BAFF-R mutation: A novel contributor to systemic autoimmunity.

摘要

Systemic lupus erythematosus is an autoimmune disease of unknown etiology that reflects autoantibody-mediated damage due to a failure of B lymphocyte tolerance. Since excessive BAFF expression correlates with human and murine lupus, and BAFF signals B cell survival through BAFF-R, it is believed that excessive BAFF-R signaling can subvert B cell tolerance and facilitate lupus development. A/WySnJ mice carry the Bcmd-1 mutant allele of the Baffr gene. Bcmd-1 causes premature B cell death and profound B cell deficiency. During genetic studies of A/WySnJ mice, we noted that many animals developed weight loss, patchy fur loss, skin lesions, a hunched posture, and occasionally splenomegaly as they aged. Upon further study, we found BAFF-R-mutant A/WySnJ mice developed a lupus-like syndrome.Despite having 90% fewer splenic B cells than normal mice, A/WySnJ mice had an 18-fold increased frequency of splenocytes secreting IgM to dsDNA, and increased amounts of circulating IgM and IgG to dsDNA. A/WySnJ mice also displayed renal pathology characteristic of lupus, including proteinuria and glomerular capillary bed destruction. We genetically linked this autoimmunity to Bcmd-1, since congenic AW.Baffr +/+ mice carrying a wild-type allele developed none of these phenotypes.We next sought to ascertain how Bcmd-1 could contribute to a loss in self tolerance. To determine if Bcmd-1 is a complete loss-of-function Baffr allele, we produced B6. Bcmd-1 and AW.Baffr-/- congenic mice, and compared them to B6.Baffr-/- and A/WySnJ mice. The 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 B6.Bcmd-1, B6. Baffr-/-, AW.Baffr-/-, and A/WySnJ mice for lupus-like phenotypes to determine whether Bcmd-1 is necessary and sufficient for disease. 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, additional 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.