Regulation of B Cell Tolerance by the Lupus Susceptibility Gene <i>Ly108</i>

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