Regulation of B cell tolerance by the lupus susceptibility gene Ly108

The susceptibility locus for the autoimmune disease lupus on murine chromosome 1, Sle1(z)/Sle1b(z), and the orthologous human locus are associated with production of autoantibody to chromatin. We report that the presence of Sle1(z)/Sle1b(z) impairs B cell anergy, receptor revision, and deletion. Members of the SLAM costimulatory molecule family constitute prime candidates for Sle1b(z), among which the Ly108.1 isoform of the Ly108 gene was most highly expressed in immature B cells from lupus-prone B6. Sle1(z) mice. The normal Ly108.2 allele, but not the lupus-associated Ly108.1 allele, was found to sensitize immature B cells to deletion and RAG reexpression. As a potential regulator of tolerance checkpoints, Ly108 may censor self-reactive B cells, hence safeguarding against autoimmunity.