The hidden diversity of antibody heavy chains implications for myasthenia gravis 3919

Abstract Description Acetylcholine receptor (AChR) antibody-positive myasthenia gravis (MG) is an autoimmune disorder leading severe muscle weakness. We hypothesize that these pathogenic antibodies show distinct immunogenomic patterns, including specific usage of variable (V), diversity (D), joining (J), and constant (C) alleles in immunoglobulin heavy chains (IGH). Here, we employed two long-read sequencing Methods IGcapture for high-resolution IGH genotyping and FLAIRR-seq (near Full-Length Adaptive Immune Receptor Repertoire sequencing) to examine IGH expression in AChR-MG (n = 48) and healthy controls (n = 48). FLAIRR-seq revealed significant clonal expansion in IGHG1, IGHG2, and IGHG4 genes in MG individuals. A notable increase in IGHG3 usage was also observed, warranting further examination due to the pathogenic role of IgG3 autoantibodies in AChR-MG. Genes like IGHV1-69 and IGHV3-9 were shown to be used at common frequencies by groups of AChR-MG individuals in IGHG3 repertoires. Moreover, preliminary data identified 70 novel C alleles in AChR-MG versus 44 in healthy controls. Additionally, IGHG3 alleles with truncated hinge regions, associated with elevated complement activity in previous studies were more frequent in AChR-MG individuals. Understanding the genetic diversity, specifically in the C region of IGH, may reveal key residues that mediate complement activation. These discoveries could help identify variants that contribute to disease severity and progression among individuals. Funding Sources Funding from the Myasthenia Gravis Rare Disease Network (“Supported by NIH U54NS115054 and the MGNet.”) Topic Categories Basic Autoimmunity (BA)