Development of Murine Lupus Involves the Combined Genetic Contribution of the SLAM and FcγR Intervals within the Nba2 Autoimmune Susceptibility Locus

Autoantibodies are of central importance in the pathogenesis of Ab-mediated autoimmune disorders. The murine lupus susceptibility locus Nba2 on chromosome I and the syntenic human locus are associated with a loss of immune tolerance that leads to antinuclear Ab production. To identify gene intervals within Nba2 that control the development of autoantibody-producing B cells and to determine the cellular components through which Nba2 genes accomplish this, we generated congenic mice expressing various Nba2 intervals where genes for the Fc gamma R, SLAM, and IFN-inducible families are encoded. Analysis of congenic strains demonstrated that the Fc gamma R and SLAM intervals independently controlled the severity of autoantibody production and renal disease, yet are both required for lupus susceptibility. Deregulated homeostasis of terminally differentiated B cells was found to be controlled by the Fc gamma R interval where Fc gamma RIIb-mediated apoptosis of germinal center B cells and plasma cells was impaired. Increased numbers of activated plasmacytoid dendritic cells that were distinctly CD19(+) and promoted plasma cell differentiation via the proinflammatory cytokines IL-10 and IFN alpha were linked to the SLAM interval. These findings suggest that SLAM and Fc gamma R intervals act cooperatively to influence the clinical course of disease through supporting the differentiation and survival of autoantibody-producing cells. The Journal of Immunology, 2010,184: 775-786.