Abstract
We explored mechanisms involved in B cell self-tolerance in a double- and triple-transgenic mouse model bearing the LamH-C mu Ig H chain conventional transgene and a gene-targeted replacement for a functional V kappa 8J kappa 5 L chain gene. Whereas the H chain is known to generate anti-laminin Ig in combination with multiple L chains, the H + L Ig binds ssDNA in addition to laminin. Immune phenotyping indicates that H + L transgenic B cells are regulated by clonal deletion, receptor editing via secondary rearrangements at the nontargeted kappa allele, and anergy. Collectively, the data suggest that multiple receptor-tolerogen interactions regulate autoreactive cells in the H + L double-transgenic mice. Generation of H + LL triple-transgenic mice homozygous for the targeted L chain to exclude secondary kappa rearrangements resulted in profound B cell depletion with absence of mature B cells in the bone marrow. We propose that the primary tolerogen of dual reactive B cells in this model is not ssDNA, but a strongly cross-linking tolerogen, presumably basement membrane laminin, that triggers recombination-activating gene activity, L chain editing, and deletion.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies, Monoclonal / chemistry
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Antibodies, Monoclonal / genetics
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Antibody Specificity / genetics*
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Autoantibodies / biosynthesis
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Autoantibodies / genetics*
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Autoantibodies / metabolism
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B-Lymphocyte Subsets / immunology*
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B-Lymphocyte Subsets / metabolism*
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B-Lymphocyte Subsets / pathology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Division / genetics
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Cell Division / immunology
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Cell Survival / genetics
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Cell Survival / immunology
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Clonal Deletion / genetics*
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Gene Rearrangement, B-Lymphocyte, Light Chain
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Immunoglobulin Constant Regions / genetics
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Immunoglobulin Heavy Chains / biosynthesis
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Immunoglobulin Heavy Chains / genetics
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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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Immunoglobulin kappa-Chains / metabolism
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Immunoglobulin mu-Chains / biosynthesis
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Laminin / immunology*
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Laminin / metabolism
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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, Transgenic
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RNA Editing / immunology
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Self Tolerance / genetics*
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Spleen / immunology
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Spleen / metabolism
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Spleen / pathology
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Transfection
Substances
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Antibodies, Monoclonal
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Autoantibodies
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Immunoglobulin Constant Regions
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Immunoglobulin Heavy Chains
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Immunoglobulin Variable Region
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Immunoglobulin kappa-Chains
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Immunoglobulin mu-Chains
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Laminin