Update on IgG4-mediated autoimmune diseases: New insights and new family members

Koneczny, Inga

doi:10.1016/j.autrev.2020.102646

Cited by 65 publications

(64 citation statements)

References 350 publications

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“…THSD7A-IgG4 was hypothesized to block protein-protein interactions of THSD7 and cell-cell interactions, therefore affecting the glomerular filtration and causing proteinuria (73)(74)(75). Potentially affected binding partners of PLA2R are collagen IV (76), which is important for cell adhesion, or the At2-complex (14,77), which is important to maintain cell architecture and affect podocyte function. Perhaps a blocking of PLA2R interaction with these binding partners affects cell adhesion and/or cell architecture.…”

Section: Known Igg4 Autoantibody-associated Disease: a Colorful Bouquetmentioning

confidence: 99%

“…IgG4 autoimmune diseases were first appreciated as a group in 2015 (13). The number of suspected IgG4-AID is constantly growing and to date, 29 candidate antigens are known [Figure 1, (14)]. Most antigens are located in the central and peripheral nervous system, but there are also antigens in the skin and mucosa, kidneys and in the hematological system (Figure 1).…”

Section: Introduction To Igg4-aidmentioning

confidence: 99%

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Common Denominators in the Immunobiology of IgG4 Autoimmune Diseases: What Do Glomerulonephritis, Pemphigus Vulgaris, Myasthenia Gravis, Thrombotic Thrombocytopenic Purpura and Autoimmune Encephalitis Have in Common?

et al. 2021

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IgG4 autoimmune diseases (IgG4-AID) are an emerging group of autoimmune diseases that are caused by pathogenic autoantibodies of the IgG4 subclass. It has only recently been appreciated, that members of this group share relevant immunobiological and therapeutic aspects even though different antigens, tissues and organs are affected: glomerulonephritis (kidney), pemphigus vulgaris (skin), thrombotic thrombocytopenic purpura (hematologic system) muscle-specific kinase (MuSK) in myasthenia gravis (peripheral nervous system) and autoimmune encephalitis (central nervous system) to give some examples. In all these diseases, patients’ IgG4 subclass autoantibodies block protein-protein interactions instead of causing complement mediated tissue injury, patients respond favorably to rituximab and share a genetic predisposition: at least five HLA class II genes have been reported in individual studies to be associated with several different IgG4-AID. This suggests a role for the HLA class II region and specifically the DRβ1 chain for aberrant priming of autoreactive T-cells toward a chronic immune response skewed toward the production of IgG4 subclass autoantibodies. The aim of this review is to provide an update on findings arguing for a common pathogenic mechanism in IgG4-AID in general and to provide hypotheses about the role of distinct HLA haplotypes, T-cells and cytokines in IgG4-AID.

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Section: Known Igg4 Autoantibody-associated Disease: a Colorful Bouquetmentioning

confidence: 99%

Section: Introduction To Igg4-aidmentioning

confidence: 99%

Common Denominators in the Immunobiology of IgG4 Autoimmune Diseases: What Do Glomerulonephritis, Pemphigus Vulgaris, Myasthenia Gravis, Thrombotic Thrombocytopenic Purpura and Autoimmune Encephalitis Have in Common?

et al. 2021

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“…In addition to Fab-arm exchange, the lower mobility of IgG4s due to their shorter-compared to IgG1-hinge region complicates their structure, making IgG4 even less likely to be crosslinking antigens (111). Overall, the IgG4 subclass remains relatively poorly studied yet plays a fundamental role in neurological and non-neurological autoimmunity (58)(59)(60)(61).…”

Section: Mechanistic Differences Between Igg1 and Igg4 Antibodiesmentioning

confidence: 99%

Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders

2021

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As B cells differentiate into antibody-secreting cells (ASCs), short-lived plasmablasts (SLPBs) are produced by a primary extrafollicular response, followed by the generation of memory B cells and long-lived plasma cells (LLPCs) in germinal centers (GCs). Generation of IgG4 antibodies is T helper type 2 (Th2) and IL-4, -13, and -10-driven and can occur parallel to IgE, in response to chronic stimulation by allergens and helminths. Although IgG4 antibodies are non-crosslinking and have limited ability to mobilize complement and cellular cytotoxicity, when self-tolerance is lost, they can disrupt ligand-receptor binding and cause a wide range of autoimmune disorders including neurological autoimmunity. In myasthenia gravis with predominantly IgG4 autoantibodies against muscle-specific kinase (MuSK), it has been observed that one-time CD20+ B cell depletion with rituximab commonly leads to long-term remission and a marked reduction in autoantibody titer, pointing to a short-lived nature of autoantibody-secreting cells. This is also observed in other predominantly IgG4 autoantibody-mediated neurological disorders, such as chronic inflammatory demyelinating polyneuropathy and autoimmune encephalitis with autoantibodies against the Ranvier paranode and juxtaparanode, respectively, and extends beyond neurological autoimmunity as well. Although IgG1 autoantibody-mediated neurological disorders can also respond well to rituximab induction therapy in combination with an autoantibody titer drop, remission tends to be less long-lasting and cases where titers are refractory tend to occur more often than in IgG4 autoimmunity. Moreover, presence of GC-like structures in the thymus of myasthenic patients with predominantly IgG1 autoantibodies against the acetylcholine receptor and in ovarian teratomas of autoimmune encephalitis patients with predominantly IgG1 autoantibodies against the N‐methyl‐d‐aspartate receptor (NMDAR) confers increased the ability to generate LLPCs. Here, we review available information on the short-and long-lived nature of ASCs in IgG1 and IgG4 autoantibody-mediated neurological disorders and highlight common mechanisms as well as differences, all of which can inform therapeutic strategies and personalized medical approaches.

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“…IgG4 | autoimmunity | myasthenia gravis | MuSK | monoclonal antibodies R ecently, a growing class of antibody-mediated autoimmune diseases characterized by predominant pathogenic immunoglobulin (Ig) G4 responses has been described (1)(2)(3)(4). IgG4 is a peculiar antibody with unique characteristics.…”

mentioning

confidence: 99%

Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis

Vergoossen

Plomp

Gstöttner

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Human immunoglobulin (Ig) G4 usually displays antiinflammatory activity, and observations of IgG4 autoantibodies causing severe autoimmune disorders are therefore poorly understood. In blood, IgG4 naturally engages in a stochastic process termed “Fab-arm exchange” in which unrelated IgG4s exchange half-molecules continuously. The resulting IgG4 antibodies are composed of two different binding sites, thereby acquiring monovalent binding and inability to cross-link for each antigen recognized. Here, we demonstrate that this process amplifies autoantibody pathogenicity in a classic IgG4-mediated autoimmune disease: muscle-specific kinase (MuSK) myasthenia gravis. In mice, monovalent anti-MuSK IgG4s caused rapid and severe myasthenic muscle weakness, whereas the same antibodies in their parental bivalent form were less potent or did not induce a phenotype. Mechanistically this could be explained by opposing effects on MuSK signaling. Isotype switching to IgG4 in an autoimmune response thereby may be a critical step in the development of disease. Our study establishes functional monovalency as a pathogenic mechanism in IgG4-mediated autoimmune disease and potentially other disorders.

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Update on IgG4-mediated autoimmune diseases: New insights and new family members

Cited by 65 publications

References 350 publications

Common Denominators in the Immunobiology of IgG4 Autoimmune Diseases: What Do Glomerulonephritis, Pemphigus Vulgaris, Myasthenia Gravis, Thrombotic Thrombocytopenic Purpura and Autoimmune Encephalitis Have in Common?

Common Denominators in the Immunobiology of IgG4 Autoimmune Diseases: What Do Glomerulonephritis, Pemphigus Vulgaris, Myasthenia Gravis, Thrombotic Thrombocytopenic Purpura and Autoimmune Encephalitis Have in Common?

Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders

Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis

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