PMC:5118424 / 4263-9755 JSONTXT

{"project":"TEST0","denotations":[{"id":"27920778-234-240-2673478","span":{"begin":391,"end":393},"obj":"[\"25367570\"]"},{"id":"27920778-209-215-2673479","span":{"begin":746,"end":748},"obj":"[\"25367570\"]"},{"id":"27920778-213-219-2673480","span":{"begin":750,"end":752},"obj":"[\"20810318\"]"},{"id":"27920778-233-239-2673481","span":{"begin":1012,"end":1014},"obj":"[\"11104797\"]"},{"id":"27920778-237-243-2673482","span":{"begin":1016,"end":1018},"obj":"[\"11104798\"]"},{"id":"27920778-197-203-2673483","span":{"begin":1368,"end":1370},"obj":"[\"9815267\"]"},{"id":"27920778-133-139-2673484","span":{"begin":1506,"end":1508},"obj":"[\"18602282\"]"},{"id":"27920778-116-122-2673485","span":{"begin":1627,"end":1629},"obj":"[\"18599325\"]"},{"id":"27920778-147-153-2673486","span":{"begin":1974,"end":1976},"obj":"[\"19949086\"]"},{"id":"27920778-122-128-2673487","span":{"begin":2101,"end":2103},"obj":"[\"22990011\"]"},{"id":"27920778-100-106-2673488","span":{"begin":2206,"end":2208},"obj":"[\"22922259\"]"},{"id":"27920778-216-222-2673489","span":{"begin":2427,"end":2429},"obj":"[\"24907346\"]"},{"id":"27920778-139-145-2673490","span":{"begin":3427,"end":3429},"obj":"[\"22922259\"]"},{"id":"27920778-237-243-2673491","span":{"begin":3736,"end":3738},"obj":"[\"22387550\"]"},{"id":"27920778-233-239-2673492","span":{"begin":3740,"end":3742},"obj":"[\"22922258\"]"},{"id":"27920778-236-242-2673493","span":{"begin":4068,"end":4070},"obj":"[\"24907346\"]"},{"id":"27920778-233-239-2673494","span":{"begin":5309,"end":5311},"obj":"[\"27335502\"]"},{"id":"27920778-237-243-2673495","span":{"begin":5313,"end":5315},"obj":"[\"27342848\"]"}],"text":"Follicular Helper T Cells in the GCs of Hyperplastic Follicles During the Course of HIV Infection\nSpecific CD4 T helper cells termed TFH cells differentiate from precursors under the control of the transcription factor Bcl6 and are characterized by their function, which is to provide T cell help for B cells, and are distinct from other CD4 T cell subsets such as Th1, Th2, and Th17 cells (20). In lymphoid tissues, information on the location of CD4 T cells within follicles is also vital to identifying resident TFH cells (Figure 1). Although there is no single marker for distinguishing TFH cells from other CD4 subsets, they are defined by their expression of surface co-stimulatory molecules CXCR5, CD200, ICOS, and a high density of PD-1 (20, 21). These memory type cells generally express low levels of CCR7 but are able to migrate toward B cell follicles in lymphoid organs, produce IL-21, and deliver B cell help in the GC environment for the development of T cell-dependent humoral adaptive immunity (22, 23). Studies using knock-out mice for IL-6 and IL-21 have shown that both are necessary for TFH differentiation and GC development in secondary follicles. IL-6-deficient mice exhibited a marked defect in GCs formation, STAT1 and STAT3 signaling, downstream IL-21 production, and IgG production primarily due to the lack of TFH differentiation in vivo (24). IL-21 deficiency also results in a severe reduction of GCs though this signal seems downstream of the one caused by IL-6 deficiency (25). Moreover, IL-6 and IL-21 appear to regulate the generation of TFH cells in the absence of Th1, Th2, and Th17 cells (26), suggesting that conversely, increases in the expression of IL-6, IL-21, or both cytokines may lead to lymphoid hyperplasia and rapid development of GCs, as observed during HIV and SIV infection. In fact, in HIV-infected individuals, a decrease in levels of circulating IL-21 and decreased production of IL-21 by CD4 cells was noted in blood (27). Similar to HIV infection, substantial depletion of IL-21+ CD4 T cells was reported in the blood in SIV-infected macaques (28). In lymphoid tissues of HIV patients, however, a marked expansion of IL-21-secreting TFHs was noted (29). Moreover, concurrent accumulation of TFH cells and particularly within the GCs of lymph node follicles and more precisely at the periphery of the GC had significantly increased IL-21 expression during SIV infection (30), suggesting trafficking of IL-21-producing TFH cells during the chronic immune activation characteristic of chronic SIV infection.\nFigure 1 Abnormal accumulation of TFH cells in hyperplastic GC during HIV/SIV primary infection. Naïve mature CD4 T cells are activated through dendritic cells. The persistent viral antigens stimulate primed CD4 T cells, resulting in the formation of hyperplastic GC with the massive B cell expansion, TFH accumulation, and development of network of follicular dendritic cells. Treg and PD-L1 expressing cells within GCs are capable of modulating GC TFH cells to suppress GC-related responses at the end stage of HIV infection. Upon HIV infection, there is a rapid infiltration of these TFH cells and formation of numerous GCs within lymphoid organs, characteristic of lymphocyte hyperplasia seen early in chronic infection. Recent studies demonstrated that HIV-infected patients displayed an aberrant accumulation of TFH cells compared to uninfected individuals (29). Similar observations were reported in lymph nodes, spleen, and gut tissues of rhesus macaques, in which the resident TFH cells (PD-1high CD4+ T cells) within GCs of hyperplastic follicles were markedly expanded, with a parallel increase and accumulation of Ki67+ GC B cells during chronic SIV infection (31, 32) (Figure 2). Of interest though, was the observation that as TFH accumulated within GCs, their expression of Ki67 decreased with up to 80% of TFH negative for this proliferation marker, suggesting that the continued input of this lineage to be contributed from cells migrating into follicles rather than local proliferation (30), and potentially, these cells have reached a terminal differentiation stage and function, which is to deliver help to local B cell differentiation and maturation. These findings are consistent with the limited proliferative capacity of human TFH cells whereby cross-linking their high level of PD-1 may dissociate continuous TCR signaling.\nFigure 2 Hyperplastic follicle in gut tissue during chronic SIV infection. Representative H\u0026E (upper) and immunofluorescence image (lower) of hyperplastic follicle staining with Ki67 (blue), PD-1 (green), and CD20 (red) in ileum from a chronically SIV-infected rhesus macaque. Understanding whether GC TFH cells accumulated during HIV/SIV infection are viral antigen-specific is also important. However, this has, hitherto, rarely been addressed because of the difficulty in identifying their responses. In this respect, there is also little experimental evidence demonstrating the dynamics between antigen-specific TFH cells and hyperplastic GCs. Interestingly, two recent articles have reported a novel assay to determine the frequencies of antigen-specific TFH cells within secondary lymphoid tissues of humans and macaques using cytokine-independent activation-induced markers CD25 and OX40 (33, 34). Such new technique is expected to markedly enhance our comprehension of the role of antigen specificity in the lymphoid hyperplasia that is observed during SIV/HIV infection."}

{"project":"2_test","denotations":[{"id":"27920778-25367570-34327085","span":{"begin":391,"end":393},"obj":"25367570"},{"id":"27920778-25367570-34327086","span":{"begin":746,"end":748},"obj":"25367570"},{"id":"27920778-20810318-34327087","span":{"begin":750,"end":752},"obj":"20810318"},{"id":"27920778-11104797-34327088","span":{"begin":1012,"end":1014},"obj":"11104797"},{"id":"27920778-11104798-34327089","span":{"begin":1016,"end":1018},"obj":"11104798"},{"id":"27920778-9815267-34327090","span":{"begin":1368,"end":1370},"obj":"9815267"},{"id":"27920778-18602282-34327091","span":{"begin":1506,"end":1508},"obj":"18602282"},{"id":"27920778-18599325-34327092","span":{"begin":1627,"end":1629},"obj":"18599325"},{"id":"27920778-19949086-34327093","span":{"begin":1974,"end":1976},"obj":"19949086"},{"id":"27920778-22990011-34327094","span":{"begin":2101,"end":2103},"obj":"22990011"},{"id":"27920778-22922259-34327095","span":{"begin":2206,"end":2208},"obj":"22922259"},{"id":"27920778-24907346-34327096","span":{"begin":2427,"end":2429},"obj":"24907346"},{"id":"27920778-22922259-34327097","span":{"begin":3427,"end":3429},"obj":"22922259"},{"id":"27920778-22387550-34327098","span":{"begin":3736,"end":3738},"obj":"22387550"},{"id":"27920778-22922258-34327099","span":{"begin":3740,"end":3742},"obj":"22922258"},{"id":"27920778-24907346-34327100","span":{"begin":4068,"end":4070},"obj":"24907346"},{"id":"27920778-27335502-34327101","span":{"begin":5309,"end":5311},"obj":"27335502"},{"id":"27920778-27342848-34327102","span":{"begin":5313,"end":5315},"obj":"27342848"}],"text":"Follicular Helper T Cells in the GCs of Hyperplastic Follicles During the Course of HIV Infection\nSpecific CD4 T helper cells termed TFH cells differentiate from precursors under the control of the transcription factor Bcl6 and are characterized by their function, which is to provide T cell help for B cells, and are distinct from other CD4 T cell subsets such as Th1, Th2, and Th17 cells (20). In lymphoid tissues, information on the location of CD4 T cells within follicles is also vital to identifying resident TFH cells (Figure 1). Although there is no single marker for distinguishing TFH cells from other CD4 subsets, they are defined by their expression of surface co-stimulatory molecules CXCR5, CD200, ICOS, and a high density of PD-1 (20, 21). These memory type cells generally express low levels of CCR7 but are able to migrate toward B cell follicles in lymphoid organs, produce IL-21, and deliver B cell help in the GC environment for the development of T cell-dependent humoral adaptive immunity (22, 23). Studies using knock-out mice for IL-6 and IL-21 have shown that both are necessary for TFH differentiation and GC development in secondary follicles. IL-6-deficient mice exhibited a marked defect in GCs formation, STAT1 and STAT3 signaling, downstream IL-21 production, and IgG production primarily due to the lack of TFH differentiation in vivo (24). IL-21 deficiency also results in a severe reduction of GCs though this signal seems downstream of the one caused by IL-6 deficiency (25). Moreover, IL-6 and IL-21 appear to regulate the generation of TFH cells in the absence of Th1, Th2, and Th17 cells (26), suggesting that conversely, increases in the expression of IL-6, IL-21, or both cytokines may lead to lymphoid hyperplasia and rapid development of GCs, as observed during HIV and SIV infection. In fact, in HIV-infected individuals, a decrease in levels of circulating IL-21 and decreased production of IL-21 by CD4 cells was noted in blood (27). Similar to HIV infection, substantial depletion of IL-21+ CD4 T cells was reported in the blood in SIV-infected macaques (28). In lymphoid tissues of HIV patients, however, a marked expansion of IL-21-secreting TFHs was noted (29). Moreover, concurrent accumulation of TFH cells and particularly within the GCs of lymph node follicles and more precisely at the periphery of the GC had significantly increased IL-21 expression during SIV infection (30), suggesting trafficking of IL-21-producing TFH cells during the chronic immune activation characteristic of chronic SIV infection.\nFigure 1 Abnormal accumulation of TFH cells in hyperplastic GC during HIV/SIV primary infection. Naïve mature CD4 T cells are activated through dendritic cells. The persistent viral antigens stimulate primed CD4 T cells, resulting in the formation of hyperplastic GC with the massive B cell expansion, TFH accumulation, and development of network of follicular dendritic cells. Treg and PD-L1 expressing cells within GCs are capable of modulating GC TFH cells to suppress GC-related responses at the end stage of HIV infection. Upon HIV infection, there is a rapid infiltration of these TFH cells and formation of numerous GCs within lymphoid organs, characteristic of lymphocyte hyperplasia seen early in chronic infection. Recent studies demonstrated that HIV-infected patients displayed an aberrant accumulation of TFH cells compared to uninfected individuals (29). Similar observations were reported in lymph nodes, spleen, and gut tissues of rhesus macaques, in which the resident TFH cells (PD-1high CD4+ T cells) within GCs of hyperplastic follicles were markedly expanded, with a parallel increase and accumulation of Ki67+ GC B cells during chronic SIV infection (31, 32) (Figure 2). Of interest though, was the observation that as TFH accumulated within GCs, their expression of Ki67 decreased with up to 80% of TFH negative for this proliferation marker, suggesting that the continued input of this lineage to be contributed from cells migrating into follicles rather than local proliferation (30), and potentially, these cells have reached a terminal differentiation stage and function, which is to deliver help to local B cell differentiation and maturation. These findings are consistent with the limited proliferative capacity of human TFH cells whereby cross-linking their high level of PD-1 may dissociate continuous TCR signaling.\nFigure 2 Hyperplastic follicle in gut tissue during chronic SIV infection. Representative H\u0026E (upper) and immunofluorescence image (lower) of hyperplastic follicle staining with Ki67 (blue), PD-1 (green), and CD20 (red) in ileum from a chronically SIV-infected rhesus macaque. Understanding whether GC TFH cells accumulated during HIV/SIV infection are viral antigen-specific is also important. However, this has, hitherto, rarely been addressed because of the difficulty in identifying their responses. In this respect, there is also little experimental evidence demonstrating the dynamics between antigen-specific TFH cells and hyperplastic GCs. Interestingly, two recent articles have reported a novel assay to determine the frequencies of antigen-specific TFH cells within secondary lymphoid tissues of humans and macaques using cytokine-independent activation-induced markers CD25 and OX40 (33, 34). Such new technique is expected to markedly enhance our comprehension of the role of antigen specificity in the lymphoid hyperplasia that is observed during SIV/HIV infection."}

{"project":"MyTest","denotations":[{"id":"27920778-25367570-34327085","span":{"begin":391,"end":393},"obj":"25367570"},{"id":"27920778-25367570-34327086","span":{"begin":746,"end":748},"obj":"25367570"},{"id":"27920778-20810318-34327087","span":{"begin":750,"end":752},"obj":"20810318"},{"id":"27920778-11104797-34327088","span":{"begin":1012,"end":1014},"obj":"11104797"},{"id":"27920778-11104798-34327089","span":{"begin":1016,"end":1018},"obj":"11104798"},{"id":"27920778-9815267-34327090","span":{"begin":1368,"end":1370},"obj":"9815267"},{"id":"27920778-18602282-34327091","span":{"begin":1506,"end":1508},"obj":"18602282"},{"id":"27920778-18599325-34327092","span":{"begin":1627,"end":1629},"obj":"18599325"},{"id":"27920778-19949086-34327093","span":{"begin":1974,"end":1976},"obj":"19949086"},{"id":"27920778-22990011-34327094","span":{"begin":2101,"end":2103},"obj":"22990011"},{"id":"27920778-22922259-34327095","span":{"begin":2206,"end":2208},"obj":"22922259"},{"id":"27920778-24907346-34327096","span":{"begin":2427,"end":2429},"obj":"24907346"},{"id":"27920778-22922259-34327097","span":{"begin":3427,"end":3429},"obj":"22922259"},{"id":"27920778-22387550-34327098","span":{"begin":3736,"end":3738},"obj":"22387550"},{"id":"27920778-22922258-34327099","span":{"begin":3740,"end":3742},"obj":"22922258"},{"id":"27920778-24907346-34327100","span":{"begin":4068,"end":4070},"obj":"24907346"},{"id":"27920778-27335502-34327101","span":{"begin":5309,"end":5311},"obj":"27335502"},{"id":"27920778-27342848-34327102","span":{"begin":5313,"end":5315},"obj":"27342848"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"Follicular Helper T Cells in the GCs of Hyperplastic Follicles During the Course of HIV Infection\nSpecific CD4 T helper cells termed TFH cells differentiate from precursors under the control of the transcription factor Bcl6 and are characterized by their function, which is to provide T cell help for B cells, and are distinct from other CD4 T cell subsets such as Th1, Th2, and Th17 cells (20). In lymphoid tissues, information on the location of CD4 T cells within follicles is also vital to identifying resident TFH cells (Figure 1). Although there is no single marker for distinguishing TFH cells from other CD4 subsets, they are defined by their expression of surface co-stimulatory molecules CXCR5, CD200, ICOS, and a high density of PD-1 (20, 21). These memory type cells generally express low levels of CCR7 but are able to migrate toward B cell follicles in lymphoid organs, produce IL-21, and deliver B cell help in the GC environment for the development of T cell-dependent humoral adaptive immunity (22, 23). Studies using knock-out mice for IL-6 and IL-21 have shown that both are necessary for TFH differentiation and GC development in secondary follicles. IL-6-deficient mice exhibited a marked defect in GCs formation, STAT1 and STAT3 signaling, downstream IL-21 production, and IgG production primarily due to the lack of TFH differentiation in vivo (24). IL-21 deficiency also results in a severe reduction of GCs though this signal seems downstream of the one caused by IL-6 deficiency (25). Moreover, IL-6 and IL-21 appear to regulate the generation of TFH cells in the absence of Th1, Th2, and Th17 cells (26), suggesting that conversely, increases in the expression of IL-6, IL-21, or both cytokines may lead to lymphoid hyperplasia and rapid development of GCs, as observed during HIV and SIV infection. In fact, in HIV-infected individuals, a decrease in levels of circulating IL-21 and decreased production of IL-21 by CD4 cells was noted in blood (27). Similar to HIV infection, substantial depletion of IL-21+ CD4 T cells was reported in the blood in SIV-infected macaques (28). In lymphoid tissues of HIV patients, however, a marked expansion of IL-21-secreting TFHs was noted (29). Moreover, concurrent accumulation of TFH cells and particularly within the GCs of lymph node follicles and more precisely at the periphery of the GC had significantly increased IL-21 expression during SIV infection (30), suggesting trafficking of IL-21-producing TFH cells during the chronic immune activation characteristic of chronic SIV infection.\nFigure 1 Abnormal accumulation of TFH cells in hyperplastic GC during HIV/SIV primary infection. Naïve mature CD4 T cells are activated through dendritic cells. The persistent viral antigens stimulate primed CD4 T cells, resulting in the formation of hyperplastic GC with the massive B cell expansion, TFH accumulation, and development of network of follicular dendritic cells. Treg and PD-L1 expressing cells within GCs are capable of modulating GC TFH cells to suppress GC-related responses at the end stage of HIV infection. Upon HIV infection, there is a rapid infiltration of these TFH cells and formation of numerous GCs within lymphoid organs, characteristic of lymphocyte hyperplasia seen early in chronic infection. Recent studies demonstrated that HIV-infected patients displayed an aberrant accumulation of TFH cells compared to uninfected individuals (29). Similar observations were reported in lymph nodes, spleen, and gut tissues of rhesus macaques, in which the resident TFH cells (PD-1high CD4+ T cells) within GCs of hyperplastic follicles were markedly expanded, with a parallel increase and accumulation of Ki67+ GC B cells during chronic SIV infection (31, 32) (Figure 2). Of interest though, was the observation that as TFH accumulated within GCs, their expression of Ki67 decreased with up to 80% of TFH negative for this proliferation marker, suggesting that the continued input of this lineage to be contributed from cells migrating into follicles rather than local proliferation (30), and potentially, these cells have reached a terminal differentiation stage and function, which is to deliver help to local B cell differentiation and maturation. These findings are consistent with the limited proliferative capacity of human TFH cells whereby cross-linking their high level of PD-1 may dissociate continuous TCR signaling.\nFigure 2 Hyperplastic follicle in gut tissue during chronic SIV infection. Representative H\u0026E (upper) and immunofluorescence image (lower) of hyperplastic follicle staining with Ki67 (blue), PD-1 (green), and CD20 (red) in ileum from a chronically SIV-infected rhesus macaque. Understanding whether GC TFH cells accumulated during HIV/SIV infection are viral antigen-specific is also important. However, this has, hitherto, rarely been addressed because of the difficulty in identifying their responses. In this respect, there is also little experimental evidence demonstrating the dynamics between antigen-specific TFH cells and hyperplastic GCs. Interestingly, two recent articles have reported a novel assay to determine the frequencies of antigen-specific TFH cells within secondary lymphoid tissues of humans and macaques using cytokine-independent activation-induced markers CD25 and OX40 (33, 34). Such new technique is expected to markedly enhance our comprehension of the role of antigen specificity in the lymphoid hyperplasia that is observed during SIV/HIV infection."}