Characterization and specificity of B-cell responses in lupus induced by Mycobacterium bovis in NOD/Lt mice.
A single dose of pasteurized Mycobacterium bovis administered intravenously to prediabetic non-obese diabetic (NOD) mice prevented the onset of type 1 diabetes but precipitated a systemic 'autoimmune rheumatic disease' (ARD) similar to systemic lupus erythematosus. This syndrome was characterized by haemolytic anaemia, anti-dsDNA and anti-Smith antigen (Sm) antinuclear autoantibodies, increased severity of sialadenitis and glomerular immune complex deposition. Here, we examine the specificity of the autoantibody responses in M. bovis-treated NOD mice. Large amounts of antibody were detected to the Sm/ribonucleoprotein (RNP) complex, of which the 28 000 MW polypeptide appeared to be immunodominant. The IgG subclass involved in the anti-Sm response was primarily IgG2a. Antibodies against dsDNA were also detected, but the subclass of this response was mixed, with IgG2a and IgG2b being present in equal amounts. Together, these findings argue against a role for immune deviation towards T helper type 2 (Th2) responses in pathogenesis of the disease. The anti-dsDNA and anti-Sm reactivities were not mediated by polyreactive antibodies since neither antigen could cross-compete plasma antibody binding to the other in competitive enzyme-linked immunosorbent assay. The role of polyclonal B-cell activation was examined by measuring total gamma-globulin as well as IgG reactive with other nuclear antigens including Ro60, Ro52 and La, which although not a major component of the autoantibody responses in these mice, did show small but significant increases following immunization with M. bovis. Thus polyclonal stimulation, while likely to be occurring, was not directly responsible for production of anti-Sm antibodies.
Kennedy Institute of Rheumatology, Hammersmith, London, UK.
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AC
Horsfall
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R
Howson
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P
Silveira
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DG
Williams
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Baxter
D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis; D001323:Autoantibodies / Q000032:analysis; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D001500:BCG Vaccine / Q000009:adverse effects*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control; D004195:Disease Models, Animal; D004587:Electrophoresis, Agar Gel; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting / Q000379:methods; D007074:Immunoglobulin G / Q000032:analysis; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D016688:Mice, Inbred NOD; D017411:Ribonucleoproteins, Small Nuclear; D018418:Th2 Cells / Q000276:immunology; D055517:snRNP Core Proteins
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D001324:Autoantigens; D001500:BCG Vaccine; D007074:Immunoglobulin G; D017411:Ribonucleoproteins, Small Nuclear; D055517:snRNP Core Proteins