have demonstrated that oligodendrocyte-specific antibodies can induce biochemical and morphological changes in glial cells.

T43205

48519-48661

Sentence

denotes

Other laboratories have demonstrated that oligodendrocyte-specific antibodies can induce biochemical and morphological changes in glial cells.

TextSentencer_T245

48662-49033

Sentence

denotes

For example, Dyer and colleagues showed that antibodies directed against oligodendrocyte surface epitopes, including antibodies to galactocerebroside, sulfatide, and myelin/oligodendrocyte-specific protein, can induce changes in the organization of oligodendrocyte plasma membrane and can alter cytoskeletal structure (Dyer and Benjamins, 1988; Dyer and Matthieu, 1994) .

TextSentencer_T245

48662-49033

Sentence

denotes

For example, Dyer and colleagues showed that antibodies directed against oligodendrocyte surface epitopes, including antibodies to galactocerebroside, sulfatide, and myelin/oligodendrocyte-specific protein, can induce changes in the organization of oligodendrocyte plasma membrane and can alter cytoskeletal structure (Dyer and Benjamins, 1988; Dyer and Matthieu, 1994) .

T63038

48662-49033

Sentence

denotes

For example, Dyer and colleagues showed that antibodies directed against oligodendrocyte surface epitopes, including antibodies to galactocerebroside, sulfatide, and myelin/oligodendrocyte-specific protein, can induce changes in the organization of oligodendrocyte plasma membrane and can alter cytoskeletal structure (Dyer and Benjamins, 1988; Dyer and Matthieu, 1994) .

TextSentencer_T246

49034-49339

Sentence

denotes

These changes in cellular structure were preceded by antibodyinduced calcium influx (Dyer, 1993; Dyer and Benjamins, 1990; , suggesting that the gating of calcium may play an important role in the regulation of oligodendrocyte structure and function, and may play a role in antibody-induced remyelination.

TextSentencer_T246

49034-49339

Sentence

denotes

These changes in cellular structure were preceded by antibodyinduced calcium influx (Dyer, 1993; Dyer and Benjamins, 1990; , suggesting that the gating of calcium may play an important role in the regulation of oligodendrocyte structure and function, and may play a role in antibody-induced remyelination.

T23727

49034-49339

Sentence

denotes

These changes in cellular structure were preceded by antibodyinduced calcium influx (Dyer, 1993; Dyer and Benjamins, 1990; , suggesting that the gating of calcium may play an important role in the regulation of oligodendrocyte structure and function, and may play a role in antibody-induced remyelination.

TextSentencer_T247

49340-49579

Sentence

denotes

In support of this hypothesis, we recently reported similar changes in intracellular calcium concentration in oligodendrocytes after treatment with remyelinationpromoting monoclonal antibodies (Howe et al., 2004; Paz Soldan et al., 2003) .

TextSentencer_T247

49340-49579

Sentence

denotes

In support of this hypothesis, we recently reported similar changes in intracellular calcium concentration in oligodendrocytes after treatment with remyelinationpromoting monoclonal antibodies (Howe et al., 2004; Paz Soldan et al., 2003) .

T526

49340-49579

Sentence

denotes

In support of this hypothesis, we recently reported similar changes in intracellular calcium concentration in oligodendrocytes after treatment with remyelinationpromoting monoclonal antibodies (Howe et al., 2004; Paz Soldan et al., 2003) .

TextSentencer_T248

49580-49761

Sentence

denotes

We assessed the direct effect of mouse and human monoclonal IgMs on CNS glial cells by using ratiometric fluorescent monitoring of intracellular calcium concentration ([Ca 2+ ] i ).

TextSentencer_T248

49580-49761

Sentence

denotes

We assessed the direct effect of mouse and human monoclonal IgMs on CNS glial cells by using ratiometric fluorescent monitoring of intracellular calcium concentration ([Ca 2+ ] i ).

T91934

49580-49761

Sentence

denotes

We assessed the direct effect of mouse and human monoclonal IgMs on CNS glial cells by using ratiometric fluorescent monitoring of intracellular calcium concentration ([Ca 2+ ] i ).

TextSentencer_T249

49762-49835

Sentence

denotes

A change in [Ca 2+ ] i was used as a marker for physiological activation.

TextSentencer_T249

49762-49835

Sentence

denotes

A change in [Ca 2+ ] i was used as a marker for physiological activation.

T77809

49762-49835

Sentence

denotes

A change in [Ca 2+ ] i was used as a marker for physiological activation.

TextSentencer_T250

49836-49972

Sentence

denotes

We found that remyelination-promoting antibodies stimulated a transient elevation of [Ca 2+ ] i in both astrocytes and oligodendrocytes.

TextSentencer_T250

49836-49972

Sentence

denotes

We found that remyelination-promoting antibodies stimulated a transient elevation of [Ca 2+ ] i in both astrocytes and oligodendrocytes.

T66975

49836-49972

Sentence

denotes

We found that remyelination-promoting antibodies stimulated a transient elevation of [Ca 2+ ] i in both astrocytes and oligodendrocytes.

TextSentencer_T251

49973-50149

Sentence

denotes

Of importance, all remyelination-promoting antibodies tested evoked Ca 2+ transients in mixed glial cultures; isotype-and species-matched control antibodies did not (Fig. 19) .

TextSentencer_T251

49973-50149

Sentence

denotes

Of importance, all remyelination-promoting antibodies tested evoked Ca 2+ transients in mixed glial cultures; isotype-and species-matched control antibodies did not (Fig. 19) .

T70197

49973-50149

Sentence

denotes

Of importance, all remyelination-promoting antibodies tested evoked Ca 2+ transients in mixed glial cultures; isotype-and species-matched control antibodies did not (Fig. 19) .

TextSentencer_T252

50150-50372

Sentence

denotes

We observed calcium responses of two types: a rapid transient calcium increase that occurred immediately upon exposure to antibody, and a slower transient calcium increase that was slightly delayed after antibody exposure.

TextSentencer_T252

50150-50372

Sentence

denotes

We observed calcium responses of two types: a rapid transient calcium increase that occurred immediately upon exposure to antibody, and a slower transient calcium increase that was slightly delayed after antibody exposure.

T8966

50150-50372

Sentence

denotes

We observed calcium responses of two types: a rapid transient calcium increase that occurred immediately upon exposure to antibody, and a slower transient calcium increase that was slightly delayed after antibody exposure.

TextSentencer_T253

50373-50553

Sentence

denotes

Morphological examination of the responding cells revealed that the immediate type response occurred in astrocytes, whereas the delayed type response occurred in oligodendrocytes .

TextSentencer_T253

50373-50553

Sentence

denotes

Morphological examination of the responding cells revealed that the immediate type response occurred in astrocytes, whereas the delayed type response occurred in oligodendrocytes .

T93560

50373-50553

Sentence

denotes

Morphological examination of the responding cells revealed that the immediate type response occurred in astrocytes, whereas the delayed type response occurred in oligodendrocytes .

TextSentencer_T254

50554-50751

Sentence

denotes

We also investigated the state of differentiation in oligodendrocytes that showed the delayed calcium response, and found that approximately 60% of delayed response cells showed surface immunoreac-

TextSentencer_T254

50554-50751

Sentence

denotes

We also investigated the state of differentiation in oligodendrocytes that showed the delayed calcium response, and found that approximately 60% of delayed response cells showed surface immunoreac-

T32548

50554-50751

Sentence

denotes

We also investigated the state of differentiation in oligodendrocytes that showed the delayed calcium response, and found that approximately 60% of delayed response cells showed surface immunoreac-

TextSentencer_T255

50752-50834

Sentence

denotes

Remyelination as Neuroprotection tivity to A2B5, a marker for preoligodendrocytes.

TextSentencer_T255

50752-50834

Sentence

denotes

Remyelination as Neuroprotection tivity to A2B5, a marker for preoligodendrocytes.

T85031

50752-50834

Sentence

denotes

Remyelination as Neuroprotection tivity to A2B5, a marker for preoligodendrocytes.

TextSentencer_T256

50835-51022

Sentence

denotes

The remaining 40% of cells exhibiting the delayed type response showed surface immunoreactivity to O4, an antisulfatide antibody that serves as a marker for more mature oligodendrocytes .

TextSentencer_T256

50835-51022

Sentence

denotes

The remaining 40% of cells exhibiting the delayed type response showed surface immunoreactivity to O4, an antisulfatide antibody that serves as a marker for more mature oligodendrocytes .

T98539

50835-51022

Sentence

denotes

The remaining 40% of cells exhibiting the delayed type response showed surface immunoreactivity to O4, an antisulfatide antibody that serves as a marker for more mature oligodendrocytes .

TextSentencer_T257

51023-51156

Sentence

denotes

Further characterization showed that the immediate astrocyte and delayed oligodendrocyte responses use distinct Ca 2+ entry pathways.

TextSentencer_T257

51023-51156

Sentence

denotes

Further characterization showed that the immediate astrocyte and delayed oligodendrocyte responses use distinct Ca 2+ entry pathways.

T38804

51023-51156

Sentence

denotes

Further characterization showed that the immediate astrocyte and delayed oligodendrocyte responses use distinct Ca 2+ entry pathways.

TextSentencer_T258

51157-51373

Sentence

denotes

We found that the immediate Ca 2+ response occurred in either the presence or absence of extracellular calcium, but that thapsigargin-induced depletion of endoplasmic reticulum calcium stores abrogated this response.

TextSentencer_T258

51157-51373

Sentence

denotes

We found that the immediate Ca 2+ response occurred in either the presence or absence of extracellular calcium, but that thapsigargin-induced depletion of endoplasmic reticulum calcium stores abrogated this response.

T21871

51157-51373

Sentence

denotes

We found that the immediate Ca 2+ response occurred in either the presence or absence of extracellular calcium, but that thapsigargin-induced depletion of endoplasmic reticulum calcium stores abrogated this response.

TextSentencer_T259

51374-51477

Sentence

denotes

In contrast, the delayed type response was pre-vented by removal and chelation of extracellular Ca 2+ .

TextSentencer_T259

51374-51477

Sentence

denotes

In contrast, the delayed type response was pre-vented by removal and chelation of extracellular Ca 2+ .

T10703

51374-51477

Sentence

denotes

In contrast, the delayed type response was pre-vented by removal and chelation of extracellular Ca 2+ .

TextSentencer_T260

51478-51833

Sentence

denotes

Moreover, although the number of cells exhibiting an immediate response to treatment with the O4 monoclonal IgM was not affected by blocking several classes of plasma membrane Ca 2+ channels, pharmacologically blocking the activity of phospholipase C (PLC) significantly decreased the percentage of astrocytes that exhibited elevated intracellular Ca 2+ .

TextSentencer_T260

51478-51833

Sentence

denotes

Moreover, although the number of cells exhibiting an immediate response to treatment with the O4 monoclonal IgM was not affected by blocking several classes of plasma membrane Ca 2+ channels, pharmacologically blocking the activity of phospholipase C (PLC) significantly decreased the percentage of astrocytes that exhibited elevated intracellular Ca 2+ .

T90690

51478-51833

Sentence

denotes

Moreover, although the number of cells exhibiting an immediate response to treatment with the O4 monoclonal IgM was not affected by blocking several classes of plasma membrane Ca 2+ channels, pharmacologically blocking the activity of phospholipase C (PLC) significantly decreased the percentage of astrocytes that exhibited elevated intracellular Ca 2+ .

TextSentencer_T261

51834-52097

Sentence

denotes

In contrast, the delayed Ca 2+ response in oligodendrocytes was not dependent on intracellular stores, but was sensitive to pharmacological inhibition of Ca 2+ flux through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-sensitive glutamate channels .

TextSentencer_T261

51834-52097

Sentence

denotes

In contrast, the delayed Ca 2+ response in oligodendrocytes was not dependent on intracellular stores, but was sensitive to pharmacological inhibition of Ca 2+ flux through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-sensitive glutamate channels .

T90292

51834-52097

Sentence

denotes

In contrast, the delayed Ca 2+ response in oligodendrocytes was not dependent on intracellular stores, but was sensitive to pharmacological inhibition of Ca 2+ flux through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-sensitive glutamate channels .

TextSentencer_T262

52098-52446

Sentence

denotes

These data support the conclusion that the delayed response in oligodendrocytes is dependent on Ca 2+ entry through AMPA receptor Ca 2+ channels, whereas the immediate response in astrocytes is dependent on Ca 2+ release from endoplasmic reticulum stores, likely through PLC-mediated generation of IP 3 and gating of IP 3sensitive calcium channels.

TextSentencer_T262

52098-52446

Sentence

denotes

These data support the conclusion that the delayed response in oligodendrocytes is dependent on Ca 2+ entry through AMPA receptor Ca 2+ channels, whereas the immediate response in astrocytes is dependent on Ca 2+ release from endoplasmic reticulum stores, likely through PLC-mediated generation of IP 3 and gating of IP 3sensitive calcium channels.

T85614

52098-52446

Sentence

denotes

These data support the conclusion that the delayed response in oligodendrocytes is dependent on Ca 2+ entry through AMPA receptor Ca 2+ channels, whereas the immediate response in astrocytes is dependent on Ca 2+ release from endoplasmic reticulum stores, likely through PLC-mediated generation of IP 3 and gating of IP 3sensitive calcium channels.

TextSentencer_T263

52447-52583

Sentence

denotes

We also determined that the antigen-binding domain of remyelination-promoting antibodies is required for Ca 2+ signaling in glial cells.

TextSentencer_T263

52447-52583

Sentence

denotes

We also determined that the antigen-binding domain of remyelination-promoting antibodies is required for Ca 2+ signaling in glial cells.

T47957

52447-52583

Sentence

denotes

We also determined that the antigen-binding domain of remyelination-promoting antibodies is required for Ca 2+ signaling in glial cells.

TextSentencer_T264

52584-52718

Sentence

denotes

As described previously, Theiler's virusinfected mice treated with mouse monoclonal IgM antibody 94.03 exhibit enhanced remyelination.

TextSentencer_T264

52584-52718

Sentence

denotes

As described previously, Theiler's virusinfected mice treated with mouse monoclonal IgM antibody 94.03 exhibit enhanced remyelination.

T67637

52584-52718

Sentence

denotes

As described previously, Theiler's virusinfected mice treated with mouse monoclonal IgM antibody 94.03 exhibit enhanced remyelination.

TextSentencer_T265

52719-53060

Sentence

denotes

In contrast, mice treated with species-and isotype-matched control monoclonal antibody CH12 exhibit fourfold to sixfold less myelin repair, similar to saline treatment; 94.03 and CH12 have greater than 99% amino acid identity, differing only in the third complementarity determining region (CDR3) by five amino acids (Asakura et al., 1998) .

TextSentencer_T265

52719-53060

Sentence

denotes

In contrast, mice treated with species-and isotype-matched control monoclonal antibody CH12 exhibit fourfold to sixfold less myelin repair, similar to saline treatment; 94.03 and CH12 have greater than 99% amino acid identity, differing only in the third complementarity determining region (CDR3) by five amino acids (Asakura et al., 1998) .

T29952

52719-53060

Sentence

denotes

In contrast, mice treated with species-and isotype-matched control monoclonal antibody CH12 exhibit fourfold to sixfold less myelin repair, similar to saline treatment; 94.03 and CH12 have greater than 99% amino acid identity, differing only in the third complementarity determining region (CDR3) by five amino acids (Asakura et al., 1998) .

TextSentencer_T266

53061-53358

Sentence

denotes

The CDR3 is critical in the formation of the antigen-binding domain, and the difference in remyelination potential engendered by the sequence difference between 94.03 and CH12 suggests that antigen specificity, rather than some other component of antibody structure, is required for remyelination.

TextSentencer_T266

53061-53358

Sentence

denotes

The CDR3 is critical in the formation of the antigen-binding domain, and the difference in remyelination potential engendered by the sequence difference between 94.03 and CH12 suggests that antigen specificity, rather than some other component of antibody structure, is required for remyelination.

T97988

53061-53358

Sentence

denotes

The CDR3 is critical in the formation of the antigen-binding domain, and the difference in remyelination potential engendered by the sequence difference between 94.03 and CH12 suggests that antigen specificity, rather than some other component of antibody structure, is required for remyelination.

TextSentencer_T267

53359-53526

Sentence

denotes

Finally, mixed primary glial cultures exposed to SCH 94.03 exhibited a transient rise in [Ca 2+ ] i , while similar cultures exposed to CH12 showed no calcium changes.

TextSentencer_T267

53359-53526

Sentence

denotes

Finally, mixed primary glial cultures exposed to SCH 94.03 exhibited a transient rise in [Ca 2+ ] i , while similar cultures exposed to CH12 showed no calcium changes.

T49011

53359-53526

Sentence

denotes

Finally, mixed primary glial cultures exposed to SCH 94.03 exhibited a transient rise in [Ca 2+ ] i , while similar cultures exposed to CH12 showed no calcium changes.

TextSentencer_T268

53527-53684

Sentence

denotes

Therefore, remyelination-promoting antibody-induced Ca 2+ signaling in glial cells depends on antigen specificity defined by the CDR3 region of the antibody.

TextSentencer_T268

53527-53684

Sentence

denotes

Therefore, remyelination-promoting antibody-induced Ca 2+ signaling in glial cells depends on antigen specificity defined by the CDR3 region of the antibody.

T18843

53527-53684

Sentence

denotes

Therefore, remyelination-promoting antibody-induced Ca 2+ signaling in glial cells depends on antigen specificity defined by the CDR3 region of the antibody.

TextSentencer_T269

53685-53813

Sentence

denotes

Of primary importance, antibody-mediated Ca 2+ signaling in vitro correlated statistically with remyelination promotion in vivo.

TextSentencer_T269

53685-53813

Sentence

denotes

Of primary importance, antibody-mediated Ca 2+ signaling in vitro correlated statistically with remyelination promotion in vivo.

T96560

53685-53813

Sentence

denotes

Of primary importance, antibody-mediated Ca 2+ signaling in vitro correlated statistically with remyelination promotion in vivo.

TextSentencer_T270

53814-54011

Sentence

denotes

To establish a relationship between the ability of an antibody to elicit a Ca 2+ response and its ability to promote remyelination, we studied several remyelinationpromoting and control antibodies.

TextSentencer_T270

53814-54011

Sentence

denotes

To establish a relationship between the ability of an antibody to elicit a Ca 2+ response and its ability to promote remyelination, we studied several remyelinationpromoting and control antibodies.

T11097

53814-54011

Sentence

denotes

To establish a relationship between the ability of an antibody to elicit a Ca 2+ response and its ability to promote remyelination, we studied several remyelinationpromoting and control antibodies.

TextSentencer_T271

54012-54145

Sentence

denotes

Mouse remyelinationpromoting antibodies SCH 94.03, SCH 79.08, and O4 all mediated Ca 2+ responses in astrocytes and oligodendrocytes.

TextSentencer_T271

54012-54145

Sentence

denotes

Mouse remyelinationpromoting antibodies SCH 94.03, SCH 79.08, and O4 all mediated Ca 2+ responses in astrocytes and oligodendrocytes.

T12328

54012-54145

Sentence

denotes

Mouse remyelinationpromoting antibodies SCH 94.03, SCH 79.08, and O4 all mediated Ca 2+ responses in astrocytes and oligodendrocytes.

TextSentencer_T272

54146-54251

Sentence

denotes

The control mouse antibody CH12, which did not promote remyelination, also did not evoke Ca 2+ responses.

TextSentencer_T272

54146-54251

Sentence

denotes

The control mouse antibody CH12, which did not promote remyelination, also did not evoke Ca 2+ responses.

T56631

54146-54251

Sentence

denotes

The control mouse antibody CH12, which did not promote remyelination, also did not evoke Ca 2+ responses.

TextSentencer_T273

54252-54422

Sentence

denotes

Likewise, human remyelination-promoting antibodies sHIgM22, sHIgM46, and CB2BG8 all mediated Ca 2+ responses in astrocytes and oligodendrocytes, whereas the control human

TextSentencer_T273

54252-54422

Sentence

denotes

Likewise, human remyelination-promoting antibodies sHIgM22, sHIgM46, and CB2BG8 all mediated Ca 2+ responses in astrocytes and oligodendrocytes, whereas the control human

T45080

54252-54422

Sentence

denotes

Likewise, human remyelination-promoting antibodies sHIgM22, sHIgM46, and CB2BG8 all mediated Ca 2+ responses in astrocytes and oligodendrocytes, whereas the control human

TextSentencer_T274

54423-54595

Sentence

denotes

Time ( Immediately after treatment with sHIgM22, there is a brief influx of calcium in astrocytes, followed by a slower but transient influx of calcium in oligodendrocytes.

TextSentencer_T274

54423-54595

Sentence

denotes

Time ( Immediately after treatment with sHIgM22, there is a brief influx of calcium in astrocytes, followed by a slower but transient influx of calcium in oligodendrocytes.

T66358

54423-54595

Sentence

denotes

Time ( Immediately after treatment with sHIgM22, there is a brief influx of calcium in astrocytes, followed by a slower but transient influx of calcium in oligodendrocytes.

TextSentencer_T275

54596-54757

Sentence

denotes

Ionophore (Bromo-A23187) induces maximal calcium influx in all cells. (B) Fluorescent image of two cells (8, 9) fluxing calcium in response to sHIgM22 treatment.

TextSentencer_T275

54596-54757

Sentence

denotes

Ionophore (Bromo-A23187) induces maximal calcium influx in all cells. (B) Fluorescent image of two cells (8, 9) fluxing calcium in response to sHIgM22 treatment.

T58816

54596-54757

Sentence

denotes

Ionophore (Bromo-A23187) induces maximal calcium influx in all cells. (B) Fluorescent image of two cells (8, 9) fluxing calcium in response to sHIgM22 treatment.

TextSentencer_T276

54758-54993

Sentence

denotes

It is important to note that after treatment with antibody, calcium levels return to baseline, suggesting that the calcium influx is not toxic but is rather an element in a specific signal transduction cascade elicited by the antibody.

TextSentencer_T276

54758-54993

Sentence

denotes

It is important to note that after treatment with antibody, calcium levels return to baseline, suggesting that the calcium influx is not toxic but is rather an element in a specific signal transduction cascade elicited by the antibody.

T75829

54758-54993

Sentence

denotes

It is important to note that after treatment with antibody, calcium levels return to baseline, suggesting that the calcium influx is not toxic but is rather an element in a specific signal transduction cascade elicited by the antibody.

TextSentencer_T277

54994-55111

Sentence

denotes

antibodies sHIgM12, sHIgM14, sHIgM47, and AKJR4, which did not promote remyelination, did not evoke Ca 2+ responses .

TextSentencer_T277

54994-55111

Sentence

denotes

antibodies sHIgM12, sHIgM14, sHIgM47, and AKJR4, which did not promote remyelination, did not evoke Ca 2+ responses .

T25348

54994-55111

Sentence

denotes

antibodies sHIgM12, sHIgM14, sHIgM47, and AKJR4, which did not promote remyelination, did not evoke Ca 2+ responses .

TextSentencer_T278

55112-55352

Sentence

denotes

Thus, there appears to be a high degree of correlation between the ability of monoclonal IgM antibodies to promote remyelination and the stimulation of calcium influx, suggesting a potential signaling connection between these two phenomena.

TextSentencer_T278

55112-55352

Sentence

denotes

Thus, there appears to be a high degree of correlation between the ability of monoclonal IgM antibodies to promote remyelination and the stimulation of calcium influx, suggesting a potential signaling connection between these two phenomena.

T29674

55112-55352

Sentence

denotes

Thus, there appears to be a high degree of correlation between the ability of monoclonal IgM antibodies to promote remyelination and the stimulation of calcium influx, suggesting a potential signaling connection between these two phenomena.

TextSentencer_T279

55353-55623

Sentence

denotes

Further evidence in support of a causal link between calcium signaling and remyelination is provided by experiments showing that rHIgM22 elicits a transient elevation in intracellular calcium in CG4 cells, a model of premyelinating oligodendrocytes (Howe et al., 2004) .

TextSentencer_T279

55353-55623

Sentence

denotes

Further evidence in support of a causal link between calcium signaling and remyelination is provided by experiments showing that rHIgM22 elicits a transient elevation in intracellular calcium in CG4 cells, a model of premyelinating oligodendrocytes (Howe et al., 2004) .

T44527

55353-55623

Sentence

denotes

Further evidence in support of a causal link between calcium signaling and remyelination is provided by experiments showing that rHIgM22 elicits a transient elevation in intracellular calcium in CG4 cells, a model of premyelinating oligodendrocytes (Howe et al., 2004) .

TextSentencer_T280

55624-55784

Sentence

denotes

As with primary oligodendrocytes, we found that this calcium signal was dependent on the influx of extracellular calcium through AMPA receptor calcium channels.

TextSentencer_T280

55624-55784

Sentence

denotes

As with primary oligodendrocytes, we found that this calcium signal was dependent on the influx of extracellular calcium through AMPA receptor calcium channels.

T86116

55624-55784

Sentence

denotes

As with primary oligodendrocytes, we found that this calcium signal was dependent on the influx of extracellular calcium through AMPA receptor calcium channels.

TextSentencer_T281

55785-56023

Sentence

denotes

More importantly, we showed that rHIgM22 was able to rescue CG4 cells from death induced by either hydrogen peroxide or TNFα, and that this rescue was dependent on calcium flux through CNQX-sensitive calcium channels (Howe et al., 2004) .

TextSentencer_T281

55785-56023

Sentence

denotes

More importantly, we showed that rHIgM22 was able to rescue CG4 cells from death induced by either hydrogen peroxide or TNFα, and that this rescue was dependent on calcium flux through CNQX-sensitive calcium channels (Howe et al., 2004) .

T52912

55785-56023

Sentence

denotes

More importantly, we showed that rHIgM22 was able to rescue CG4 cells from death induced by either hydrogen peroxide or TNFα, and that this rescue was dependent on calcium flux through CNQX-sensitive calcium channels (Howe et al., 2004) .

TextSentencer_T282

56024-56154

Sentence

denotes

Biochemically, rHIgM22 appears to block cell death by preventing c-jun N-terminal kinase (JNK) signaling and caspase-3 activation.

TextSentencer_T282

56024-56154

Sentence

denotes

Biochemically, rHIgM22 appears to block cell death by preventing c-jun N-terminal kinase (JNK) signaling and caspase-3 activation.

T50844

56024-56154

Sentence

denotes

Biochemically, rHIgM22 appears to block cell death by preventing c-jun N-terminal kinase (JNK) signaling and caspase-3 activation.

TextSentencer_T283

56155-56468

Sentence

denotes

In support of this model for rHIgM22 survival signaling, we also found that antibody treatment of SJL mice chronically infected with Theiler's virus led to a significant decrease in caspase family gene expression and caspase-3 activity within demyelinated lesions of the cervical spinal cord (Howe et al., 2004) .

TextSentencer_T283

56155-56468

Sentence

denotes

In support of this model for rHIgM22 survival signaling, we also found that antibody treatment of SJL mice chronically infected with Theiler's virus led to a significant decrease in caspase family gene expression and caspase-3 activity within demyelinated lesions of the cervical spinal cord (Howe et al., 2004) .

T78384

56155-56468

Sentence

denotes

In support of this model for rHIgM22 survival signaling, we also found that antibody treatment of SJL mice chronically infected with Theiler's virus led to a significant decrease in caspase family gene expression and caspase-3 activity within demyelinated lesions of the cervical spinal cord (Howe et al., 2004) .

TextSentencer_T284

56469-56775

Sentence

denotes

As rHIgM22 induced substantial remyelination in these animals, we concluded that rHIgM22-induced calcium signaling blocked caspase-3 activation in premyelinating oligodendrocytes and thereby promoted their survival and consequent differentiation into myelin-producing oligodendrocytes (Howe et al., 2004) .

TextSentencer_T284

56469-56775

Sentence

denotes

As rHIgM22 induced substantial remyelination in these animals, we concluded that rHIgM22-induced calcium signaling blocked caspase-3 activation in premyelinating oligodendrocytes and thereby promoted their survival and consequent differentiation into myelin-producing oligodendrocytes (Howe et al., 2004) .

T98527

56469-56775

Sentence

denotes

As rHIgM22 induced substantial remyelination in these animals, we concluded that rHIgM22-induced calcium signaling blocked caspase-3 activation in premyelinating oligodendrocytes and thereby promoted their survival and consequent differentiation into myelin-producing oligodendrocytes (Howe et al., 2004) .

TextSentencer_T285

56776-57088

Sentence

denotes

Another important clue as to the mechanism of remyelination-promoting antibody action was provided by experiments showing that the ability of rHIgM22 to induce calcium influx and rescue CG4 cells from death was dependent on the integrity of lipid rafts in the plasma membrane of these cells (Howe et al., 2004) .

TextSentencer_T285

56776-57088

Sentence

denotes

Another important clue as to the mechanism of remyelination-promoting antibody action was provided by experiments showing that the ability of rHIgM22 to induce calcium influx and rescue CG4 cells from death was dependent on the integrity of lipid rafts in the plasma membrane of these cells (Howe et al., 2004) .

T97413

56776-57088

Sentence

denotes

Another important clue as to the mechanism of remyelination-promoting antibody action was provided by experiments showing that the ability of rHIgM22 to induce calcium influx and rescue CG4 cells from death was dependent on the integrity of lipid rafts in the plasma membrane of these cells (Howe et al., 2004) .

TextSentencer_T286

57089-57415

Sentence

denotes

Treatment with β-methylcyclodextrin, a cholesterol-chelating compound that effectively destroys lipid raft structure, prevented rHIgM22-induced survival signaling, suggesting that perhaps redistribution or aggregation of lipid raft domains is necessary for antibody-mediated signal transduction (Howe et al., 2004) (Fig. 20) .

TextSentencer_T286

57089-57415

Sentence

denotes

Treatment with β-methylcyclodextrin, a cholesterol-chelating compound that effectively destroys lipid raft structure, prevented rHIgM22-induced survival signaling, suggesting that perhaps redistribution or aggregation of lipid raft domains is necessary for antibody-mediated signal transduction (Howe et al., 2004) (Fig. 20) .

T85652

57089-57415

Sentence

denotes

Treatment with β-methylcyclodextrin, a cholesterol-chelating compound that effectively destroys lipid raft structure, prevented rHIgM22-induced survival signaling, suggesting that perhaps redistribution or aggregation of lipid raft domains is necessary for antibody-mediated signal transduction (Howe et al., 2004) (Fig. 20) .

TextSentencer_T287

57416-57704

Sentence

denotes

This hypothesis is further supported by evidence that monovalent forms of sHIgM22 are unable to elicit remyelination or calcium signaling , suggesting that multivalency, and therefore oligomerization of cognate antigen, is necessary for the function of remyelination-promoting antibodies.

TextSentencer_T287

57416-57704

Sentence

denotes

This hypothesis is further supported by evidence that monovalent forms of sHIgM22 are unable to elicit remyelination or calcium signaling , suggesting that multivalency, and therefore oligomerization of cognate antigen, is necessary for the function of remyelination-promoting antibodies.

T33435

57416-57704

Sentence

denotes

This hypothesis is further supported by evidence that monovalent forms of sHIgM22 are unable to elicit remyelination or calcium signaling , suggesting that multivalency, and therefore oligomerization of cognate antigen, is necessary for the function of remyelination-promoting antibodies.

TextSentencer_T288

57705-58039

Sentence

denotes

In fact, on the basis of the evidence at hand regarding antibodyinduced signaling, we hypothesize that remyelination-promoting antibodies function as soluble initiators of the type of clustering and consequent signaling described for integrins and proteoglycans involved in cell-cell adhesion and contactmediated signaling (Fig. 21 ).

TextSentencer_T288

57705-58039

Sentence

denotes

In fact, on the basis of the evidence at hand regarding antibodyinduced signaling, we hypothesize that remyelination-promoting antibodies function as soluble initiators of the type of clustering and consequent signaling described for integrins and proteoglycans involved in cell-cell adhesion and contactmediated signaling (Fig. 21 ).

T62761

57705-58039

Sentence

denotes

In fact, on the basis of the evidence at hand regarding antibodyinduced signaling, we hypothesize that remyelination-promoting antibodies function as soluble initiators of the type of clustering and consequent signaling described for integrins and proteoglycans involved in cell-cell adhesion and contactmediated signaling (Fig. 21 ).

TextSentencer_T289

58040-58216

Sentence

denotes

Integrins and cell surface proteoglycans are associated with plasma membrane lipid raft microdomains and with the oligomeric scaffolding protein caveolin (Baron et al., 2003) .

TextSentencer_T289

58040-58216

Sentence

denotes

Integrins and cell surface proteoglycans are associated with plasma membrane lipid raft microdomains and with the oligomeric scaffolding protein caveolin (Baron et al., 2003) .

T92818

58040-58216

Sentence

denotes

Integrins and cell surface proteoglycans are associated with plasma membrane lipid raft microdomains and with the oligomeric scaffolding protein caveolin (Baron et al., 2003) .

TextSentencer_T290

58217-58363

Sentence

denotes

Therefore, lipid rafts, enriched in a number of receptor and nonreceptor kinases, serve as a locus of integrin-and proteoglycan-related signaling.

TextSentencer_T290

58217-58363

Sentence

denotes

Therefore, lipid rafts, enriched in a number of receptor and nonreceptor kinases, serve as a locus of integrin-and proteoglycan-related signaling.

T75239

58217-58363

Sentence

denotes

Therefore, lipid rafts, enriched in a number of receptor and nonreceptor kinases, serve as a locus of integrin-and proteoglycan-related signaling.

TextSentencer_T291

58364-58718

Sentence

denotes

As a result of clustering induced by binding to extracellular matrix elements, integrin-associated structural and signaling molecules are also clustered within lipid raft domains, and the resulting increase in density and proximity of these molecules results in the initiation of several important signals (Harder et al., 1998; Harder and Simons, 1997) .

TextSentencer_T291

58364-58718

Sentence

denotes

As a result of clustering induced by binding to extracellular matrix elements, integrin-associated structural and signaling molecules are also clustered within lipid raft domains, and the resulting increase in density and proximity of these molecules results in the initiation of several important signals (Harder et al., 1998; Harder and Simons, 1997) .

T27701

58364-58718

Sentence

denotes

As a result of clustering induced by binding to extracellular matrix elements, integrin-associated structural and signaling molecules are also clustered within lipid raft domains, and the resulting increase in density and proximity of these molecules results in the initiation of several important signals (Harder et al., 1998; Harder and Simons, 1997) .

TextSentencer_T292

58719-58946

Sentence

denotes

The reorganization of actin filaments into stress fibers occurs at the focal point of this clustering activity, and results in a positive feedback loop that encourages further integrin and proteoglycan clustering and signaling.

TextSentencer_T292

58719-58946

Sentence

denotes

The reorganization of actin filaments into stress fibers occurs at the focal point of this clustering activity, and results in a positive feedback loop that encourages further integrin and proteoglycan clustering and signaling.

T4221

58719-58946

Sentence

denotes

The reorganization of actin filaments into stress fibers occurs at the focal point of this clustering activity, and results in a positive feedback loop that encourages further integrin and proteoglycan clustering and signaling.

TextSentencer_T293

58947-59131

Sentence

denotes

These focal adhesions are highly enriched in signaling molecules such as FAK (focal adhesion kinase) and members of the Src-family of nonreceptor tyrosine kinase (Hanks et al., 2003) .

TextSentencer_T293

58947-59131

Sentence

denotes

These focal adhesions are highly enriched in signaling molecules such as FAK (focal adhesion kinase) and members of the Src-family of nonreceptor tyrosine kinase (Hanks et al., 2003) .

T30638

58947-59131

Sentence

denotes

These focal adhesions are highly enriched in signaling molecules such as FAK (focal adhesion kinase) and members of the Src-family of nonreceptor tyrosine kinase (Hanks et al., 2003) .

TextSentencer_T294

59132-59281

Sentence

denotes

FAK is recruited to integrin clusters either through direct interaction with the integrin β subunit or via interaction with reorganized actin fibers.

TextSentencer_T294

59132-59281

Sentence

denotes

FAK is recruited to integrin clusters either through direct interaction with the integrin β subunit or via interaction with reorganized actin fibers.

T16462

59132-59281

Sentence

denotes

FAK is recruited to integrin clusters either through direct interaction with the integrin β subunit or via interaction with reorganized actin fibers.

TextSentencer_T295

59282-59478

Sentence

denotes

Activated FAK in turn activates phosphoinositide-3 kinase (PI3-K), Src, and elements of the mitogen-activated protein kinase (MAPK) cascades (Bernfield et al., 1999; Bokoch, 2003; Juliano, 2002) .

TextSentencer_T295

59282-59478

Sentence

denotes

Activated FAK in turn activates phosphoinositide-3 kinase (PI3-K), Src, and elements of the mitogen-activated protein kinase (MAPK) cascades (Bernfield et al., 1999; Bokoch, 2003; Juliano, 2002) .

T78991

59282-59478

Sentence

denotes

Activated FAK in turn activates phosphoinositide-3 kinase (PI3-K), Src, and elements of the mitogen-activated protein kinase (MAPK) cascades (Bernfield et al., 1999; Bokoch, 2003; Juliano, 2002) .

TextSentencer_T296

59479-59640

Sentence

denotes

Likewise, lipid raft clustering leads to signaling through the myristoylated and palmitoylated Src-family kinases Src, Fyn, Yes, and Lck (Hoessli et al., 2000) .

TextSentencer_T296

59479-59640

Sentence

denotes

Likewise, lipid raft clustering leads to signaling through the myristoylated and palmitoylated Src-family kinases Src, Fyn, Yes, and Lck (Hoessli et al., 2000) .

T38397

59479-59640

Sentence

denotes

Likewise, lipid raft clustering leads to signaling through the myristoylated and palmitoylated Src-family kinases Src, Fyn, Yes, and Lck (Hoessli et al., 2000) .

TextSentencer_T297

59641-59787

Sentence

denotes

These nonreceptor tyrosine kinases are activated by clustering, and they initiate signaling cascades that result in activation of the MAPK Erk1/2.

TextSentencer_T297

59641-59787

Sentence

denotes

These nonreceptor tyrosine kinases are activated by clustering, and they initiate signaling cascades that result in activation of the MAPK Erk1/2.

T53642

59641-59787

Sentence

denotes

These nonreceptor tyrosine kinases are activated by clustering, and they initiate signaling cascades that result in activation of the MAPK Erk1/2.

TextSentencer_T298

59788-59967

Sentence

denotes

Erk1/2 signaling results in phosphorylation of elements of the ternary complex factor, and thus promotes transcription of the immediate early gene c-fos (Sofroniew et al., 2001) .

TextSentencer_T298

59788-59967

Sentence

denotes

Erk1/2 signaling results in phosphorylation of elements of the ternary complex factor, and thus promotes transcription of the immediate early gene c-fos (Sofroniew et al., 2001) .

T89960

59788-59967

Sentence

denotes

Erk1/2 signaling results in phosphorylation of elements of the ternary complex factor, and thus promotes transcription of the immediate early gene c-fos (Sofroniew et al., 2001) .

TextSentencer_T299

59968-60200

Sentence

denotes

In parallel, lipid raft clustering of integrins and proteoglycans engages the MAPK JNK, leading to phosphorylation of the transcription factor c-jun, and association of c-jun with c-fos to form the AP-1 transcription factor complex.

TextSentencer_T299

59968-60200

Sentence

denotes

In parallel, lipid raft clustering of integrins and proteoglycans engages the MAPK JNK, leading to phosphorylation of the transcription factor c-jun, and association of c-jun with c-fos to form the AP-1 transcription factor complex.

T43515

59968-60200

Sentence

denotes

In parallel, lipid raft clustering of integrins and proteoglycans engages the MAPK JNK, leading to phosphorylation of the transcription factor c-jun, and association of c-jun with c-fos to form the AP-1 transcription factor complex.

TextSentencer_T300

60201-60291

Sentence

denotes

This complex is a critical regulator of genes involved in cell proliferation (Lin, 2003) .

TextSentencer_T300

60201-60291

Sentence

denotes

This complex is a critical regulator of genes involved in cell proliferation (Lin, 2003) .

T18482

60201-60291

Sentence

denotes

This complex is a critical regulator of genes involved in cell proliferation (Lin, 2003) .

TextSentencer_T301

60292-60526

Sentence

denotes

Likewise, clusteringinduced activation of FAK and PI3-K leads to signaling through Akt, a protein kinase that promotes survival by phosphorylating and inactivating the proapoptotic proteins Bad and caspase-9 (Sofroniew et al., 2001) .

TextSentencer_T301

60292-60526

Sentence

denotes

Likewise, clusteringinduced activation of FAK and PI3-K leads to signaling through Akt, a protein kinase that promotes survival by phosphorylating and inactivating the proapoptotic proteins Bad and caspase-9 (Sofroniew et al., 2001) .

T67736

60292-60526

Sentence

denotes

Likewise, clusteringinduced activation of FAK and PI3-K leads to signaling through Akt, a protein kinase that promotes survival by phosphorylating and inactivating the proapoptotic proteins Bad and caspase-9 (Sofroniew et al., 2001) .

TextSentencer_T302

60527-60704

Sentence

denotes

Finally, lipid raft clustering of integrins in response to extracellular matrix binding results in the activation of the Rho family of small guanine nucleotide-binding proteins.

TextSentencer_T302

60527-60704

Sentence

denotes

Finally, lipid raft clustering of integrins in response to extracellular matrix binding results in the activation of the Rho family of small guanine nucleotide-binding proteins.

T9467

60527-60704

Sentence

denotes

Finally, lipid raft clustering of integrins in response to extracellular matrix binding results in the activation of the Rho family of small guanine nucleotide-binding proteins.

TextSentencer_T303

60705-60854

Sentence

denotes

These molecules include Rac, Cdc42, and RhoA, which are involved in induction of filopodia and formation of focal adhesions (Kaibuchi et al., 1999) .

TextSentencer_T303

60705-60854

Sentence

denotes

These molecules include Rac, Cdc42, and RhoA, which are involved in induction of filopodia and formation of focal adhesions (Kaibuchi et al., 1999) .

T98059

60705-60854

Sentence

denotes

These molecules include Rac, Cdc42, and RhoA, which are involved in induction of filopodia and formation of focal adhesions (Kaibuchi et al., 1999) .

TextSentencer_T304

60855-61024

Sentence

denotes

An additional signaling mechanism invoked by clustering of integrins within lipid rafts involves the concomitant aggregation of growth factor receptors and ion channels.

TextSentencer_T304

60855-61024

Sentence

denotes

An additional signaling mechanism invoked by clustering of integrins within lipid rafts involves the concomitant aggregation of growth factor receptors and ion channels.

T30044

60855-61024

Sentence

denotes

An additional signaling mechanism invoked by clustering of integrins within lipid rafts involves the concomitant aggregation of growth factor receptors and ion channels.

TextSentencer_T305

61025-61157

Sentence

denotes

Aggregation of growth factor receptors results in partial activation via proximity-dependent transphosphorylation (Ferguson, 2003) .

TextSentencer_T305

61025-61157

Sentence

denotes

Aggregation of growth factor receptors results in partial activation via proximity-dependent transphosphorylation (Ferguson, 2003) .

T45204

61025-61157

Sentence

denotes

Aggregation of growth factor receptors results in partial activation via proximity-dependent transphosphorylation (Ferguson, 2003) .

TextSentencer_T306

61158-61509

Sentence

denotes

This partial activation brings the growth Stacking of the individual images shows the relative "patchiness" of the rHIgM22 staining pattern, suggesting that rHIgM22 antigen is localized to a specific plasma membrane microdomain. (F) rHIgM22 rescues premyelinating oligodendrocytes from death induced by treatment with hydrogen peroxide for 30 minutes.

TextSentencer_T306

61158-61509

Sentence

denotes

This partial activation brings the growth Stacking of the individual images shows the relative "patchiness" of the rHIgM22 staining pattern, suggesting that rHIgM22 antigen is localized to a specific plasma membrane microdomain. (F) rHIgM22 rescues premyelinating oligodendrocytes from death induced by treatment with hydrogen peroxide for 30 minutes.

T95307

61158-61509

Sentence

denotes

This partial activation brings the growth Stacking of the individual images shows the relative "patchiness" of the rHIgM22 staining pattern, suggesting that rHIgM22 antigen is localized to a specific plasma membrane microdomain. (F) rHIgM22 rescues premyelinating oligodendrocytes from death induced by treatment with hydrogen peroxide for 30 minutes.

TextSentencer_T307

61510-61913

Sentence

denotes

Cholesterol chelation with methyl-β-cyclodextrin (β-MCD) completely abrogates the protective effect of rHIgM22, suggesting that signaling from lipid rafts is critical for the ability of rHIgM22 to rescue oligodendrocytes from oxidative stress-induced apoptosis. β-MCD rHIgM22 + β-MCD F factor receptors closer to a threshold for full activation induced by substantially less extracellular growth factor.

TextSentencer_T307

61510-61913

Sentence

denotes

Cholesterol chelation with methyl-β-cyclodextrin (β-MCD) completely abrogates the protective effect of rHIgM22, suggesting that signaling from lipid rafts is critical for the ability of rHIgM22 to rescue oligodendrocytes from oxidative stress-induced apoptosis. β-MCD rHIgM22 + β-MCD F factor receptors closer to a threshold for full activation induced by substantially less extracellular growth factor.

T77594

61510-61913

Sentence

denotes

Cholesterol chelation with methyl-β-cyclodextrin (β-MCD) completely abrogates the protective effect of rHIgM22, suggesting that signaling from lipid rafts is critical for the ability of rHIgM22 to rescue oligodendrocytes from oxidative stress-induced apoptosis. β-MCD rHIgM22 + β-MCD F factor receptors closer to a threshold for full activation induced by substantially less extracellular growth factor.

TextSentencer_T308

61914-62164

Sentence

denotes

For example, PDGFα receptors (PDGFR) are sequestered in lipid rafts of oligodendrocytes committed to terminal differentiation, and PDGFR signaling from these rafts is required for survival of oligodendrocytes (Frost et al., 2003; Park et al., 2001) .

TextSentencer_T308

61914-62164

Sentence

denotes

For example, PDGFα receptors (PDGFR) are sequestered in lipid rafts of oligodendrocytes committed to terminal differentiation, and PDGFR signaling from these rafts is required for survival of oligodendrocytes (Frost et al., 2003; Park et al., 2001) .

T82302

61914-62164

Sentence

denotes

For example, PDGFα receptors (PDGFR) are sequestered in lipid rafts of oligodendrocytes committed to terminal differentiation, and PDGFR signaling from these rafts is required for survival of oligodendrocytes (Frost et al., 2003; Park et al., 2001) .

TextSentencer_T309

62165-62333

Sentence

denotes

Likewise, axonal laminin-2 provides a targetdependent survival signal for differentiating oligodendrocytes via signaling through the lipid raft localized α6β1 integrin.

TextSentencer_T309

62165-62333

Sentence

denotes

Likewise, axonal laminin-2 provides a targetdependent survival signal for differentiating oligodendrocytes via signaling through the lipid raft localized α6β1 integrin.

T91942

62165-62333

Sentence

denotes

Likewise, axonal laminin-2 provides a targetdependent survival signal for differentiating oligodendrocytes via signaling through the lipid raft localized α6β1 integrin.

TextSentencer_T310

62334-62502

Sentence

denotes

Laminin-induced clustering of integrin within lipid rafts leads to substantial amplification of PI3-K and Akt signaling downstream from the PDGFR (Baron et al., 2003) .

TextSentencer_T310

62334-62502

Sentence

denotes

Laminin-induced clustering of integrin within lipid rafts leads to substantial amplification of PI3-K and Akt signaling downstream from the PDGFR (Baron et al., 2003) .

T34994

62334-62502

Sentence

denotes

Laminin-induced clustering of integrin within lipid rafts leads to substantial amplification of PI3-K and Akt signaling downstream from the PDGFR (Baron et al., 2003) .

TextSentencer_T311

62503-62696

Sentence

denotes

Therefore, lipid raft microdomain-localized clustering of integrins and subsequent amplification of growth factor receptor signaling is an important signaling mechanism within oligodendrocytes.

TextSentencer_T311

62503-62696

Sentence

denotes

Therefore, lipid raft microdomain-localized clustering of integrins and subsequent amplification of growth factor receptor signaling is an important signaling mechanism within oligodendrocytes.

T29856

62503-62696

Sentence

denotes

Therefore, lipid raft microdomain-localized clustering of integrins and subsequent amplification of growth factor receptor signaling is an important signaling mechanism within oligodendrocytes.

TextSentencer_T312

62697-63017

Sentence

denotes

Similarly, integrin clustering within lipid rafts leads to a signaling cascade that uses Src and calcium calmodulin-dependent protein kinase II (CaMKII) activation to phosphorylate AMPA receptors, resulting in a slow-building potentiation of calcium flux through the AMPA receptor calcium channel (Kramar et al., 2003) .

TextSentencer_T312

62697-63017

Sentence

denotes

Similarly, integrin clustering within lipid rafts leads to a signaling cascade that uses Src and calcium calmodulin-dependent protein kinase II (CaMKII) activation to phosphorylate AMPA receptors, resulting in a slow-building potentiation of calcium flux through the AMPA receptor calcium channel (Kramar et al., 2003) .

T28316

62697-63017

Sentence

denotes

Similarly, integrin clustering within lipid rafts leads to a signaling cascade that uses Src and calcium calmodulin-dependent protein kinase II (CaMKII) activation to phosphorylate AMPA receptors, resulting in a slow-building potentiation of calcium flux through the AMPA receptor calcium channel (Kramar et al., 2003) .

TextSentencer_T313

63018-63202

Sentence

denotes

Clustering of oligodendrocyte cell surface proteoglycans within lipid raft microdomains initiates many of the same signaling events as integrin clustering (Simons and Horowitz, 2001) .

TextSentencer_T313

63018-63202

Sentence

denotes

Clustering of oligodendrocyte cell surface proteoglycans within lipid raft microdomains initiates many of the same signaling events as integrin clustering (Simons and Horowitz, 2001) .

T332

63018-63202

Sentence

denotes

Clustering of oligodendrocyte cell surface proteoglycans within lipid raft microdomains initiates many of the same signaling events as integrin clustering (Simons and Horowitz, 2001) .

TextSentencer_T314

63203-63447

Sentence

denotes

For example, syndecan-4 is a transmembrane heparan sulfate proteoglycan that is recruited to focal adhesions in response to extracellular matrix-dependent clustering or antibody-induced clustering (Lim et al., 2003; Tkachenko and Simons 2002) .

TextSentencer_T314

63203-63447

Sentence

denotes

For example, syndecan-4 is a transmembrane heparan sulfate proteoglycan that is recruited to focal adhesions in response to extracellular matrix-dependent clustering or antibody-induced clustering (Lim et al., 2003; Tkachenko and Simons 2002) .

T60357

63203-63447

Sentence

denotes

For example, syndecan-4 is a transmembrane heparan sulfate proteoglycan that is recruited to focal adhesions in response to extracellular matrix-dependent clustering or antibody-induced clustering (Lim et al., 2003; Tkachenko and Simons 2002) .

TextSentencer_T315

63448-63579

Sentence

denotes

Syndecan-4 signals through protein kinase Cα (PKCα) by potentiating its response to phosphatidylinositol 4,5-bisphosphate (PIP 2 ).

TextSentencer_T315

63448-63579

Sentence

denotes

Syndecan-4 signals through protein kinase Cα (PKCα) by potentiating its response to phosphatidylinositol 4,5-bisphosphate (PIP 2 ).

T1669

63448-63579

Sentence

denotes

Syndecan-4 signals through protein kinase Cα (PKCα) by potentiating its response to phosphatidylinositol 4,5-bisphosphate (PIP 2 ).

TextSentencer_T316

63580-63838

Sentence

denotes

This potentiation is accomplished by a clustering-dependent increase in the association of syndecan-4 with both PIP 2 and PKCα, resulting in the formation of a multimeric ternary complex of these three molecules (Bass and Humphries, 2002; Lim et al., 2003) .

TextSentencer_T316

63580-63838

Sentence

denotes

This potentiation is accomplished by a clustering-dependent increase in the association of syndecan-4 with both PIP 2 and PKCα, resulting in the formation of a multimeric ternary complex of these three molecules (Bass and Humphries, 2002; Lim et al., 2003) .

T59071

63580-63838

Sentence

denotes

This potentiation is accomplished by a clustering-dependent increase in the association of syndecan-4 with both PIP 2 and PKCα, resulting in the formation of a multimeric ternary complex of these three molecules (Bass and Humphries, 2002; Lim et al., 2003) .

TextSentencer_T317

63839-64056

Sentence

denotes

Syndecan-4 clustering also induces the activation of Rho family GTPases and FAK, leading to substantial reorganization of the actin cytoskeleton downstream from syndecan-4 multimerization (Yoneda and Couchman, 2003) .

TextSentencer_T317

63839-64056

Sentence

denotes

Syndecan-4 clustering also induces the activation of Rho family GTPases and FAK, leading to substantial reorganization of the actin cytoskeleton downstream from syndecan-4 multimerization (Yoneda and Couchman, 2003) .

T88857

63839-64056

Sentence

denotes

Syndecan-4 clustering also induces the activation of Rho family GTPases and FAK, leading to substantial reorganization of the actin cytoskeleton downstream from syndecan-4 multimerization (Yoneda and Couchman, 2003) .

TextSentencer_T318

64057-64181

Sentence

denotes

Proteoglycan clustering within lipid raft microdomains also results in substantial modification of calcium channel activity.

TextSentencer_T318

64057-64181

Sentence

denotes

Proteoglycan clustering within lipid raft microdomains also results in substantial modification of calcium channel activity.

T40941

64057-64181

Sentence

denotes

Proteoglycan clustering within lipid raft microdomains also results in substantial modification of calcium channel activity.

TextSentencer_T319

64182-64304

Sentence

denotes

NG2 is a transmembrane proteoglycan that is enriched on the surface of oligodendrocyte progenitors (Dawson et al., 2000) .

TextSentencer_T319

64182-64304

Sentence

denotes

NG2 is a transmembrane proteoglycan that is enriched on the surface of oligodendrocyte progenitors (Dawson et al., 2000) .

T56019

64182-64304

Sentence

denotes

NG2 is a transmembrane proteoglycan that is enriched on the surface of oligodendrocyte progenitors (Dawson et al., 2000) .

TextSentencer_T320

64305-64455

Sentence

denotes

This proteoglycan associates with the glutamate receptor interaction protein (GRIP1) via a PDZ domain-mediated interaction (Stegmuller et al., 2003) .

TextSentencer_T320

64305-64455

Sentence

denotes

This proteoglycan associates with the glutamate receptor interaction protein (GRIP1) via a PDZ domain-mediated interaction (Stegmuller et al., 2003) .

T76144

64305-64455

Sentence

denotes

This proteoglycan associates with the glutamate receptor interaction protein (GRIP1) via a PDZ domain-mediated interaction (Stegmuller et al., 2003) .

TextSentencer_T321

64456-64645

Sentence

denotes

As a result of this molecular linkage, NG2 is indirectly associated with the AMPA receptor within lipid rafts of oligodendrocyte progenitors (Hering et al., 2003; Stegmuller et al., 2003) .

TextSentencer_T321

64456-64645

Sentence

denotes

As a result of this molecular linkage, NG2 is indirectly associated with the AMPA receptor within lipid rafts of oligodendrocyte progenitors (Hering et al., 2003; Stegmuller et al., 2003) .

T62103

64456-64645

Sentence

denotes

As a result of this molecular linkage, NG2 is indirectly associated with the AMPA receptor within lipid rafts of oligodendrocyte progenitors (Hering et al., 2003; Stegmuller et al., 2003) .

TextSentencer_T322

64646-64953

Sentence

denotes

Immature oligodendrocyte AMPA channels are involved in regulation of proliferation and differentiation (Yuan et al., 1998) , and the association of AMPA channels with NG2 suggests that adhesion-mediated clustering of NG2 may modify glial calcium signaling and thereby control maturation of oligodendrocytes.

TextSentencer_T322

64646-64953

Sentence

denotes

Immature oligodendrocyte AMPA channels are involved in regulation of proliferation and differentiation (Yuan et al., 1998) , and the association of AMPA channels with NG2 suggests that adhesion-mediated clustering of NG2 may modify glial calcium signaling and thereby control maturation of oligodendrocytes.

T38286

64646-64953

Sentence

denotes

Immature oligodendrocyte AMPA channels are involved in regulation of proliferation and differentiation (Yuan et al., 1998) , and the association of AMPA channels with NG2 suggests that adhesion-mediated clustering of NG2 may modify glial calcium signaling and thereby control maturation of oligodendrocytes.

TextSentencer_T323

64954-65248

Sentence

denotes

It is interesting to note that AMPA channel function is substantially modified by lectin binding, and concanavalin A binding leads to desensitization of the AMPA channel and a consequent increase in calcium permeability in the absence of changes in glutamate binding (Thalhammer et al., 2002) .

TextSentencer_T323

64954-65248

Sentence

denotes

It is interesting to note that AMPA channel function is substantially modified by lectin binding, and concanavalin A binding leads to desensitization of the AMPA channel and a consequent increase in calcium permeability in the absence of changes in glutamate binding (Thalhammer et al., 2002) .

T51747

64954-65248

Sentence

denotes

It is interesting to note that AMPA channel function is substantially modified by lectin binding, and concanavalin A binding leads to desensitization of the AMPA channel and a consequent increase in calcium permeability in the absence of changes in glutamate binding (Thalhammer et al., 2002) .

TextSentencer_T324

65249-65447

Sentence

denotes

Moreover, sialidase treatment modulates AMPA function by alleviating desensitization, and this effect is indirect, as sialic acid residues are not found on the AMPA receptor (Hoffman et al., 1997) .

TextSentencer_T324

65249-65447

Sentence

denotes

Moreover, sialidase treatment modulates AMPA function by alleviating desensitization, and this effect is indirect, as sialic acid residues are not found on the AMPA receptor (Hoffman et al., 1997) .

T81981

65249-65447

Sentence

denotes

Moreover, sialidase treatment modulates AMPA function by alleviating desensitization, and this effect is indirect, as sialic acid residues are not found on the AMPA receptor (Hoffman et al., 1997) .

TextSentencer_T325

65448-65646

Sentence

denotes

Because NG2 does bear sialic acid residues, it is reasonable to speculate that the effect of deglycosylation or lectin binding is mediated by an alteration in NG2 association with the AMPA receptor.

TextSentencer_T325

65448-65646

Sentence

denotes

Because NG2 does bear sialic acid residues, it is reasonable to speculate that the effect of deglycosylation or lectin binding is mediated by an alteration in NG2 association with the AMPA receptor.

T36880

65448-65646

Sentence

denotes

Because NG2 does bear sialic acid residues, it is reasonable to speculate that the effect of deglycosylation or lectin binding is mediated by an alteration in NG2 association with the AMPA receptor.

TextSentencer_T326

65647-65811

Sentence

denotes

Therefore, as with integrins, multimerization of proteoglycans is an important modulator of oligodendrocyte signaling, survival, proliferation, and differentiation.

TextSentencer_T326

65647-65811

Sentence

denotes

Therefore, as with integrins, multimerization of proteoglycans is an important modulator of oligodendrocyte signaling, survival, proliferation, and differentiation.

T36567

65647-65811

Sentence

denotes

Therefore, as with integrins, multimerization of proteoglycans is an important modulator of oligodendrocyte signaling, survival, proliferation, and differentiation.

TextSentencer_T327

65812-66259

Sentence

denotes

The pentameric structure of the IgM antibodies we have identified as remyelination-promoting antibodies immediately suggests that clustering and multimerization of cell surface antigens is an important element in the signal transduction elicited downstream from antibody binding (Asakura et al., 1996 (Asakura et al., , 1998 Bieber et al., 2001; Miller et al., 1994; Rodriguez and Lennon 1990; Sommer and Schachner 1981; Warrington et al., 2000) .

TextSentencer_T327

65812-66259

Sentence

denotes

The pentameric structure of the IgM antibodies we have identified as remyelination-promoting antibodies immediately suggests that clustering and multimerization of cell surface antigens is an important element in the signal transduction elicited downstream from antibody binding (Asakura et al., 1996 (Asakura et al., , 1998 Bieber et al., 2001; Miller et al., 1994; Rodriguez and Lennon 1990; Sommer and Schachner 1981; Warrington et al., 2000) .

T68708

65812-66259

Sentence

denotes

The pentameric structure of the IgM antibodies we have identified as remyelination-promoting antibodies immediately suggests that clustering and multimerization of cell surface antigens is an important element in the signal transduction elicited downstream from antibody binding (Asakura et al., 1996 (Asakura et al., , 1998 Bieber et al., 2001; Miller et al., 1994; Rodriguez and Lennon 1990; Sommer and Schachner 1981; Warrington et al., 2000) .

TextSentencer_T328

66260-66436

Sentence

denotes

Therefore, we propose that our remyelination-promoting antibodies function as soluble initiators of the type of clustering described previously for integrins and proteoglycans.

TextSentencer_T328

66260-66436

Sentence

denotes

Therefore, we propose that our remyelination-promoting antibodies function as soluble initiators of the type of clustering described previously for integrins and proteoglycans.

T53152

66260-66436

Sentence

denotes

Therefore, we propose that our remyelination-promoting antibodies function as soluble initiators of the type of clustering described previously for integrins and proteoglycans.

TextSentencer_T329

66437-66699

Sentence

denotes

It is important to note that several of the antibodies we have shown to promote remyelination are reactive with sialic acid residues (A2B5), other carbohydrate domains (HNK-1), and lipid raft-localized molecules (O1, O4) (Asakura et al., 1998; Warrington et al.,

TextSentencer_T329

66437-66699

Sentence

denotes

It is important to note that several of the antibodies we have shown to promote remyelination are reactive with sialic acid residues (A2B5), other carbohydrate domains (HNK-1), and lipid raft-localized molecules (O1, O4) (Asakura et al., 1998; Warrington et al.,

T99396

66437-66699

Sentence

denotes

It is important to note that several of the antibodies we have shown to promote remyelination are reactive with sialic acid residues (A2B5), other carbohydrate domains (HNK-1), and lipid raft-localized molecules (O1, O4) (Asakura et al., 1998; Warrington et al.,

TextSentencer_T330

66701-66740

Sentence

denotes

Remyelination as Neuroprotection 2000).

TextSentencer_T330

66701-66740

Sentence

denotes

Remyelination as Neuroprotection 2000).

T5617

66701-66740

Sentence

denotes

Remyelination as Neuroprotection 2000).

TextSentencer_T331

66741-67113

Sentence

denotes

Moreover, several of these antibodies have been shown to alter oligodendrocyte morphology, initiate calcium signals, and induce differentiation (Dyer 1993; Dyer and Benjamins, 1989; , and the general lack of similar effects induced by IgG antibodies reactive with similar epitopes suggests that multimerization is an important element in the transduction of these effects.

TextSentencer_T331

66741-67113

Sentence

denotes

Moreover, several of these antibodies have been shown to alter oligodendrocyte morphology, initiate calcium signals, and induce differentiation (Dyer 1993; Dyer and Benjamins, 1989; , and the general lack of similar effects induced by IgG antibodies reactive with similar epitopes suggests that multimerization is an important element in the transduction of these effects.

T67789

66741-67113

Sentence

denotes

Moreover, several of these antibodies have been shown to alter oligodendrocyte morphology, initiate calcium signals, and induce differentiation (Dyer 1993; Dyer and Benjamins, 1989; , and the general lack of similar effects induced by IgG antibodies reactive with similar epitopes suggests that multimerization is an important element in the transduction of these effects.

TextSentencer_T332

67114-67380

Sentence

denotes

It is also important to note, however, that cellular context is a critical factor in the signaling initiated by remyelination-promoting antibodies, as many of these antibodies recognize rather broad classes of molecules but only initiate signals in a limited manner.

TextSentencer_T332

67114-67380

Sentence

denotes

It is also important to note, however, that cellular context is a critical factor in the signaling initiated by remyelination-promoting antibodies, as many of these antibodies recognize rather broad classes of molecules but only initiate signals in a limited manner.

T51994

67114-67380

Sentence

denotes

It is also important to note, however, that cellular context is a critical factor in the signaling initiated by remyelination-promoting antibodies, as many of these antibodies recognize rather broad classes of molecules but only initiate signals in a limited manner.

TextSentencer_T333

67381-67655

Sentence

denotes

Thus we hypothesize that remyelination-promoting antibodies recognize oligodendrocyte surface molecules that are presented within specific contexts, and that this recognition event leads to the clustering of signal transducers within plasma membrane lipid raft microdomains.

TextSentencer_T333

67381-67655

Sentence

denotes

Thus we hypothesize that remyelination-promoting antibodies recognize oligodendrocyte surface molecules that are presented within specific contexts, and that this recognition event leads to the clustering of signal transducers within plasma membrane lipid raft microdomains.

T97812

67381-67655

Sentence

denotes

Thus we hypothesize that remyelination-promoting antibodies recognize oligodendrocyte surface molecules that are presented within specific contexts, and that this recognition event leads to the clustering of signal transducers within plasma membrane lipid raft microdomains.

TextSentencer_T334

67656-67744

Sentence

denotes

Myelin reactive autoantibodies may also enhance repair through more indirect mechanisms.

TextSentencer_T334

67656-67744

Sentence

denotes

Myelin reactive autoantibodies may also enhance repair through more indirect mechanisms.

T30192

67656-67744

Sentence

denotes

Myelin reactive autoantibodies may also enhance repair through more indirect mechanisms.

TextSentencer_T335

67745-67926

Sentence

denotes

Antibodies binding to damaged oligodendrocytes and myelin may stimulate repair by enhancing the opsonization and clearance of myelin debris by macrophages (DeJong and Smith, 1997) .

TextSentencer_T335

67745-67926

Sentence

denotes

Antibodies binding to damaged oligodendrocytes and myelin may stimulate repair by enhancing the opsonization and clearance of myelin debris by macrophages (DeJong and Smith, 1997) .

T65043

67745-67926

Sentence

denotes

Antibodies binding to damaged oligodendrocytes and myelin may stimulate repair by enhancing the opsonization and clearance of myelin debris by macrophages (DeJong and Smith, 1997) .

TextSentencer_T336

67927-68094

Sentence

denotes

Large numbers of macrophages are often observed in demyelinated lesions, and phagocytosis of myelin debris may be an important prerequisite to efficient remyelination.

TextSentencer_T336

67927-68094

Sentence

denotes

Large numbers of macrophages are often observed in demyelinated lesions, and phagocytosis of myelin debris may be an important prerequisite to efficient remyelination.

T48602

67927-68094

Sentence

denotes

Large numbers of macrophages are often observed in demyelinated lesions, and phagocytosis of myelin debris may be an important prerequisite to efficient remyelination.

TextSentencer_T337

68095-68330

Sentence

denotes

However, our most recent data indicate definitively that the Fc portion of the antibodies is not required for remyelination induced by sHIgM22 , and this critical piece of information has focused our attention on the direct hypothesis.

TextSentencer_T337

68095-68330

Sentence

denotes

However, our most recent data indicate definitively that the Fc portion of the antibodies is not required for remyelination induced by sHIgM22 , and this critical piece of information has focused our attention on the direct hypothesis.

T74290

68095-68330

Sentence

denotes

However, our most recent data indicate definitively that the Fc portion of the antibodies is not required for remyelination induced by sHIgM22 , and this critical piece of information has focused our attention on the direct hypothesis.

TextSentencer_T338

68331-68576

Sentence

denotes

Expanding the concept of antibody-mediated CNS repair from remyelination to axon regeneration, McKerracher and colleagues immunized animals with SCH before spinal cord hemisection or optic nerve crush (Ellezam et al., 2003; Huang et al., 1999 ).

TextSentencer_T338

68331-68576

Sentence

denotes

Expanding the concept of antibody-mediated CNS repair from remyelination to axon regeneration, McKerracher and colleagues immunized animals with SCH before spinal cord hemisection or optic nerve crush (Ellezam et al., 2003; Huang et al., 1999 ).

T43238

68331-68576

Sentence

denotes

Expanding the concept of antibody-mediated CNS repair from remyelination to axon regeneration, McKerracher and colleagues immunized animals with SCH before spinal cord hemisection or optic nerve crush (Ellezam et al., 2003; Huang et al., 1999 ).

TextSentencer_T339

68577-68769

Sentence

denotes

An identical preimmunization strategy was used, and therefore the antibody response is likely to be the same as in our earlier studies using the Theiler's virusmediated model of demyelination.

TextSentencer_T339

68577-68769

Sentence

denotes

An identical preimmunization strategy was used, and therefore the antibody response is likely to be the same as in our earlier studies using the Theiler's virusmediated model of demyelination.

T28694

68577-68769

Sentence

denotes

An identical preimmunization strategy was used, and therefore the antibody response is likely to be the same as in our earlier studies using the Theiler's virusmediated model of demyelination.

TextSentencer_T340

68770-68955

Sentence

denotes

Preimmunization with SCH resulted in significant axonal regrowth in both spinal cord and optic nerve lesion models and resulted in a functional recovery in the spinal cord lesion model.

TextSentencer_T340

68770-68955

Sentence

denotes

Preimmunization with SCH resulted in significant axonal regrowth in both spinal cord and optic nerve lesion models and resulted in a functional recovery in the spinal cord lesion model.

T92611

68770-68955

Sentence

denotes

Preimmunization with SCH resulted in significant axonal regrowth in both spinal cord and optic nerve lesion models and resulted in a functional recovery in the spinal cord lesion model.

TextSentencer_T341

68956-69155

Sentence

denotes

Sera from animals demonstrating axon regrowth contained increased titers of myelin-reactive antibodies, which, when used in vitro, allowed the outgrowth of neurites on normally inhibitory CNS myelin.

TextSentencer_T341

68956-69155

Sentence

denotes

Sera from animals demonstrating axon regrowth contained increased titers of myelin-reactive antibodies, which, when used in vitro, allowed the outgrowth of neurites on normally inhibitory CNS myelin.

T62379

68956-69155

Sentence

denotes

Sera from animals demonstrating axon regrowth contained increased titers of myelin-reactive antibodies, which, when used in vitro, allowed the outgrowth of neurites on normally inhibitory CNS myelin.

TextSentencer_T342

69156-69339

Sentence

denotes

It was hypothesized that anti-SCH antibodies promoted axon regeneration by blocking in vivo myelin-associated inhibitors of axon outgrowth (Ellezam et al., 2003; Huang et al., 1999) .

TextSentencer_T342

69156-69339

Sentence

denotes

It was hypothesized that anti-SCH antibodies promoted axon regeneration by blocking in vivo myelin-associated inhibitors of axon outgrowth (Ellezam et al., 2003; Huang et al., 1999) .

T73809

69156-69339

Sentence

denotes

It was hypothesized that anti-SCH antibodies promoted axon regeneration by blocking in vivo myelin-associated inhibitors of axon outgrowth (Ellezam et al., 2003; Huang et al., 1999) .

TextSentencer_T343

69340-69512

Sentence

denotes

However, the SCH antisera did not contain elevated titers of antibodies to known myelin inhibitors (Nogo, myelin associated glycoprotein, chondroitin sulfate proteoglycan).

TextSentencer_T343

69340-69512

Sentence

denotes

However, the SCH antisera did not contain elevated titers of antibodies to known myelin inhibitors (Nogo, myelin associated glycoprotein, chondroitin sulfate proteoglycan).

T64037

69340-69512

Sentence

denotes

However, the SCH antisera did not contain elevated titers of antibodies to known myelin inhibitors (Nogo, myelin associated glycoprotein, chondroitin sulfate proteoglycan).

TextSentencer_T344

69513-69698

Sentence

denotes

Therefore, myelin reactive antibodies might be useful not only to promote myelin repair after demyelinating disease but also for the treatment of axonal damage after spinal cord injury.

TextSentencer_T344

69513-69698

Sentence

denotes

Therefore, myelin reactive antibodies might be useful not only to promote myelin repair after demyelinating disease but also for the treatment of axonal damage after spinal cord injury.

T9415

69513-69698

Sentence

denotes

Therefore, myelin reactive antibodies might be useful not only to promote myelin repair after demyelinating disease but also for the treatment of axonal damage after spinal cord injury.

TextSentencer_T345

69699-69808

Sentence

denotes

Such antibodies may be administered exogenously or generated in vivo via appropriate immunization strategies.

TextSentencer_T345

69699-69808

Sentence

denotes

Such antibodies may be administered exogenously or generated in vivo via appropriate immunization strategies.

T13652

69699-69808

Sentence

denotes

Such antibodies may be administered exogenously or generated in vivo via appropriate immunization strategies.

TextSentencer_T346

69809-69985

Sentence

denotes

Recent work with the IN-1 antibody, also an oligodendrocyte reactive IgM, has led to very similar conclusions (Bregman et al., 1995; Chen et al., 2000; GrandPre et al., 2000) .

TextSentencer_T346

69809-69985

Sentence

denotes

Recent work with the IN-1 antibody, also an oligodendrocyte reactive IgM, has led to very similar conclusions (Bregman et al., 1995; Chen et al., 2000; GrandPre et al., 2000) .

T15808

69809-69985

Sentence

denotes

Recent work with the IN-1 antibody, also an oligodendrocyte reactive IgM, has led to very similar conclusions (Bregman et al., 1995; Chen et al., 2000; GrandPre et al., 2000) .

TextSentencer_T347

69986-70224

Sentence

denotes

There are currently few effective therapies to promote tissue repair or to prevent or reverse neurological deficits after CNS injury or disease; therefore, the characterization of endogenous immune-mediated repair mechanisms is important.

TextSentencer_T347

69986-70224

Sentence

denotes

There are currently few effective therapies to promote tissue repair or to prevent or reverse neurological deficits after CNS injury or disease; therefore, the characterization of endogenous immune-mediated repair mechanisms is important.

T51920

69986-70224

Sentence

denotes

There are currently few effective therapies to promote tissue repair or to prevent or reverse neurological deficits after CNS injury or disease; therefore, the characterization of endogenous immune-mediated repair mechanisms is important.

TextSentencer_T348

70225-70450

Sentence

denotes

An understanding of these mechanisms should open up significant new areas for the development of antibody-based therapeutics and perhaps small molecule-based therapeutics and vaccines for induction of the reparative response.

TextSentencer_T348

70225-70450

Sentence

denotes

An understanding of these mechanisms should open up significant new areas for the development of antibody-based therapeutics and perhaps small molecule-based therapeutics and vaccines for induction of the reparative response.

T62131

70225-70450

Sentence

denotes

An understanding of these mechanisms should open up significant new areas for the development of antibody-based therapeutics and perhaps small molecule-based therapeutics and vaccines for induction of the reparative response.

TextSentencer_T349

70451-70591

Sentence

denotes

Remyelination is an important therapeutic goal for the treatment of neurological disease and is likely to protect axons from further injury.

TextSentencer_T349

70451-70591

Sentence

denotes

Remyelination is an important therapeutic goal for the treatment of neurological disease and is likely to protect axons from further injury.

T80780

70451-70591

Sentence

denotes

Remyelination is an important therapeutic goal for the treatment of neurological disease and is likely to protect axons from further injury.

TextSentencer_T350

70592-70760

Sentence

denotes

Human monoclonal antibodies that promote remyelination represent a new class of therapeutics for diseases such as MS, spinal cord injury, neurodegeneration, and stroke.

TextSentencer_T350

70592-70760

Sentence

denotes

Human monoclonal antibodies that promote remyelination represent a new class of therapeutics for diseases such as MS, spinal cord injury, neurodegeneration, and stroke.

T47869

70592-70760

Sentence

denotes

Human monoclonal antibodies that promote remyelination represent a new class of therapeutics for diseases such as MS, spinal cord injury, neurodegeneration, and stroke.

TextSentencer_T351

70761-70887

Sentence

denotes

The loss of oligodendrocytes and myelin normally associated with demyelinating diseases such as MS is, of course, devastating.

TextSentencer_T351

70761-70887

Sentence

denotes

The loss of oligodendrocytes and myelin normally associated with demyelinating diseases such as MS is, of course, devastating.

T91004

70761-70887

Sentence

denotes

The loss of oligodendrocytes and myelin normally associated with demyelinating diseases such as MS is, of course, devastating.

TextSentencer_T352

70888-71134

Sentence

denotes

However, rational therapeutic approaches that may be within reach, including treatment with remyelinationpromoting antibodies or transplantation of oligodendrocyte progenitors, will likely repair and reverse myelin-related damage and dysfunction.

TextSentencer_T352

70888-71134

Sentence

denotes

However, rational therapeutic approaches that may be within reach, including treatment with remyelinationpromoting antibodies or transplantation of oligodendrocyte progenitors, will likely repair and reverse myelin-related damage and dysfunction.

T52079

70888-71134

Sentence

denotes

However, rational therapeutic approaches that may be within reach, including treatment with remyelinationpromoting antibodies or transplantation of oligodendrocyte progenitors, will likely repair and reverse myelin-related damage and dysfunction.

TextSentencer_T353

71135-71323

Sentence

denotes

In contrast, the loss of neurons, axons, and synaptic connections that may result after repeated bouts of demyelination is likely to be a far more complex and intractable problem to solve.

TextSentencer_T353

71135-71323

Sentence

denotes

In contrast, the loss of neurons, axons, and synaptic connections that may result after repeated bouts of demyelination is likely to be a far more complex and intractable problem to solve.

T45312

71135-71323

Sentence

denotes

In contrast, the loss of neurons, axons, and synaptic connections that may result after repeated bouts of demyelination is likely to be a far more complex and intractable problem to solve.

TextSentencer_T354

71324-71543

Sentence

denotes

Axons and synapses are the final physical manifestation of the neural connectivity and plasticity that develops over the lifetime of an individual; replacing these structures once lost may simply prove to be impossible.

TextSentencer_T354

71324-71543

Sentence

denotes

Axons and synapses are the final physical manifestation of the neural connectivity and plasticity that develops over the lifetime of an individual; replacing these structures once lost may simply prove to be impossible.

T3971

71324-71543

Sentence

denotes

Axons and synapses are the final physical manifestation of the neural connectivity and plasticity that develops over the lifetime of an individual; replacing these structures once lost may simply prove to be impossible.

TextSentencer_T355

71544-71685

Sentence

denotes

Therefore, it is critical that strategies be developed for protecting and maintaining axons during demyelinating episodes associated with MS.

TextSentencer_T355

71544-71685

Sentence

denotes

Therefore, it is critical that strategies be developed for protecting and maintaining axons during demyelinating episodes associated with MS.

T5145

71544-71685

Sentence

denotes

Therefore, it is critical that strategies be developed for protecting and maintaining axons during demyelinating episodes associated with MS.

TextSentencer_T356

71686-71923

Sentence

denotes

Obviously, the ultimate goal is to prevent MS altogether, but in the short term, a reasonable goal is to rapidly promote remyelination and thereby protect neurons and axons from damage and death inflicted by exposure to immune mediators.

TextSentencer_T356

71686-71923

Sentence

denotes

Obviously, the ultimate goal is to prevent MS altogether, but in the short term, a reasonable goal is to rapidly promote remyelination and thereby protect neurons and axons from damage and death inflicted by exposure to immune mediators.

T60497

71686-71923

Sentence

denotes

Obviously, the ultimate goal is to prevent MS altogether, but in the short term, a reasonable goal is to rapidly promote remyelination and thereby protect neurons and axons from damage and death inflicted by exposure to immune mediators.

TextSentencer_T357

71924-72139

Sentence

denotes

We propose that treatment with remyelination-promoting growth factor-like human IgM natural autoantibodies may be an efficacious method for quickly repairing demyelinated lesions and maintaining axonal connectivity.

TextSentencer_T357

71924-72139

Sentence

denotes

We propose that treatment with remyelination-promoting growth factor-like human IgM natural autoantibodies may be an efficacious method for quickly repairing demyelinated lesions and maintaining axonal connectivity.

T35282

71924-72139

Sentence

denotes

We propose that treatment with remyelination-promoting growth factor-like human IgM natural autoantibodies may be an efficacious method for quickly repairing demyelinated lesions and maintaining axonal connectivity.

TextSentencer_T358

72140-72275

Sentence

denotes

Likewise, another important goal of our group is to better understand the immune effector cells involved in damaging axons and neurons.

TextSentencer_T358

72140-72275

Sentence

denotes

Likewise, another important goal of our group is to better understand the immune effector cells involved in damaging axons and neurons.

T96207

72140-72275

Sentence

denotes

Likewise, another important goal of our group is to better understand the immune effector cells involved in damaging axons and neurons.

TextSentencer_T359

72276-72507

Sentence

denotes

There is substantial evidence that CD8 + T-cells are a key mediator of axon killing in patients with MS, and we will continue to study the role of these cells in a number of animal models of MS, including the Theiler's virus model.

TextSentencer_T359

72276-72507

Sentence

denotes

There is substantial evidence that CD8 + T-cells are a key mediator of axon killing in patients with MS, and we will continue to study the role of these cells in a number of animal models of MS, including the Theiler's virus model.

T57851

72276-72507

Sentence

denotes

There is substantial evidence that CD8 + T-cells are a key mediator of axon killing in patients with MS, and we will continue to study the role of these cells in a number of animal models of MS, including the Theiler's virus model.

TextSentencer_T360

72508-72623

Sentence

denotes

There is strong evidence to support the role of MHC class I in the pathogenesis of Theiler's virus-induced disease.

TextSentencer_T360

72508-72623

Sentence

denotes

There is strong evidence to support the role of MHC class I in the pathogenesis of Theiler's virus-induced disease.

T1480

72508-72623

Sentence

denotes

There is strong evidence to support the role of MHC class I in the pathogenesis of Theiler's virus-induced disease.

TextSentencer_T361

72624-72689

Sentence

denotes

The data to support this hypothesis can be summarized as follows.

TextSentencer_T361

72624-72689

Sentence

denotes

The data to support this hypothesis can be summarized as follows.

T29220

72624-72689

Sentence

denotes

The data to support this hypothesis can be summarized as follows.

TextSentencer_T362

72690-72842

Sentence

denotes

First, susceptibility vs. resistance to viral persistance and demyelination maps to the D region molecule of the class I gene (Rodriguez et al., 1986) .

TextSentencer_T362

72690-72842

Sentence

denotes

First, susceptibility vs. resistance to viral persistance and demyelination maps to the D region molecule of the class I gene (Rodriguez et al., 1986) .

T70983

72690-72842

Sentence

denotes

First, susceptibility vs. resistance to viral persistance and demyelination maps to the D region molecule of the class I gene (Rodriguez et al., 1986) .

TextSentencer_T363

72843-72978

Sentence

denotes

Second, class I genes are upregulated in neurons, astrocytes, and oligodendrocytes immediately after infection (Redwine et al., 2001) .

TextSentencer_T363

72843-72978

Sentence

denotes

Second, class I genes are upregulated in neurons, astrocytes, and oligodendrocytes immediately after infection (Redwine et al., 2001) .

T66649

72843-72978

Sentence

denotes

Second, class I genes are upregulated in neurons, astrocytes, and oligodendrocytes immediately after infection (Redwine et al., 2001) .

TextSentencer_T364

72979-73253

Sentence

denotes

Third, the upregulation of class I MHC is differentially regulated such that both K and D region molecules are upregulated during the acute phase of the infection, but only D region molecules are upregulated during the chronic demyelinating disease (Altintas et al., 1993) .

TextSentencer_T364

72979-73253

Sentence

denotes

Third, the upregulation of class I MHC is differentially regulated such that both K and D region molecules are upregulated during the acute phase of the infection, but only D region molecules are upregulated during the chronic demyelinating disease (Altintas et al., 1993) .

T34166

72979-73253

Sentence

denotes

Third, the upregulation of class I MHC is differentially regulated such that both K and D region molecules are upregulated during the acute phase of the infection, but only D region molecules are upregulated during the chronic demyelinating disease (Altintas et al., 1993) .

TextSentencer_T365

73254-73417

Sentence

denotes

Fourth, cytotoxic T-cell-mediated killing can be demonstrated for T-cells isolated directly from the infected CNS without in vitro stimulation (Lin et al., 1995) .

TextSentencer_T365

73254-73417

Sentence

denotes

Fourth, cytotoxic T-cell-mediated killing can be demonstrated for T-cells isolated directly from the infected CNS without in vitro stimulation (Lin et al., 1995) .

T11777

73254-73417

Sentence

denotes

Fourth, cytotoxic T-cell-mediated killing can be demonstrated for T-cells isolated directly from the infected CNS without in vitro stimulation (Lin et al., 1995) .

TextSentencer_T366

73418-73587

Sentence

denotes

Fifth, cytotoxic T-cell-mediated killing is directed against the viral capsid proteins of Theiler's virus, primarily VP2, and to a lesser extent VP1 (Lin et al., 1995) .

TextSentencer_T366

73418-73587

Sentence

denotes

Fifth, cytotoxic T-cell-mediated killing is directed against the viral capsid proteins of Theiler's virus, primarily VP2, and to a lesser extent VP1 (Lin et al., 1995) .

T98005

73418-73587

Sentence

denotes

Fifth, cytotoxic T-cell-mediated killing is directed against the viral capsid proteins of Theiler's virus, primarily VP2, and to a lesser extent VP1 (Lin et al., 1995) .

TextSentencer_T367

73588-73758

Sentence

denotes

Sixth, in mice of the H-2 b haplotype, VP2 121-130 is the immunodominant peptide recognized specifically within the context of the H-2D b molecule (Borson et al., 1997) .

TextSentencer_T367

73588-73758

Sentence

denotes

Sixth, in mice of the H-2 b haplotype, VP2 121-130 is the immunodominant peptide recognized specifically within the context of the H-2D b molecule (Borson et al., 1997) .

T63042

73588-73758

Sentence

denotes

Sixth, in mice of the H-2 b haplotype, VP2 121-130 is the immunodominant peptide recognized specifically within the context of the H-2D b molecule (Borson et al., 1997) .

TextSentencer_T368

73759-73985

Sentence

denotes

Seventh, FACS using fluorescently labeled tetramers of VP2 121-130 /D b demonstrate that 60% to 80% of all CD8 + T-cells in the CNS of infected mice are directed against this one immunodominant peptide (Johnson et al., 1999) .

TextSentencer_T368

73759-73985

Sentence

denotes

Seventh, FACS using fluorescently labeled tetramers of VP2 121-130 /D b demonstrate that 60% to 80% of all CD8 + T-cells in the CNS of infected mice are directed against this one immunodominant peptide (Johnson et al., 1999) .

T71821

73759-73985

Sentence

denotes

Seventh, FACS using fluorescently labeled tetramers of VP2 121-130 /D b demonstrate that 60% to 80% of all CD8 + T-cells in the CNS of infected mice are directed against this one immunodominant peptide (Johnson et al., 1999) .

TextSentencer_T369

73986-74217

Sentence

denotes

Eighth, we have shown that mice with a dysfunctional MHC class I induced by genetic deletion of β2microglobulin exhibit profound demyelination of the spinal cord despite normal neurological function (Rivera-Quinones et al., 1998) .

TextSentencer_T369

73986-74217

Sentence

denotes

Eighth, we have shown that mice with a dysfunctional MHC class I induced by genetic deletion of β2microglobulin exhibit profound demyelination of the spinal cord despite normal neurological function (Rivera-Quinones et al., 1998) .

T2174

73986-74217

Sentence

denotes

Eighth, we have shown that mice with a dysfunctional MHC class I induced by genetic deletion of β2microglobulin exhibit profound demyelination of the spinal cord despite normal neurological function (Rivera-Quinones et al., 1998) .

TextSentencer_T370

74218-74407

Sentence

denotes

Preservation of physiological function was likely due to preservation of axons, and, in fact, we showed that axons upregulated and redistributed sodium channels along demyelinated segments.

TextSentencer_T370

74218-74407

Sentence

denotes

Preservation of physiological function was likely due to preservation of axons, and, in fact, we showed that axons upregulated and redistributed sodium channels along demyelinated segments.

T37826

74218-74407

Sentence

denotes

Preservation of physiological function was likely due to preservation of axons, and, in fact, we showed that axons upregulated and redistributed sodium channels along demyelinated segments.

TextSentencer_T371

74408-74593

Sentence

denotes

Ninth, retrograde labeling of descending axon tracts demonstrated a failure in retrograde axonal transport in mice with demyelination and functional deficits (Ure and Rodriguez, 2000) .

TextSentencer_T371

74408-74593

Sentence

denotes

Ninth, retrograde labeling of descending axon tracts demonstrated a failure in retrograde axonal transport in mice with demyelination and functional deficits (Ure and Rodriguez, 2000) .

T94961

74408-74593

Sentence

denotes

Ninth, retrograde labeling of descending axon tracts demonstrated a failure in retrograde axonal transport in mice with demyelination and functional deficits (Ure and Rodriguez, 2000) .

TextSentencer_T372

74594-74716

Sentence

denotes

However, axonal transport was preserved in demyelinated mice with deletion of β2-microglobulin (Ure and Rodriguez, 2002) .

TextSentencer_T372

74594-74716

Sentence

denotes

However, axonal transport was preserved in demyelinated mice with deletion of β2-microglobulin (Ure and Rodriguez, 2002) .

T82780

74594-74716

Sentence

denotes

However, axonal transport was preserved in demyelinated mice with deletion of β2-microglobulin (Ure and Rodriguez, 2002) .

TextSentencer_T373

74717-74896

Sentence

denotes

Tenth, we recently showed that depletion of antigen-specific cytotoxic T-cells restricted to VP2 121-130 resulted in preservation of neurological function (Johnson et al., 2001) .

TextSentencer_T373

74717-74896

Sentence

denotes

Tenth, we recently showed that depletion of antigen-specific cytotoxic T-cells restricted to VP2 121-130 resulted in preservation of neurological function (Johnson et al., 2001) .

T89491

74717-74896

Sentence

denotes

Tenth, we recently showed that depletion of antigen-specific cytotoxic T-cells restricted to VP2 121-130 resulted in preservation of neurological function (Johnson et al., 2001) .

TextSentencer_T374

74897-75260

Sentence

denotes

These results suggest that axonal injury mediates neurological impairment during the chronic phase of Theiler's virus infection that is separable from virus-induced demyelination, and also suggest that CD8 + cytotoxic T-lymphocytes directed against a specific viral peptide presented by MHC class I on axons and neurons may play an important role in this process.

TextSentencer_T374

74897-75260

Sentence

denotes

These results suggest that axonal injury mediates neurological impairment during the chronic phase of Theiler's virus infection that is separable from virus-induced demyelination, and also suggest that CD8 + cytotoxic T-lymphocytes directed against a specific viral peptide presented by MHC class I on axons and neurons may play an important role in this process.

T29399

74897-75260

Sentence

denotes

These results suggest that axonal injury mediates neurological impairment during the chronic phase of Theiler's virus infection that is separable from virus-induced demyelination, and also suggest that CD8 + cytotoxic T-lymphocytes directed against a specific viral peptide presented by MHC class I on axons and neurons may play an important role in this process.

TextSentencer_T375

75261-75431

Sentence

denotes

We favor the hypothesis that demyelination is necessary but not sufficient for development of permanent deficits in primary demyelinating disorders of humans and animals.

TextSentencer_T375

75261-75431

Sentence

denotes

We favor the hypothesis that demyelination is necessary but not sufficient for development of permanent deficits in primary demyelinating disorders of humans and animals.

T79071

75261-75431

Sentence

denotes

We favor the hypothesis that demyelination is necessary but not sufficient for development of permanent deficits in primary demyelinating disorders of humans and animals.

TextSentencer_T376

75432-75495

Sentence

denotes

Demyelination predisposes axons to subsequent secondary injury.

TextSentencer_T376

75432-75495

Sentence

denotes

Demyelination predisposes axons to subsequent secondary injury.

T55536

75432-75495

Sentence

denotes

Demyelination predisposes axons to subsequent secondary injury.

TextSentencer_T377

75496-75577

Sentence

denotes

A major function of myelin is to protect axons against subsequent injury or loss.

TextSentencer_T377

75496-75577

Sentence

denotes

A major function of myelin is to protect axons against subsequent injury or loss.

T51671

75496-75577

Sentence

denotes

A major function of myelin is to protect axons against subsequent injury or loss.

TextSentencer_T378

75578-75746

Sentence

denotes

This secondary injury to the axon may be the result of either (1) T-cell cytotoxicity or (2) failure of neurotrophic support from death of myelinating oligodendrocytes.

TextSentencer_T378

75578-75746

Sentence

denotes

This secondary injury to the axon may be the result of either (1) T-cell cytotoxicity or (2) failure of neurotrophic support from death of myelinating oligodendrocytes.

T9410

75578-75746

Sentence

denotes

This secondary injury to the axon may be the result of either (1) T-cell cytotoxicity or (2) failure of neurotrophic support from death of myelinating oligodendrocytes.

TextSentencer_T379

75747-76073

Sentence

denotes

It is not known how long an axon can remain demyelinated in the CNS before death or remyelination takes place; however, strategies to prevent cytotoxic T-cell-mediated injury to axons and strategies to maintain axons may ultimately prove to be the most efficacious means of preventing long-term disability after demyelination.

TextSentencer_T379

75747-76073

Sentence

denotes

It is not known how long an axon can remain demyelinated in the CNS before death or remyelination takes place; however, strategies to prevent cytotoxic T-cell-mediated injury to axons and strategies to maintain axons may ultimately prove to be the most efficacious means of preventing long-term disability after demyelination.

T93763

75747-76073

Sentence

denotes

It is not known how long an axon can remain demyelinated in the CNS before death or remyelination takes place; however, strategies to prevent cytotoxic T-cell-mediated injury to axons and strategies to maintain axons may ultimately prove to be the most efficacious means of preventing long-term disability after demyelination.

TextSentencer_T380

76074-76319

Sentence

denotes

Rapid remyelination of these preserved axons, induced perhaps by treatment with growth factor-like human monoclonal IgM antibodies directed against myelin antigens, may protect them from further injury and thereby preserve neurological function.

TextSentencer_T380

76074-76319

Sentence

denotes

Rapid remyelination of these preserved axons, induced perhaps by treatment with growth factor-like human monoclonal IgM antibodies directed against myelin antigens, may protect them from further injury and thereby preserve neurological function.

T85615

76074-76319

Sentence

denotes

Rapid remyelination of these preserved axons, induced perhaps by treatment with growth factor-like human monoclonal IgM antibodies directed against myelin antigens, may protect them from further injury and thereby preserve neurological function.

CORD-19:16a812de72963ceda960a168236e8dbe91832d45 JSON TXT 11 Projects

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CORD-19:16a812de72963ceda960a168236e8dbe91832d45 JSONTXT 11 Projects

Annnotations TAB TSV DIC JSON TextAE

CORD-19:16a812de72963ceda960a168236e8dbe91832d45 JSON TXT 11 Projects