Alterations in the stoichiometric balance between members of Bcl-2 and Fas apoptotic pathway could lead to the pathogenesis of systemic lupus erythematosus (SLE). We showed that patients with SLE displayed increased expression in antiapoptotic members of the Bcl-2 and Fas apoptotic pathways in isolated mononuclear cells. Further, mice (Bcl2l11-/-Faslpr/lpr) lacking the Bcl-2 pro-apoptotic member, Bim (Bcl2l11-/-) and and with an lpr mutation in the gene encoding Fas (Faslpr/lpr) developed severe SLE-like disease by 16 weeks of age unlike Bcl2l11-/- or Faslpr/lpr mice. Bcl2l11-/-Faslpr/lpr antigen-presenting cells (APCs) were markedly activated, and their numbers were increased in lymphoid tissues and in kidneys, yet numerous TUNEL-positive cells were observed in glomeruli of Bcl2l11-/-Faslpr/lpr mice. These data demonstrate that dysregulation of the Bcl-2 or Fas pathways can alter the function of APCs, thereby leading to SLE pathogenesis.