Altered BAFF-receptor signaling and additional modifier loci contribute to systemic autoimmunity in A/WySnJ mice

Systemic lupus erythematosus pathology reflects autoantibody-mediated damage due to a failure of B-lymphocyte tolerance. We previously reported that B-lymphopenic A/WySnJ mice develop a lupus-like syndrome and linked this syndrome to the B-cell maturation defect-1 (Bcmd-1) mutant allele of the B-cell-activating factor belonging to the TNF family-receptor (Baffr) gene. Here, we further evaluate the genetic basis for autoimmunity in A/WySnJ mice. We produced B6.Bcmd-1 and AW.Baffr⁻/⁻ congenic mice (N5), and compared them with B6.Baffr⁻/⁻ and A/WySnJ mice with respect to B-lymphocyte development. Bcmd-1-expressing mice had more B cells with greater maturity than Baffr⁻/⁻ mice regardless of genetic background, indicating that Bcmd-1 encodes a partially functional BAFF-R. We also compared these mice for lupus phenotypes to determine whether Bcmd-1 is necessary and sufficient for disease, or whether the Baffr⁻/⁻ ⁻ allele can also cause autoimmunity. The Baffr⁻/⁻ allele did not lead to autoimmunity on either genetic background. In contrast, the Bcmd-1 allele was necessary and sufficient for development of low levels of IgM autoantibodies in B6.Bcmd-1 mice. However, Bcmd-1 plus unidentified A/WySnJ modifier genes were necessary for development of IgG autoantibodies and renal pathology. We propose that in A/WySnJ mice an excess of BAFF per B cell rescues self-reactive B cells through a partially functional BAFF-R in a B-lymphopenic environment.