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• W2116631495 abstract "This article introduces a series of reviews covering Fc Receptors appearing in Volume 268 of Immunological Reviews. The innate and adaptive immune responses jointly provide optimized mechanisms of protection. The receptors for immunoglobulins we know as Fc receptors (FcR), which are primarily expressed on/in innate immune cells, provide the antibodies – the archetypal mediators of the adaptive immunity – with cell-based systems of innate resistance and control. The academic, medical, and industry interest in FcR has increasingly been driven by the mounting evidence that these receptors are central to, or participate in, a surprisingly diverse range of ‘desirable’ and ‘undesirable’ immune functions. This diversity of roles reflects the extraordinary range of protective or modulating functions of immunoglobulins in normal host immunity and of destructive actions of antibodies in pathological immunity. It is the same modulating or destructive functions that the industry has so spectacularly harnessed in several effective antibody or Fc-based biological therapies. Indeed the diversity of review topics in this volume, reflects the remarkable diversity of antibody: FcR actions. The proposition that the biological properties of antibodies were conferred by their Fc portion and involved cell-based receptors was suggested over 50 years ago by Brambell et al. 1-3. Indeed, similarities between antitoxin (γ-globulin) sensitization and transport had already been identified (1 and citations therein). Boyden and Sorkin in the 1960s showed that exogenously produced 7S γ-globulin bound to the surface of macrophages allowing subsequent capture of antigen. They concluded that ‘…some active process…might be involved in the uptake of antigen, perhaps leaving the antibody free on the (cell) surface to react with more antigen’ 4. Over the ensuing decade, it became clear that preformed antigen–antibody complexes also bound to leukocytes in an Fc-dependent manner not only to phagocytes but also to cells of the adaptive immune system, i.e. B cells. It was also about this time that the term ‘Fc receptors’ emerged in the literature 5-8. These early studies either proposed or established the concept of cellular receptor-based, Fc-dependent systems. The research of the last 50 years has revealed that such FcR (in all their forms) provide more than a simple pathogen disposal mechanism. They are diverse in structure and function and represent a sophisticated system of immune modulation/regulation that control/modulate immune responses and consequential inflammatory responses. Although they form a critical part of immunity, not all FcR restricted to leukocytes and can be abundantly expressed on non-hematopoietic cells. Indeed, FcR activate and modulate pro-inflammatory and cytotoxic effector systems. They are necessary in anti-pathogen immunity even for the effectiveness of neutralizing antibodies. They are important for humoral immune defense against infection, indeed many pathogens design evasion mechanisms to frustrate or subvert FcR effector systems. In the adaptive immune system they regulate B-cell function. They deliver antigen captured by antibody into the antigen-presenting pathways for further stimulation of immunity. They control the transport and catabolism of circulating immunoglobulin G (IgG). They have causal or significant secondary roles in human disease pathogenesis as in heparin-induced thrombocytopenia (HIT) and most spectacularly seen in IgE-dependent allergy where they are of great clinical interest. They are of significant industrial importance because of their roles in the effectiveness of many therapeutic monoclonal antibodies (mAbs). The majority of FcR literature is dominated by studies that relate to those receptors present on leukocytes and predominately those receptors that belong to the Ig gene superfamily often referred to as the classical or canonical FcR. These include IgG receptors, FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16), and the IgE receptor FcεRI all of which are highly related, and FcαRI (CD89), also an Ig superfamily member but only distantly related. These receptors are sometimes referred to as Type I FcR. Other leukocyte-expressed FcR include a number of C-type lectins which include FcεRII (CD23) and more recently, sialo-receptors such as DC-SIGN in humans and SIGN-RI in the mouse, sometimes referred to as Type II FcR. Other FcR do not comfortably fit into the Type I/Type II definition including Fcα/μ receptor, the poly-Ig receptor and FcRn which is related to major histocompatibility complex class I. FcR action is not the exclusive province of the cell membrane and discovery of Fc binding by TRIM 21 defines the existence of intracellular FcR. This volume of Immunological Reviews provides analyses of the new and wide-ranging aspects of the actions of FcR in inflammation, infection, and immunity from in vivo and in vitro studies. The genetics, biology, structure, function, and clinical relevance of the classical FcR and emerging roles of non-classical FcR are detailed. New opportunities for the FcR targeting and manipulation for treatment of disease are also presented. The genetics of the FcγR family is complex and is a significant determining factor in disease susceptibility and from a practical perspective in the success of antibody therapy. Hargreaves et al. 9 provide a comprehensive analysis of the complexity of human FcγR genetics, the evolution of the family, and the impact of polymorphism in disease. In addition, they propose new approaches to exploring FcγR genetic variation. Understanding the roles of FcR in antibody effector functions have been facilitated by using mouse models, but differences in mouse and human immune biology have confounded analyses. Bruhns and Jonsson 10 provide a broad and comprehensive analysis of models of human and mouse FcγR function-using transgenic, gene knockout, or replacement strategies, which have been powerful tools in defining and redefining FcR function in vivo (Fig. 1). The possible molecular interplay between classical and non-classical FcγR in determining the nature and extent of pro- and anti-inflammatory cell responses to immune complexes is a recent concept 11, 12. Tissue macrophages and related cells such as osteoclasts and monocytes in the circulation express an array of FcR under different circumstances. Gordan et al. 12 describe the impact of FcR expression on the pro- and anti-inflammatory activity of IgG in macrophages in a variety of settings and how the cellular and molecular interplay of the classical FcR (Type I) and non-classical, (Type II) FcR affects macrophage function in autoimmunity and antibody-dependent cytotoxic killing. Continuing the theme of FcR control of leukocyte effector function and immunity, Bournazos and Ravetch 11 detail the consequences of the interplay between activating and inhibitory FcR – the classical Type I FcγR and non-classical Type II FcγR in activating or modulating effector cells and immunity in natural active immunity or passive immune manipulation. The immunoreceptor tyrosine-based activation motif and immunoreceptor tyrosine-based inhibition motif (ITAM/ITIM) system of immune complex-driven ‘outside in’ signaling and signal inhibition is well defined. However, it is now evident that this clear distinction between activation and inhibition has become somewhat blurred. Getahun and Cambier 13 provide a comparative analysis of the recently described dualism of the ITAM function which, under certain circumstances, and in the absence of receptor aggregation, can deliver inhibitory/tonic (ITAMi) signals. Brandsma et al. 14 then contrast the ‘outside in’ ITAM/ITIM signaling pathways, with the ‘inside out’ signaling. Effector cells in vivo operate in diverse environments, i.e. depending on the circumstances, cells can experience normal homoeostatic, pro-inflammatory, or anti-inflammatory environments. The ‘inside out’ signaling which can, for example, be modulated by cytokines, influences immune complex (ligand) binding and functional capacity of the FcR. The authors suggest that manipulation of the environments in therapeutic settings may improve FcR Ig binding and function for better therapeutic outcome. This is also discussed by Aleyd et al. 15 in the context of IgA function. As indicated above, the high-affinity FcγRI (CD64) was almost certainly responsible for the binding of uncomplexed cytophilic Ig described by Boyden and Sorkin 4. Yet, despite the passing of 55 years, this receptor remains the least characterized and possibly most misunderstood of the classical leukocyte (Type I) FcR. Its high affinity, around 1 nM, and its expression on cells in the presence of IgG concentrations in excess of 10 000 nM has historically presented something of a conundrum – how does a high-affinity receptor function in vivo in the presence of large excess of ligand of a multitude of specificities? The analysis of genetically manipulated mouse models by Bruhns and Jonsson 10 also describes the in vivo analysis of FcγRI function. Chenoweth et al. 16 tackle structure, signaling and function of human and macaque FcγRI and Swisher and Feldman 17 also look at activating and modulating functions of FcγRI and the implications of these for the use of therapeutic antibodies. The first two, and recently published, X-ray crystallographic structures of IgG1:FcγRI complexes are discussed by Lu and Sun 18 and Caaveiro et al. 19. The authors provide an extensive analysis of the similarities and differences between their respective structures and in a comprehensive analysis, relate these to the previously solved structures of Ig liganded, classical FcR. The role of FcR in the success of new biological medicines, particularly mAbs and Fc fusion proteins in several human therapeutic settings, has become an area of intense interest. mAb therapies are mostly based on human IgG and IgG1 in particular, and therefore FcγR are of importance. Much has been learned from the therapy of blood cancers and Dahal et al. 20 describe features of FcγR that are necessary for successful IgG antibody-based therapy. This success of mAb therapies and the growing knowledge base of FcR structure and function has spurred significant interest in the further manipulations of IgFc, particularly IgG for altered FcR functions. A structure-based ‘blueprint’ for antibody design based on FcR structures is provided by Caaveiro et al. 19 together with Lu and Sun 18 for IgG design. Many of the ‘rules’ of IgG FcR engagement have been formulated largely from studies of human IgG1. One on the ‘gaps’ in our understanding of human IgG:FcR biology is the role of IgG4. It is a high-affinity ligand (cytophilic IgG) for the high-affinity IgG receptor FcγRI and in immune complex form is an avid binder of the inhibitory FcγRIIb. Yet, relatively little is known of its biology and until recently, virtually nothing of its structure and function. Davies and Sutton 21 provide a comprehensive and comparative analysis of IgG4 structure and potential interaction with FcγRI and the other FcγR and the implications of its structure for its unusual biological functions. While much attention is focused on IgG and FcγR in the context of human disease pathogenesis and the development of biological therapeutics, Aleyd et al. 15 describe the pro- and anti-inflammatory activities of IgA and FcαRI in health and disease. Their analysis suggests strategies to harness these features in the treatment of inflammatory diseases or for mAb anti-cancer therapy. IgE-dependent allergy and allergic asthma is a major human affliction and an outstanding example of the involvement of FcR in human disease. Sutton and Davies 22 analyze new structural data for the interaction between IgE and its two leukocyte receptors – the FcεRI, a classical leukocyte ‘Type I’ FcR and the FcεRII (CD23), a non-classical Type II FcR C-type lectin family member. The effects of surprising flexibility within the IgE molecule on regulating receptor interactions have significant implications for FcR-dependent cell function and have potential to offer new opportunities for therapy. Moreover, these studies also serve as a well-defined structure-based paradigm for the dynamic interplay between the antibody ligands and classical and non-classical FcR in affecting receptor binding and cell function. Resistance to pathogens is the raison d’être of the immune system. During infection and inflammation, FcR do not work in isolation. van Egmond et al. 23 address the functional relationships between pattern recognition receptors and FcR. These mechanisms influence optimal anti-pathogen resistance and also in adverse settings, can relate to ongoing pathological inflammation. Boesch et al. 24 also draw together laboratory, in vivo, and clinical evidence that suggest the critical importance of FcR:antibody interactions in passive and active antibody resistance to HIV. In the constant struggle between host and pathogen, immune evasion systems have been developed by pathogens to circumvent or frustrate immunity. Taylor et al. 25 describe how some viruses turn FcR effector systems to their considerable advantage in antibody-dependent enhancement (ADE). While this is most recognized in flavivirus infections such as dengue fever, ADE may also be clinically relevant in a number of other major human viral pathogens as different as Ebola and corona viruses. The FcR armory against infection is not restricted to the classical leukocyte FcR of the cell surface. Foss et al. 26 describe the roles and characteristics of the cytoplasmic FcR, TRIM21. This unique receptor has broad specificity for Ig isotypes and provides an intracellular-based resistance, perhaps a ‘last line of defense’, which also has broad implications in vaccine design. The biological, medical, and industrial interest in FcR and antibody function has been focused mostly on FcR of nucleated leukocytes. However, there are two specific and important areas that have somewhat been neglected but are coming into prominence. Qiao et al. 27 highlight aspects of the uniquely primate FcγRIIa and its biochemistry and function that have been revealed by studies of the platelet. They review the roles of platelet FcγRIIa in injury, infection, and in autoimmunity and life-threatening HIT – a truly FcγR-dependent pathology – and suggest diagnostic strategies for HIT detection based on analysis of HIT patient plasma. The second area is the expression of canonical Type I FcR on non-hematopoietic cells. Anderson et al. 28 provide a perspective on non-hemopoietic expression of the inhibitory FcγRIIb. Its expression in liver endothelial cells makes this one of the most abundantly expressed receptors and, ironically, in cells that are not directly related to the immune system. The authors pose interesting questions for understanding the inhibitory FcR biology in the absence of ITAM-dependent immunoreceptor signaling. They raise the possibility of new pathways of FcR function in non-hemopoietic cells which may pose opportunities for antibody engineers and new challenges for regulatory authorities. FcRn or the ‘Brambell receptor’ 2 is well known for its importance in neonatal transport of IgG subclasses and for protection of IgG from catabolism resulting in the long half-life of certain IgG subclasses. This is important in biologics for the manipulation of the in vivo half-life of Fc fusion proteins and mAbs. However, broader roles in immunity have emerged for FcRn. Stapleton et al. 29 comprehensively describe new biological and immunological functions including phagocytosis and antigen sampling for the purposes of antigen presentation. Cervenak et al. 30 follow on from this and describe how FcRn can be used in vivo to both qualitatively and quantitatively enhance and improve humoral immunity and how such improvements may be practically used. The regulation of B-cell function by the inhibitory FcγRIIb or FcεRII is well documented. However, Shibuya and Honda 31 describe Fcα/μR (CD351) – one of the less well-known receptors and one of the few receptors for IgM. They describe its expression on marginal zone B cells and its involvement in the development of humoral immune responses. In the development of this volume of Immunological Reviews, I thank all the authors for their insightful, informative, and sometimes provocative reviews. I would also like to thank Justina Stadanlick and the journal editorial staff, particularly Nicky Cotterill, for their work on this volume. Finally, thanks also to Ms. Alicia Chenoweth, Dr. Bruce Wines, Prof. Sally Ward, and John Cambier for helpful comments." @default.
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• W2116631495 title "Fc Receptors: Introduction" @default.
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