Interleukin-4 produces a breakdown of tolerance in vivo with autoantibody formation and tissue damage

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.