ABSTRACT
We have used an Ig transgene (VH3H9) that increases the frequency of anti-DNA autoantibodies to address whether the production of antinuclear Abs in systemic lupus erythematosus is the consequence of a breakdown of B cell tolerance. We have shown that nonautoimmune mice regulate anti-DNA B cells, and that lupus-prone MRL-lpr/lpr mice are defective in this regulation. Here we show that a subset of anti-DNA B cells, namely those that stain nuclei in a homogeneous fashion, not only fail to be deleted in MRL-lpr/lpr mice, but undergo preferential clonal expansion. In addition, we describe a surprising finding: the VH3H9 transgene is less efficient at inhibiting endogenous heavy chain gene rearrangement on the autoimmune-prone MRL-lpr/lpr genetic background than on the nonautoimmune BALB/c background.
Subject(s)
Antibodies, Antinuclear/genetics , B-Lymphocytes/immunology , Immunoglobulin Allotypes/genetics , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Light Chains/genetics , Amino Acid Sequence , Animals , Antibodies, Antinuclear/biosynthesis , Base Sequence , Gene Expression Regulation/immunology , Hybridomas/immunology , Immunoglobulin Heavy Chains/biosynthesis , Immunoglobulin Isotypes/biosynthesis , Immunoglobulin Isotypes/genetics , Immunoglobulin Light Chains/biosynthesis , Lupus Erythematosus, Systemic/immunology , Mice , Mice, Inbred BALB C , Mice, Mutant Strains , Mice, Transgenic , Molecular Sequence DataABSTRACT
Anti-DNA antibodies, specifically those that stain nuclei in a homogenous nuclear (HN) fashion, are diagnostic of systemic lupus erythematosus (SLE) and the MRL-lpr/lpr SLE murine model. We have used a heavy chain transgene that increases the frequency of anti-HN antibodies to address whether their production in SLE is the consequence of a defect in B cell tolerance. Anti-HN B cells were undetectable in nonautoimmune-prone transgenic mice, but in MRL-lpr/lpr transgenic mice their Ig was evident in the sera and they were readily retrievable as hybridomas. We conclude that nonautoimmune animals actively delete anti-HN-specific B cells, and that MRL-lpr/lpr mice are defective in this process possibly because of the lpr defect in the fas gene.
