Diverse endogenous light chains contribute to basement membrane reactivity in nonautoimmune mice transgenic for an anti-laminin Ig heavy chain.
Basement membrane proteins are targeted in a variety of pathologic autoimmune responses, yet little is known regarding the origins and regulation of this subset of pathogenic lymphocytes. To examine the generation and fate of B cells reactive with a matrix autoantigen, nonautoimmune C57BL/6 mice were rendered transgenic for a nephrotropic lupus anti-laminin immunoglobulin (Ig) H chain, termed LamH-Cmu. We previously reported recovery of two distinct phenotypes among LamH-Cmu-transgenic mice: progeny of founders M6 and M29 contained abundant transgene-expressing B cells but little anti-laminin Ig, whereas spontaneous autoreactivity was readily recovered from the M7 lineage that expressed minimal B-cell mIgM. To explore the spectrum of autoreactivity generated in vivo by different LamH-Cmu-endogenous L-chain combinations, we determined in vitro and in vivo antigen reactivity and L-chain V-region sequences of 17 LamH-Cmu-transgenic anti-laminin Igs. The results reveal a heterogeneous population of anti-laminin Igs with different fine specificities encoded by diverse endogenous L chains, encompassing nine different Vk gene families, 11 Vk genes, and three Jk genes. Many of the L chains are identical to known or putative unmutated germline Vk genes used to encode Igs reactive with self and foreign antigens in nonautoimmune and genetically autoimmune-prone mouse strains. These observations confirm that the LamH-Cmu H chain plays a dominant role in determining anti-laminin reactivity, and indicate that nonautoimmune B6 mice are fully capable of generating a diverse pool of basement-membrane-reactive B cells using unmutated Ig genes. When interpreted in the context of the divergent M6/M29 and M7 transgenic mouse phenotypes, our findings further suggest that these matrix-reactive lymphocytes are not spontaneously activated in vivo under normal circumstances.
Fitzsimons
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Renal Electrolyte and Hypertension Division, 700 Clinical Research Building, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104-6144, USA.
Chen
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Foster
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D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D000918:Antibody Specificity / Q000235:genetics / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D001485:Basement Membrane / Q000276:immunology*; D005803:Genes, Immunoglobulin; D006825:Hybridomas / Q000276:immunology / Q000637:transplantation; D007126:Immunoglobulin Allotypes / Q000235:genetics / Q000276:immunology; D007075:Immunoglobulin M / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D007148:Immunoglobulin mu-Chains / Q000235:genetics* / Q000276:immunology*; D007668:Kidney / Q000276:immunology; D007797:Laminin / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D019076:Transgenes / Q000235:genetics*
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D001324:Autoantigens; D007126:Immunoglobulin Allotypes; D007075:Immunoglobulin M; D007145:Immunoglobulin kappa-Chains; D007148:Immunoglobulin mu-Chains; D007797:Laminin