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      IgG4 Autoantibodies in Organ-Specific Autoimmunopathies: Reviewing Class Switching, Antibody-Producing Cells, and Specific Immunotherapies

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          Abstract

          Organ-specific autoimmunity is often characterized by autoantibodies targeting proteins expressed in the affected tissue. A subgroup of autoimmunopathies has recently emerged that is characterized by predominant autoantibodies of the IgG4 subclass (IgG4-autoimmune diseases; IgG4-AID). This group includes pemphigus vulgaris, thrombotic thrombocytopenic purpura, subtypes of autoimmune encephalitis, inflammatory neuropathies, myasthenia gravis and membranous nephropathy. Although the associated autoantibodies target specific antigens in different organs and thus cause diverse syndromes and diseases, they share surprising similarities in genetic predisposition, disease mechanisms, clinical course and response to therapies. IgG4-AID appear to be distinct from another group of rare immune diseases associated with IgG4, which are the IgG4-related diseases (IgG4-RLD), such as IgG4-related which have distinct clinical and serological properties and are not characterized by antigen-specific IgG4. Importantly, IgG4-AID differ significantly from diseases associated with IgG1 autoantibodies targeting the same organ. This may be due to the unique functional characteristics of IgG4 autoantibodies (e.g. anti-inflammatory and functionally monovalent) that affect how the antibodies cause disease, and the differential response to immunotherapies of the IgG4 producing B cells/plasmablasts. These clinical and pathophysiological clues give important insight in the immunopathogenesis of IgG4-AID. Understanding IgG4 immunobiology is a key step towards the development of novel, IgG4 specific treatments. In this review we therefore summarize current knowledge on IgG4 regulation, the relevance of class switching in the context of health and disease, describe the cellular mechanisms involved in IgG4 production and provide an overview of treatment responses in IgG4-AID.

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          IgG Subclasses and Allotypes: From Structure to Effector Functions

          Of the five immunoglobulin isotypes, immunoglobulin G (IgG) is most abundant in human serum. The four subclasses, IgG1, IgG2, IgG3, and IgG4, which are highly conserved, differ in their constant region, particularly in their hinges and upper CH2 domains. These regions are involved in binding to both IgG-Fc receptors (FcγR) and C1q. As a result, the different subclasses have different effector functions, both in terms of triggering FcγR-expressing cells, resulting in phagocytosis or antibody-dependent cell-mediated cytotoxicity, and activating complement. The Fc-regions also contain a binding epitope for the neonatal Fc receptor (FcRn), responsible for the extended half-life, placental transport, and bidirectional transport of IgG to mucosal surfaces. However, FcRn is also expressed in myeloid cells, where it participates in both phagocytosis and antigen presentation together with classical FcγR and complement. How these properties, IgG-polymorphisms and post-translational modification of the antibodies in the form of glycosylation, affect IgG-function will be the focus of the current review.
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            Regulatory B cells: origin, phenotype, and function.

            Regulatory B (Breg) cells are immunosuppressive cells that support immunological tolerance. Through the production of interleukin-10 (IL-10), IL-35, and transforming growth factor β (TGF-β), Breg cells suppress immunopathology by prohibiting the expansion of pathogenic T cells and other pro-inflammatory lymphocytes. Recent work has shown that different inflammatory environments induce distinct Breg cell populations. Although these findings highlight the relevance of inflammatory signals in the differentiation of Breg cells, they also raise other questions about Breg cell biology and phenotype. For example, what are the functional properties and phenotype of Breg cells? Can a Breg cell arise at every stage in B cell development? Is inflammation the primary requisite for Breg cell differentiation? Here, we use these questions to discuss the advances in understanding Breg cell biology, with a particular emphasis on their ontogeny; we propose that multiple Breg cell subsets can be induced in response to inflammation at different stages in development.
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              FcRn: the neonatal Fc receptor comes of age.

              The neonatal Fc receptor for IgG (FcRn) has been well characterized in the transfer of passive humoral immunity from a mother to her fetus. In addition, throughout life, FcRn protects IgG from degradation, thereby explaining the long half-life of this class of antibody in the serum. In recent years, it has become clear that FcRn is expressed in various sites in adults, where its potential function is now beginning to emerge. In addition, recent studies have examined the interaction between FcRn and the Fc portion of IgG with the aim of either improving the serum half-life of therapeutic monoclonal antibodies or reducing the half-life of pathogenic antibodies. This Review summarizes these two areas of FcRn biology.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                24 March 2022
                2022
                : 13
                : 834342
                Affiliations
                [1] 1 Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna , Vienna, Austria
                [2] 2 Neuroimmunology, Tzartos NeuroDiagnostics , Athens, Greece
                [3] 3 2nd Department of Neurology, “Attikon” University Hospital, School of Medicine, National and Kapodistrian University of Athens , Athens, Greece
                [4] 4 Research Group Neuroinflammation and Autoimmunity, Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University , Maastricht, Netherlands
                [5] 5 Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University , Istanbul, Turkey
                [6] 6 Department of Human Genetics, Leiden University Medical Center , Leiden, Netherlands
                [7] 7 Department of Neurology, Leiden University Medical Center , Leiden, Netherlands
                [8] 8 Department of Immunology, Laboratory of Immunology, Hellenic Pasteur Institute , Athens, Greece
                [9] 9 Department of Neurobiology, Hellenic Pasteur Institute , Athens, Greece
                [10] 10 Neuroimmunology, Institute of Clinical Chemistry and Department of Neurology, UKSH Kiel/Lübeck, Kiel University , Kiel, Germany
                Author notes

                Edited by: Robert Eisenberg, University of Pennsylvania, United States

                Reviewed by: Katrina Louise Randall, Australian National University, Australia; Matteo Gastaldi, Neurological Institute Foundation Casimiro Mondino (IRCCS), Italy

                *Correspondence: Inga Koneczny, inga.koneczny@ 123456meduniwien.ac.at

                †These authors have contributed equally to this work

                This article was submitted to B Cell Biology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2022.834342
                8986991
                35401530
                77f9a772-b23c-47fe-90e7-ef09f6f7ba24
                Copyright © 2022 Koneczny, Tzartos, Mané-Damas, Yilmaz, Huijbers, Lazaridis, Höftberger, Tüzün, Martinez-Martinez, Tzartos and Leypoldt

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 13 December 2021
                : 28 February 2022
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 258, Pages: 20, Words: 8799
                Funding
                Funded by: Austrian Science Fund , doi 10.13039/501100002428;
                Categories
                Immunology
                Review

                Immunology
                igg4 autoimmune disease,mhc,autoimmunity,il-4,il-10,fab-arm exchange,memory b cells
                Immunology
                igg4 autoimmune disease, mhc, autoimmunity, il-4, il-10, fab-arm exchange, memory b cells

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