MHC haplotype and B cell autoimmunity: Correlation with pathogenic IgG autoantibody subclasses and Fc glycosylation patterns

Abstract

Genome-wide association studies (GWAS) have identified many genes that are associated with the development of certain autoimmune disorders, but the MHC haplotypes still represent the most prevalent genetic risk factor for many autoimmune diseases. The mechanisms by which MHC-associated genetic susceptibility translates into B cell autoimmunity and the development of autoimmune diseases are complex. There is increasing evidence that the MHC haplotype modulates autoreactive B cell responses in multiple ways. Instead of merely inhibiting the production of IgG autoantibodies and mediating complete immunological tolerance, the non-permitting MHC haplotypes seem to facilitate the production of IgG autoantibodies exhibiting Fc glycosylation patterns that are associated with reduced pathogenicity and a protective cytokine profile of T follicular helper (Tfh) cells. Here, we discuss mechanisms linking MHC haplotypes to the production of pathogenic IgG autoantibodies, which could be relevant for the development of improved diagnosis, particularly in the context of individual medicine.

Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies

“…Our results suggest that distinct pathophysiological pathways may be underlying the production of several autoantibodies in the same individual (e.g., anti-Jo1 and anti-Ro52). The mechanisms behind the co-occurrence of autoantibodies in the IIM subgroups described herein may result from the exposure of several cryptic antigens after cell apoptosis in inflamed and damaged tissue, such as muscle, skin, or lung, leading to a concerted loss of peripheral tolerance and presence of autoreactive T-cells 31 , 32 , 33 , 34 –for an illustration of the concept, see Fig. 4 .…”

Distinct HLA Associations with Autoantibody-Defined Subgroups in Idiopathic Inflammatory Myopathies

“…Our results suggest that distinct pathophysiological pathways may be underlying the production of several autoantibodies in the same individual (e.g., anti-Jo1 and anti-Ro52). The mechanisms behind the co-occurrence of autoantibodies in the IIM subgroups described herein may result from the exposure of several cryptic antigens after cell apoptosis in inflamed and damaged tissue, such as muscle, skin, or lung, leading to a concerted loss of peripheral tolerance and presence of autoreactive T-cells [31][32][33][34] -for an illustration of the concept, see Fig. 4.…”

IgG subclass and Fc glycosylation shifts are linked to the transition from pre- to inflammatory autoimmune conditions

“…Three scenarios seem to be most likely for the transition. First, unfavorable genetic predispositions such as certain MHC alleles might favor such a switch ( 14 , 68 ). Nevertheless, there is only a small overlap of the disease appearance between monozygotic twins ( 69 ), suggesting that additional factors might play an important role.…”