The primary roles of T cells and B cells in the initiation of systemic autoimmunity are unclear. To investigate the role of B ceils, we crossed the" Jh knockout" mutation onto the autoimmune Ipr/Ipr background. Animals homozygous for both traits were obtained. As expected, these animals lack B cells. These animals also show no signs of autoimmune kidney destruction nor vasculitis, in spite of carrying the lpr/Ipr mutation. In contrast, lpr/Ipr littermates that had B cells had severe nephritis and vasculitis, as well as autoantibodies. These results demonstrate a primary role for B cells and/or (auto) antibodies in initiating several types of autoimmune-mediated tissue destruction. The implications of this finding for models and therapy of autoimmunity are discussed.