Multiple Germline κ Light Chains Generate Anti-Insulin B Cells in Nonobese Diabetic Mice

Abstract

The highly selective nature of organ-specific autoimmune disease is consistent with a critical role for adaptive immune responses against specific autoantigens. In type 1 diabetes mellitus, autoantibodies to insulin are important markers of the disease process in humans and nonobese diabetic (NOD) mice; however, the Ag-specific receptors responsible for these autoantibodies are obscured by the polyclonal repertoire. NOD mice that harbor an anti-insulin transgene (Tg) (VH125Tg/NOD) circumvent this problem by generating a tractable population of insulin-binding B cells. The nucleotide structure and genetic origin of the endogenous κ L chain (Vκ or IgL) repertoire that pairs with the VH125Tg were analyzed. In contrast to oligoclonal expansion observed in systemic autoimmune disease models, insulin-binding B cells from VH125Tg/NOD mice use specific Vκ genes that are clonally independent and germline encoded. When compared with homologous IgL genes from nonautoimmune strains, Vκ genes from NOD mice are polymorphic. Analysis of the most frequently expressed Vκ1 and Vκ9 genes indicates these are shared with lupus-prone New Zealand Black/BINJ mice (e.g., Vκ1–110*02 and 9–124) and suggests that NOD mice use the infrequent b halpotype. These findings show that a diverse repertoire of anti-insulin B cells is part of the autoimmune process in NOD mice and structural or regulatory elements within the κ locus may be shared with a systemic autoimmune disease.