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) (V(H)125Tg/NOD) circumvent this problem by generating a tractable population of insulin-binding B cells. The nucleotide structure and genetic origin of the endogenous kappa L chain (Vkappa or IgL) repertoire that pairs with the V(H)125Tg were analyzed. In contrast to oligoclonal expansion observed in systemic autoimmune disease models, insulin-binding B cells from V(H)125Tg/NOD mice use specific Vkappa genes that are clonally independent and germline encoded. When compared with homologous IgL genes from nonautoimmune strains, Vkappa genes from NOD mice are polymorphic. Analysis of the most frequently expressed Vkappa1 and Vkappa9 genes indicates these are shared with lupus-prone New Zealand Black/BINJ mice (e.g., Vkappa1-110*02 and 9-124) and suggests that NOD mice use the infrequent b haplotype. 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 kappa locus may be shared with a systemic autoimmune disease.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibody Diversity / genetics*
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Autoantibodies / biosynthesis
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Autoantibodies / genetics
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B-Lymphocyte Subsets / immunology*
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B-Lymphocyte Subsets / metabolism*
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Base Sequence
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Bone Marrow Cells / immunology
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Bone Marrow Cells / metabolism
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Gene Rearrangement, B-Lymphocyte, Light Chain*
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Genetic Predisposition to Disease
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Immunoglobulin Variable Region / biosynthesis
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Immunoglobulin Variable Region / genetics
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Immunoglobulin kappa-Chains / biosynthesis
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Immunoglobulin kappa-Chains / genetics*
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Insulin / metabolism
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Insulin Antibodies / biosynthesis
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Insulin Antibodies / genetics*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Transgenic
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Molecular Sequence Data
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Multigene Family / immunology
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Polymorphism, Genetic / immunology
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Protein Binding / genetics
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Protein Binding / immunology
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Receptors, Antigen, B-Cell / metabolism
Substances
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Autoantibodies
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Immunoglobulin Variable Region
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Immunoglobulin kappa-Chains
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Insulin
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Insulin Antibodies
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Receptors, Antigen, B-Cell
Associated data
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GENBANK/AY675526
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GENBANK/AY675527
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GENBANK/AY675528
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GENBANK/AY675529
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GENBANK/AY675530
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GENBANK/AY675531
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GENBANK/AY675532
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GENBANK/AY675533
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GENBANK/AY675534
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GENBANK/AY675535
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GENBANK/AY675536
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GENBANK/AY675537
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GENBANK/AY675538
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GENBANK/AY675539
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GENBANK/AY675540
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GENBANK/AY731701
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GENBANK/AY731702
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GENBANK/AY731703
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GENBANK/AY731704
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GENBANK/AY731705
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GENBANK/AY731706
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GENBANK/AY731707
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GENBANK/AY731708
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GENBANK/AY731709