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Multiple Germline Light Chains Generate Anti-Insulin B Cells in Nonobese Diabetic Mice^1,2

Emily J. Woodward^* and James W. Thomas^3,*,

Departments of^* Microbiology and Immunology and Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232

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) (V_H125Tg/NOD) circumvent this problem by generating a tractable population of insulin-binding B cells. The nucleotide structure and genetic origin of the endogenous L chain (V or IgL) repertoire that pairs with the V_H125Tg were analyzed. In contrast to oligoclonal expansion observed in systemic autoimmune disease models, insulin-binding B cells from V_H125Tg/NOD mice use specific V genes that are clonally independent and germline encoded. When compared with homologous IgL genes from nonautoimmune strains, V genes from NOD mice are polymorphic. Analysis of the most frequently expressed V1 and V9 genes indicates these are shared with lupus-prone New Zealand Black/BINJ mice (e.g., V1–110*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 locus may be shared with a systemic autoimmune disease.

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				P. L. Kendall, G. Yu, E. J. Woodward, and J. W. Thomas Tertiary Lymphoid Structures in the Pancreas Promote Selection of B Lymphocytes in Autoimmune Diabetes J. Immunol., May 1, 2007; 178(9): 5643 - 5651. [Abstract] [Full Text] [PDF]