Autoimmunity for Slamf4 in Controlling Humoral Cutting Edge: An NK Cell-Independent Role

Several genes within a syntenic region of human and mouse chromosome 1 are associated with predisposition to systemic lupus erythematosus. Analyses of lupus-prone congenic mice have pointed to an important role for the signaling lymphocyte activation molecule family (slamf)6 surface receptor in lupus pathogenesis. In this paper , we demonstrate that a second member of the Slamf gene family, Slamf4 (Cd244), contributes to lupus-related autoimmunity. B6.Slamf4 2/2 mice spontaneously develop activated CD4 T cells and B cells and increased numbers of T follicular helper cells and a proportion develop autoantibodies to nuclear Ags. B6.Slamf4 2/2 mice also exhibit markedly increased autoantibody production in the B6.C-H-2bm12/KhEg / B6 transfer model of lupus. Although slamf4 function is best characterized in NK cells, the enhanced humoral autoimmu-nity of B6.Slamf4 2/2 mice is NK cell independent, as judged by depletion studies. Taken together, our findings reveal that slamf4 has an NK cell-independent negative regulatory role in the pathogenesis of lupus a normally non-autoimmune prone genetic background. S ystemic lupus erythematosus (SLE) is an autoimmune disease resulting from the production of multiple autoantibodies. Virtually all patients with SLE develop anti-nuclear Abs, and many develop Abs to dsDNA, which serves as a specific marker of disease activity. Multisystem organ dysfunction results from the direct effect of autoanti-bodies and deposition of immune complexes in capillaries with subsequent activation of innate immune responses. The mechanisms behind the humoral autoimmunity are complex, involving a " network " of immune cells (T, B, and dendritic cells and macrophages) and a combination of factors resulting in systemic inflammation. Genetic linkage studies are revealing some of the molecules involved in the pathogenesis of SLE (1, 2). In mice with spontaneous SLE-like disease, autoantibody production has been linked to a small region of mouse chromosome 1 (sle1) (3, 4). Genome-wide association studies have implicated the orthologous region of human chromosome 1 in SLE susceptibility (5). Further analyses revealed that sle1 contains three subloci that each contribute to autoimmunity (sle1a–1c) with sle1b having the largest contribution to autoantibody production (6–8). When the sle1b region from lupus-susceptible NZM2410 mice is bred onto the normally resistant C57BL/6 (B6) background, the resulting B6.sle1b strain develops a mild autoimmune phenotype, with activated T and B cells and Abs to nucleosomes (4). Among the 24 genes encoded in the sle1b locus, seven genes of the signaling lymphocyte activation molecule family (Slamf) are the only genes with known immunologic function. …