A systematic review and meta-analysis of HLA class II associations in patients with IgG4 autoimmunity

Panhuber, Anja; Lamorte, Giovanni; Bruno, Verónica; Çetin, Hakan; Bauer, Wolfgang; Höftberger, Romana; Erber, Astrid; Frommlet, Florian; Koneczny, Inga

doi:10.1038/s41598-022-13042-2

Cited by 14 publications

(13 citation statements)

References 118 publications

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“…A recent systematic review reports strong associations of IgG4-AIDs with HLA-DQB1*05 and HLA-DRB1*14, suggesting that these haplotypes predispose to the development of IgG4-AIDs (ref. 88 ). This may occur through directing B cell development and cytokine production, or by facilitating antigen presentation.…”

Section: Igg4-dependent Pathologymentioning

confidence: 99%

The unique properties of IgG4 and its roles in health and disease

Rispens

Huijbers

2023

Nat Rev Immunol

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IgG4 is the least abundant subclass of IgG in human serum and has unique functional features. IgG4 is largely unable to activate antibody-dependent immune effector responses and, furthermore, undergoes Fab (fragment antigen binding)-arm exchange, rendering it bispecific for antigen binding and functionally monovalent. These properties of IgG4 have a blocking effect, either on the immune response or on the target protein of IgG4. In this Review, we discuss the unique structural characteristics of IgG4 and how these contribute to its roles in health and disease. We highlight how, depending on the setting, IgG4 responses can be beneficial (for example, in responses to allergens or parasites) or detrimental (for example, in autoimmune diseases, in antitumour responses and in anti-biologic responses). The development of novel models for studying IgG4 (patho)physiology and understanding how IgG4 responses are regulated could offer insights into novel treatment strategies for these IgG4-associated disease settings.

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Section: Igg4-dependent Pathologymentioning

confidence: 99%

The unique properties of IgG4 and its roles in health and disease

Rispens

Huijbers

2023

Nat Rev Immunol

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“…Further, HLA alleles play a role in IgG4 production. There is a strong, cross-disease association with HLA-DQB1*05 ( 60 ). This HLA allele apparently predisposes to IgG4 generation, but, as shown in this study, it antagonizes the humoral immune response to anti-TSST-1.…”

Section: Discussionmentioning

confidence: 99%

Toxin exposure and HLA alleles determine serum antibody binding to toxic shock syndrome toxin 1 (TSST-1) of Staphylococcus aureus

Weiss,

Holtfreter,

Meyer

et al. 2023

Front. Immunol.

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Life-threatening toxic shock syndrome is often caused by the superantigen toxic shock syndrome toxin-1 (TSST-1) produced by Staphylococcus aureus. A well-known risk factor is the lack of neutralizing antibodies. To identify determinants of the anti-TSST-1 antibody response, we examined 976 participants of the German population-based epidemiological Study of Health in Pomerania (SHIP-TREND-0). We measured anti-TSST-1 antibody levels, analyzed the colonization with TSST-1-encoding S. aureus strains, and performed a genome-wide association analysis of genetic risk factors. TSST-1-specific serum IgG levels varied over a range of 4.2 logs and were elevated by a factor of 12.3 upon nasal colonization with TSST-1-encoding S. aureus. Moreover, the anti-TSST-1 antibody levels were strongly associated with HLA class II gene loci. HLA-DRB1*03:01 and HLA-DQB1*02:01 were positively, and HLA-DRB1*01:01 as well as HLA-DQB1*05:01 negatively associated with the anti-TSST-1 antibody levels. Thus, both toxin exposure and HLA alleles affect the human antibody response to TSST-1.

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“…One theory is that the type of antigen (time of exposure) and the specific genetic pre-disposition as mainly determined by HLA alleles, could generate the appropriate environment -genetic conditions for predisposing to a “skewed” isotype profile towards IgG4 ( 69 , 106 ). Indeed, patients with DQ5+ MuSK-MG appear to have a limited oligoclonal T-cell response that is specific for MuSK, showing a shared among patients repertoire that persists even under current immunosuppressive therapies ( 107 ).…”

Section: Musk-mg As Part Of Neurological Autoimmune Disorders With Th...mentioning

confidence: 99%

Immunotherapies in MuSK-positive Myasthenia Gravis; an IgG4 antibody-mediated disease

Vakrakou¹,

Karachaliou²,

Chroni³

et al. 2023

Front. Immunol.

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Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck, facial, and bulbar muscles) and fatigability. The pathogenic antibodies mostly belong to the immunoglobulin subclass (Ig)G4, a feature which attributes them their specific properties and pathogenic profile. On the other hand, acetylcholine receptor (AChR) MG, the most prevalent form of MG, is characterized by immunoglobulin (Ig)G1 and IgG3 antibodies to the AChR. IgG4 class autoantibodies are impotent to fix complement and only weakly bind Fc-receptors expressed on immune cells and exert their pathogenicity via interfering with the interaction between their targets and binding partners (e.g. between MuSK and LRP4). Cardinal differences between AChR and MuSK-MG are the thymus involvement (not prominent in MuSK-MG), the distinct HLA alleles, and core immunopathological patterns of pathology in neuromuscular junction, structure, and function. In MuSK-MG, classical treatment options are usually less effective (e.g. IVIG) with the need for prolonged and high doses of steroids difficult to be tapered to control symptoms. Exceptional clinical response to plasmapheresis and rituximab has been particularly observed in these patients. Reduction of antibody titers follows the clinical efficacy of anti-CD20 therapies, a feature implying the role of short-lived plasma cells (SLPB) in autoantibody production. Novel therapeutic monoclonal against B cells at different stages of their maturation (like plasmablasts), or against molecules involved in B cell activation, represent promising therapeutic targets. A revolution in autoantibody-mediated diseases is pharmacological interference with the neonatal Fc receptor, leading to a rapid reduction of circulating IgGs (including autoantibodies), an approach already suitable for AChR-MG and promising for MuSK-MG. New precision medicine approaches involve Chimeric autoantibody receptor T (CAAR-T) cells that are engineered to target antigen-specific B cells in MuSK-MG and represent a milestone in the development of targeted immunotherapies. This review aims to provide a detailed update on the pathomechanisms involved in MuSK-MG (cellular and humoral aberrations), fostering the understanding of the latest indications regarding the efficacy of different treatment strategies.

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A systematic review and meta-analysis of HLA class II associations in patients with IgG4 autoimmunity

Cited by 14 publications

References 118 publications

The unique properties of IgG4 and its roles in health and disease

The unique properties of IgG4 and its roles in health and disease

Toxin exposure and HLA alleles determine serum antibody binding to toxic shock syndrome toxin 1 (TSST-1) of Staphylococcus aureus

Immunotherapies in MuSK-positive Myasthenia Gravis; an IgG4 antibody-mediated disease

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