PMC:7228307 / 9471-21313 JSONTXT

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{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/7228307","sourcedb":"PMC","sourceid":"7228307","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7228307","text":"Human FcγR General Properties\nThe 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.\nThese FcγRs are high‐avidity sensors of immune complexes which initiate, and then modulate, cell responses. 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). These responses are not mutually exclusive and one therapeutic mAb may initiate various responses via different FcγRs and via different cell types.\nUnderstanding 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. In this review, we address only key aspects of the extensive knowledge of the human leukocyte FcγR family as it relates to effector functions. 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\nTable 2 Properties of FcγR.\nReceptor Affinity IgG specificity Cell distribution\nFcγRI High IgG1, IgG3, IgG4 Induced by interferon‐γ on monocytes, neutrophils, macrophages, dendritic cell subpopulations; mast cells\nFcγRIIa Low IgG1, IgG3, but IgG2 binding limited to the FcγRIIa‐H131 form, ~70% people) All leukocytes and platelets except T and B lymphocytes\nFcγRIIc a Low IgG1, IgG3, IgG4 NK cells\nFcγRIIIa Low IgG1, IgG3. NK cells, macrophages, subpopulation of circulating monocytes, myeloid dendritic cells, neutrophils at very low levels\nBinding avidity reduced by Phe at position 158\nFcγRIIIb Low IgG1, IgG3 Neutrophils\nFcγRIIb Low IgG1, IgG3, IgG4 B lymphocytes, some monocytes (can be upregulated); basophils; eosinophils? Plasmacytoid and myeloid dendritic cells; NK cells only of individuals with FcγRIIIb gene copy number variation\nAirway smooth muscle, LSEC, placenta, follicular dendritic cell\nIg, immunoglobulin; NK cell, natural killer cell.\na Expressed in 20% of people.\nJohn Wiley \u0026 Sons, Ltd This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. 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.\nTable 3 Unique features of IgG subclass Fc and hinge.\nIgG subclass FcγR specificity Light‐chain attachment Hinge characteristics Fc stability Comment\nIgG1 All FcγR Upper hinge Light‐chain attachment Stable Fc is \u003e100× times more stable than IgG4 and IgG2.\nStable core hinge\nIgG2 FcγRIIa His131 CH1 of Fab and/or upper hinge Stable core hinge with additional inter H‐chain disulfide bonds in the upper hinge. Unstable CH3:CH3 Alternative light‐chain attachment creates distinct conformers. Unlike IgG4, the CH3:CH3 instability does not lead to half‐molecule exchange as a result of stable core and upper hinge disulfides.\nIgG4 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\nIg, immunoglobulin.\nJohn Wiley \u0026 Sons, Ltd This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. 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.\n\nFcγR expression on hemopoietic cells\nThe 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.\nFcγR expression profiles differ between cell lineages but almost all mature human leukocytes, and platelets, express at least one FcγR (Table 2). 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\nThus, specific characteristics of leukocyte FcγR expression are summarized as follows:\nFcγRI 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. 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\nFcγRIIa is expressed only in primates and shows the broadest expression of all FcγRs, being present on all innate leukocytes. It is also present on platelets but its role in effector functions is not established but it is important in certain immune thrombocytopenias. A polymorphic form of this receptor is the only human receptor for human IgG2. 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. 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\nFcγRIIc 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. Thus FcγRIIc provides IgG4 with an activation receptor pathway and confers a new biology of IgG4 in these individuals. 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.\nFcγRIII forms are two highly related gene products, FcγRIIIa and FcγRIIIb. The FcγRIIIa is expressed on NK cells and professional phagocytes, particularly macrophages. 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. It is expressed, predominantly and abundantly, on human neutrophils.7 Its effector function depends in part on its coexpression with FcγRIIa. The lack of FcγRIIIb on macaque neutrophils appears to be compensated for by an increase in FcγRIIa expression.15\nFcγRIIbs are the inhibitory‐type FcγR and arise from a single gene. They lack intrinsic proinflammatory signaling and are instead immune checkpoints. They provide feedback regulation by antibodies, in the form of immune complexes, to inhibit B‐cell activation by specific antigen. They also control activating‐type FcγR function on innate cells. Two major splice variant forms of FcγRIIb exist with differential tissue expression profiles. 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). 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. 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.\nOne additional comment on tissue distribution is that FcγR expression on T cells has been difficult to establish unequivocally. However, there is increasing evidence that T‐lymphocyte populations express FcγR. 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\n\nExpression on nonhemopoietic cells\nThe 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. These studies suggest important roles in normal immune function and in the MOA of some therapeutic mAbs. The most extensively characterized receptor expression is FcγRIIb which is expressed on follicular dendritic cell, airway smooth muscle and liver endothelium. 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. 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.\n\nFcγR activating or inhibitory signaling\nEffector functions that are initiated via the activating‐type FcγR occur by signaling via the ITAM pathway of immune receptors. 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. 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. 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\nThe 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 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