A Systematic Review and Meta-Analysis of HLA-Class-II Associations in Patients with IgG4 Autoimmunity

Abstract

Autoimmune diseases caused by pathogenic IgG4 subclass autoantibodies (IgG4-AID) include diseases like MuSK myasthenia gravis, pemphigus vulgaris or thrombotic thrombocytopenic purpura. Their etiology is still unknown. Polymorphisms in the human leukocyte antigen (HLA) gene locus, particularly in HLA-DRB1, are known genetic susceptibility factors for autoimmune diseases. We hypothesized a similar role for HLA polymorphisms in IgG4-AID and conducted a systematic review and meta-analysis with case-control studies on IgG4-AID based on MOOSE/ HuGENet guidelines. Genotype (G) and allele (A) frequencies of HLA-DQB1*05 (G: OR 3.8; 95% CI 2.44-5.9; p < 0.00001; A: OR 2.54; 95% CI 1.82-3.55; p < 0.00001) and HLA-DRB1*14 (G: OR 4.31; 95% CI 2.82-6.59; p < 0.00001; A: OR 4.78; 95% CI 3.52-6.49; p < 0.00001) and the HLA-DRB1*14-DQB1*05 haplotype (OR 6.3; 95% CI 3.28-12.09; p < 0.00001 / OR 4.98; 95% CI 3.8-6.53; p < 0.00001) were increased while HLA-DRB1*13 (G: OR 0.48; 95% CI 0.34-0.68; p < 0.0001; A: OR 0.46; 95% CI 0.34-0.62; p < 0.00001) was decreased in IgG4-AID patients. In conclusion, the HLA-DQB1*05, HLA-DRB1*14 alleles and the HLA-DQB1*05-DRB1*14 haplotype could be genetic risk factors that predispose for the production of pathogenic IgG4 autoantibodies and the HLA-DRB1*13 allele may protect from IgG4 autoimmunity.

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

“…( 2 ) Individual predisposition for antigen-specific autoimmunity mediated by certain MHC II- antigen- T-cell receptor combinations could predispose to a “skewed” isotype profile towards IgG4, as supported by the strong genetic associations with specific HLA alleles such as HLA-DQB1*05 and HLA-DRB1*14 ( 18 , 19 ). This would mean, that IgG4-predominance occurs already early during the disease in predisposed individuals and causes chronicity rather than being a consequence of it: A recent study by Ellebrecht et al.…”

“…Antibodies involved in IgG4-AID, known to date, target antigens in mainly four organ systems: 1) the central and peripheral nervous system with diseases such as MuSK myasthenia gravis (MG), anti-LGI1 and anti-Caspr2 encephalitis, anti-IgLON5 disease or chronic inflammatory demyelinating polyneuropathy (CIDP) with antibodies against NF155/contactin-1/CASPR1, 2) the skin and mucosa with skin blistering diseases such as pemphigus vulgaris (PV) and pemphigus foliaceus (PF), 3) the kidneys with PLA2R- and THSD7A- antibody positive membranous glomerulonephritis and 4) the haematological system with diseases such as thrombotic thrombocytopenic purpura (TTP, ADAMTS13) or GPIHBP1 autoantibody syndrome. Other unifying features of IgG4-AID are their low prevalence ( 10 ), their emerging strong genetic associations with specific HLA alleles such as HLA-DQB1*05 and HLA-DRB1*14 ( 18 , 19 ), their clinical severity and chronicity and their good response to B cell depletion therapy.…”