The Mer receptor tyrosine kinase mediates apoptotic cell phagocytosis and modulates macrophage cytokine production. Mer−/− mice have defective clearance of apoptotic debris and develop a systemic lupus erythematosus-like autoimmune syndrome. It was surprising then that B6-Mer−/− recipients of bm12 spleen cells failed to develop anti-dsDNA and anti-chromatin autoantibodies, whereas B6 hosts produced the expected autoimmune chronic graft-vs-host (cGVH) reaction. The lack of autoantibody formation in cGVH was not due to the failure of Mer-deficient hosts to provoke alloreactivity, because Mer−/− spleen cells were recognized by bm12 T cells in MLR. Cell transfer experiments in Rag-knockout mice indicated that the lack of autoantibody production in Mer−/− cGVH disease hosts was due to an intrinsic B cell defect. This defect did not cause a global inability to produce autoantibodies, because in vivo exposure to LPS stimulated production of autoantibodies in both B6 and Mer−/− mice. We further observed that wild-type B6 B cells up-regulated Mer upon activation in cGVH, and that B cells from mice lacking Mer showed a decreased up-regulation of activation-associated cell surface markers. These findings indicate that Mer serves an important role in the activation of self-reactive B cells in systemic autoimmunity.