LitCovid-sample-sentences  

PMC:7228307 / 9471-21313 JSONTXT 25 Projects

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Id Subject Object Predicate Lexical cue
T52 0-29 Sentence denotes Human FcγR General Properties
T53 30-397 Sentence denotes The human leukocyte receptors fall into two functional groups, namely, proinflammatory, activating‐type receptors (FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa and FcγRIIIb, which are also known as CD64, CD32a, CD32c, CD16a and CD16b, respectively) and the anti‐inflammatory, inhibitory‐receptor group (FcγRIIb also called CD32b) which was the first immune checkpoint described.
T54 398-505 Sentence denotes These FcγRs are high‐avidity sensors of immune complexes which initiate, and then modulate, cell responses.
T55 506-714 Sentence denotes In the context of normal immune physiology, opsonized target molecules can engage various FcγRs and induce a spectrum of effector responses which can be harnessed by many therapeutic mAbs (Figure 1, Table 1).
T56 715-862 Sentence denotes These responses are not mutually exclusive and one therapeutic mAb may initiate various responses via different FcγRs and via different cell types.
T57 863-1118 Sentence denotes Understanding the importance of cell‐based effector functions in the MOA of therapeutic mAbs requires an appreciation of FcγR biology (Tables 1, 2, 3) which also underpins future efforts to tailor new mAbs for the exploitation‐specific effector responses.
T58 1119-1261 Sentence denotes In this review, we address only key aspects of the extensive knowledge of the human leukocyte FcγR family as it relates to effector functions.
T59 1262-1762 Sentence denotes A number of other reviews more comprehensively explore FcγR biology physiology, biochemistry, genetics and structure.7, 11, 12, 13, 14 Notwithstanding the recognized differences between the immunobiology of human FcγR and of rodents or nonhuman primates, animal models of FcR effector function in vivo have helped shape the strategies for the development of current therapeutic mAbs and are well reviewed.12, 15 Furthermore, humanized FcγR models will provide even greater insights into the future.16
T60 1763-1791 Sentence denotes Table 2 Properties of FcγR.
T61 1792-1846 Sentence denotes Receptor Affinity IgG specificity Cell distribution
T62 1847-1983 Sentence denotes FcγRI High IgG1, IgG3, IgG4 Induced by interferon‐γ on monocytes, neutrophils, macrophages, dendritic cell subpopulations; mast cells
T63 1984-2130 Sentence denotes FcγRIIa Low IgG1, IgG3, but IgG2 binding limited to the FcγRIIa‐H131 form, ~70% people) All leukocytes and platelets except T and B lymphocytes
T64 2131-2173 Sentence denotes FcγRIIc a Low IgG1, IgG3, IgG4 NK cells
T65 2174-2200 Sentence denotes FcγRIIIa Low IgG1, IgG3.
T66 2202-2320 Sentence denotes NK cells, macrophages, subpopulation of circulating monocytes, myeloid dendritic cells, neutrophils at very low levels
T67 2321-2367 Sentence denotes Binding avidity reduced by Phe at position 158
T68 2368-2406 Sentence denotes FcγRIIIb Low IgG1, IgG3 Neutrophils
T69 2407-2514 Sentence denotes FcγRIIb Low IgG1, IgG3, IgG4 B lymphocytes, some monocytes (can be upregulated); basophils; eosinophils?
T70 2515-2626 Sentence denotes Plasmacytoid and myeloid dendritic cells; NK cells only of individuals with FcγRIIIb gene copy number variation
T71 2627-2690 Sentence denotes Airway smooth muscle, LSEC, placenta, follicular dendritic cell
T72 2691-2740 Sentence denotes Ig, immunoglobulin; NK cell, natural killer cell.
T73 2741-2771 Sentence denotes a Expressed in 20% of people.
T74 2772-2919 Sentence denotes John Wiley & Sons, Ltd This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response.
T75 2920-3102 Sentence denotes It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
T76 3103-3157 Sentence denotes Table 3 Unique features of IgG subclass Fc and hinge.
T77 3158-3258 Sentence denotes IgG subclass FcγR specificity Light‐chain attachment Hinge characteristics Fc stability Comment
T78 3259-3369 Sentence denotes IgG1 All FcγR Upper hinge Light‐chain attachment Stable Fc is >100× times more stable than IgG4 and IgG2.
T79 3370-3387 Sentence denotes Stable core hinge
T80 3388-3524 Sentence denotes IgG2 FcγRIIa His131 CH1 of Fab and/or upper hinge Stable core hinge with additional inter H‐chain disulfide bonds in the upper hinge.
T81 3526-3607 Sentence denotes Unstable CH3:CH3 Alternative light‐chain attachment creates distinct conformers.
T82 3608-3739 Sentence denotes Unlike IgG4, the CH3:CH3 instability does not lead to half‐molecule exchange as a result of stable core and upper hinge disulfides.
T83 3740-3901 Sentence denotes IgG4 FcγRI, FcγRIIb, FcγRIIc CH1 of Fab Labile core hinge Unstable CH3:CH3 Combined instability of core hinge and CH3:CH3 permits half‐IgG molecule exchange
T84 3902-3921 Sentence denotes Ig, immunoglobulin.
T85 3922-4069 Sentence denotes John Wiley & Sons, Ltd This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response.
T86 4070-4252 Sentence denotes It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
T87 4254-4290 Sentence denotes FcγR expression on hemopoietic cells
T88 4291-4555 Sentence denotes The tissue distribution of the human leukocyte FcγR is well documented and reviewed comprehensively elsewhere.7, 11, 17 In the context of effector functions harnessed by therapeutic mAbs, several aspects of the cellular distribution (Table 2) should be emphasized.
T89 4556-4701 Sentence denotes FcγR expression profiles differ between cell lineages but almost all mature human leukocytes, and platelets, express at least one FcγR (Table 2).
T90 4702-5143 Sentence denotes It should also be appreciated that the cellular expression levels and receptor diversity as will be described later is also influenced by the activation state of the cells, anatomical location and the cytokine environment which modulates FcγR expression, particularly for FcγRI and FcγRIIb.18 For example, resting monocyte subpopulations may express only FcγRIIa but activated macrophages express FcγRI, FcγRIIa and FcγRIIIa and/or FcγRIIb.7
T91 5144-5230 Sentence denotes Thus, specific characteristics of leukocyte FcγR expression are summarized as follows:
T92 5231-5412 Sentence denotes FcγRI is not usually expressed until induced by cytokines such as interferon‐γ on monocytes, neutrophils, macrophages, microglial cells in the brain, dendritic cells and mast cells.
T93 5413-5698 Sentence denotes The sensitivity of FcγRI to interferon‐γ suggests that its in vivo activity is closely tied to immune activation events, and mouse studies have suggested that it has a critical role early in immune responses.19, 20 Its role in the MOA of antibodies may vary with anatomical location.21
T94 5699-5824 Sentence denotes FcγRIIa is expressed only in primates and shows the broadest expression of all FcγRs, being present on all innate leukocytes.
T95 5825-5967 Sentence denotes It is also present on platelets but its role in effector functions is not established but it is important in certain immune thrombocytopenias.
T96 5968-6046 Sentence denotes A polymorphic form of this receptor is the only human receptor for human IgG2.
T97 6047-6221 Sentence denotes This, together with its limited species expression and unique ITAM‐containing cytoplasmic tail (reviewed by Anania et al. 11), suggests a unique function in human leukocytes.
T98 6222-6468 Sentence denotes Interestingly, polymorphism of the receptor is associated with systemic lupus erythematosus and resistance to Gram‐negative organisms.11 A rare, hyper‐responsive form is a risk factor for neutrophil‐driven anaphylaxis in Ig replacement therapy.22
T99 6469-6908 Sentence denotes FcγRIIc is an activating FcγR whose expression is regulated single nucleotide polymorphism that permits expression in approximately 20% of humans and in whom it is present at low levels on natural killer (NK) and B cells.11 It has arisen by gene duplication/recombination resulting in an extracellular region  derived from  FcγRIIb, which binds IgG4, and with an ITAM‐containing cytoplasmic tail related to the activating receptor FcγRIIa.
T100 6909-7027 Sentence denotes Thus FcγRIIc provides IgG4 with an activation receptor pathway and confers a new biology of IgG4 in these individuals.
T101 7028-7160 Sentence denotes Its low frequency in the population may also confound in vivo mAb clinical testing or use, but as yet there is no evidence for this.
T102 7161-7235 Sentence denotes FcγRIII forms are two highly related gene products, FcγRIIIa and FcγRIIIb.
T103 7236-7328 Sentence denotes The FcγRIIIa is expressed on NK cells and professional phagocytes, particularly macrophages.
T104 7329-7576 Sentence denotes It is only recently apparent that FcγRIIIa is expressed on neutrophils, albeit at low levels, but plays a role in their function.23 FcγRIIIb is unique to humans and unlike other FcγRs it is attached to cell membrane via a glycophosphatidyl anchor.
T105 7577-7718 Sentence denotes It is expressed, predominantly and abundantly, on human neutrophils.7 Its effector function depends in part on its coexpression with FcγRIIa.
T106 7719-7832 Sentence denotes The lack of FcγRIIIb on macaque neutrophils appears to be compensated for by an increase in FcγRIIa expression.15
T107 7833-7900 Sentence denotes FcγRIIbs are the inhibitory‐type FcγR and arise from a single gene.
T108 7901-7982 Sentence denotes They lack intrinsic proinflammatory signaling and are instead immune checkpoints.
T109 7983-8113 Sentence denotes They provide feedback regulation by antibodies, in the form of immune complexes, to inhibit B‐cell activation by specific antigen.
T110 8114-8178 Sentence denotes They also control activating‐type FcγR function on innate cells.
T111 8179-8272 Sentence denotes Two major splice variant forms of FcγRIIb exist with differential tissue expression profiles.
T112 8273-8457 Sentence denotes FcγRIIb1 preferentially expressed on B lymphocytes contains a 20‐amino acid cytoplasmic insertion necessary for membrane retention and cocapping with the B‐cell antigen receptor (BCR).
T113 8458-8633 Sentence denotes FcγRIIb2 is the predominant inhibitory receptor found on basophils and neutrophils, as well as on subpopulations of mast cells, dendritic cells and some monocytes/macrophages.
T114 8634-8850 Sentence denotes FcγRIIb2 lacks the cytoplasmic insertion of FcγRIIb1 and consequently can internalize rapidly including with the activating FcR when they are co‐cross‐linked.11 It is not clear which form is present on human T cells.
T115 8851-8978 Sentence denotes One additional comment on tissue distribution is that FcγR expression on T cells has been difficult to establish unequivocally.
T116 8979-9060 Sentence denotes However, there is increasing evidence that T‐lymphocyte populations express FcγR.
T117 9061-9272 Sentence denotes Some γδ T cells express FcγRIIIa and αβ T cells reportedly express FcγRIIa, FcγRIIb or FcγRIIIa but the significance with respect to effector function mediated by antibody is presently unclear.24, 25, 26, 27, 28
T118 9274-9308 Sentence denotes Expression on nonhemopoietic cells
T119 9309-9532 Sentence denotes The immunobiology of FcγR is studied and understood almost exclusively in the context of hematopoietic cell function but relatively recent investigations have identified and explored FcγR expression on nonhemopoietic cells.
T120 9533-9637 Sentence denotes These studies suggest important roles in normal immune function and in the MOA of some therapeutic mAbs.
T121 9638-9796 Sentence denotes The most extensively characterized receptor expression is FcγRIIb which is expressed on follicular dendritic cell, airway smooth muscle and liver endothelium.
T122 9797-10187 Sentence denotes Its abundant expression on liver sinusoidal endothelial cells (LSECs) is estimated to represent the majority of in vivo FcγRIIb expression.17, 29, 30, 31 As FcγRIIb lacks intrinsic proinflammatory signaling function, its role on these nonhemopoietic cells involves immune complex handling without the danger of, or the need for, induction of local tissue destructive inflammatory responses.
T123 10188-10525 Sentence denotes On LSEC its major role appears to be immune complex sweeping, a process of removal of small immune complexes such as opsonized virus or macromolecules.17 This scavenging role by FcγRIIb on LSEC can be exploited in principle by mAbs forming small soluble complexes with their targets such as antiviral, anticytokine or similar antibodies.
T124 10527-10566 Sentence denotes FcγR activating or inhibitory signaling
T125 10567-10694 Sentence denotes Effector functions that are initiated via the activating‐type FcγR occur by signaling via the ITAM pathway of immune receptors.
T126 10695-10879 Sentence denotes This well‐characterized pathway is used by BCR and T‐cell antigen receptors, the IgE receptor FcεRI and IgA receptor FcαRI (reviewed extensively by Hogarth and Pietersz 7 Anania et al.
T127 10880-11047 Sentence denotes 11 and Getahun and Cambier 32) Induction of an activating signal requires the aggregation of activating FcγR by immune complexes, or by antigen in the case of the BCR.
T128 11048-11208 Sentence denotes This aggregation at the cell membrane results in specific tyrosine phosphorylation of the ITAM by Src kinases, thus initiating the activation cascade.32, 33, 34
T129 11209-11842 Sentence denotes The inhibitory‐type FcγRs, FcγRIIb1 and FcγRIIb2, whose expression is cell lineage restricted, modulate the ITAM signaling of the BCR or the activating‐type FcγRs, respectively.11 Their function is dependent on the immunoreceptor tyrosine inhibition motif in their cytoplasmic tail.32, 33 This checkpoint action requires that FcγRIIbs are coaggregated with the tyrosine‐phosphorylated ITAM‐signaling receptor complex which results also in immunoreceptor tyrosine inhibition motif tyrosine phosphorylation and consequential recruitment of lipid or protein tyrosine phosphatases that powerfully dampen the ITAM‐induced cell activation.