B cell susceptibility to Fas-mediated apoptosis is downmodulated by engagement of IL-4 and sIg receptors. IL-4 produces Fas-resistance in both normal and tolerant B lymphocytes and has been associated with autoantibody production in mice expressing heterogeneous B cell receptors. To study the in vivo effects of IL-4 on autoreactive B cells in a more well-defined system, mice triply transgenic for IL-4, soluble HEL and anti-HEL B cell receptors were generated. Anti-HEL/sHEL/IL-4 triple transgenic mice matured normally but accumulated increasing amounts of serum anti-HEL antibodies over time, whereas anti-HEL/sHEL double transgenic mice lacked serum anti-HEL. Autoantibodies in triple transgenic mice were accompanied by gross evidence of renal pathology, characterized by both abnormal histology and marked proteinuria, along with microscopic evidence of immune complex-type hepatic damage. Proteinuria and histopathological changes were also observed in IL-4 transgenic control mice. These results suggest that IL-4 induced a breakdown in tolerance and autoreactive B cell activity manifested by the onset and accumulation of autoantibodies and the development of frank autoimmune disease.