Induction of a cationic shift in IgG anti-DNA autoantibodies. Role of T helper cells with classical and novel phenotypes in three murine models of lupus nephritis.
We investigated the underlying mechanisms of systemic autoimmune disease in MRL-+/+, (NZB X NZW)F1, and (NZB X SWR)F1 mice, since these strains develop glomerulonephritis without the superimposition of any secondary lupus-accelerating genes. All three strains manifested a common immunoregulatory defect specific for the production of pathogenic anti-DNA autoantibodies that are of IgG class and cationic in charge. At or just before the age they began to develop lupus nephritis, spleen cells of the mice contained a subpopulation of Th cells that selectively induced their B cells in vitro to produce highly cationic IgG autoantibodies to both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA). By contrast, T cells from younger preautoimmune mice were incapable of providing this help. Moreover, only B cells of the older lupus mice could be induced to secrete cationic anti-DNA antibodies of IgG class. B cells of young lupus mice could not produce the cationic autoantibodies even with the help of T cells from the older mice, nor upon stimulation with mitogens. In the older lupus mice we found two sets of Th cells that spontaneously induced the cationic shift in autoantibodies; one set belonged to the classical Th category with L3T4+,Lyt-2- phenotype, whereas the other surprisingly belonged to a double-negative (L3T4-,Lyt-2-), Lyt-1+ subpopulation. The latter set of unusual Th cells were unexpected in these lupus mice since they lacked the lpr (lympho-proliferation) gene. Thus three apparently different murine models of systemic lupus erythematosus possess a common underlying mechanism specific for the spontaneous production of pathogenic anti-DNA autoantibodies.
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D000917:Antibody Formation; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D007111:Immunity, Cellular; D007074:Immunoglobulin G / Q000276:immunology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008934:Mitogens / Q000494:pharmacology; D010641:Phenotype; D013154:Spleen / Q000166:cytology; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D007074:Immunoglobulin G; D008934:Mitogens; D004247:DNA