PERFORIN PROTECTS AGAINST AUTOIMMUNITY IN LUPUS-PRONE MICE

The roles of cytolytic regulatory mechanisms in the immune system of l upus-prone mice were examined in perforin-deficient animals bearing fu nctional or defective (Ipr) Pas Ag (CD95). Perforin-deficient Fas(+) a nimals developed accelerated autoimmunity, characterized by increased hypergammaglobulinemia, autoantibody production, and immune deposit-re lated endorgan disease compared with perforin-intact counterparts. In comparison, perforin-deficient Ipr animals had accelerated mortality c ompared with perforin-intact Ipr mice, associated with the abnormal ac cumulation of CD3+CD4(-)CD8(-) alpha beta T cells in conjunction with unaltered hypergammaglobulinemia, autoantibody production, and immune complex renal disease. These results indicate that cytolytic lymphoid regulation plays critical roles in the immune homeostasis of lupus-pro ne animals, and identify perforin-mediated cytotoxicity as a specific mechanism in the regulation of systemic autoimmunity.