[PDF][PDF] Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity

J Hutcheson, JC Scatizzi, AM Siddiqui, GK Haines… - Immunity, 2008 - cell.com
J Hutcheson, JC Scatizzi, AM Siddiqui, GK Haines, T Wu, QZ Li, LS Davis, C Mohan
Immunity, 2008cell.com
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−/− Fas
lpr/lpr) lacking the Bcl-2 pro-apoptotic member, Bim (Bcl2l11−/−) and and with an lpr
mutation in the gene encoding Fas (Fas lpr/lpr) developed severe SLE-like disease by 16 …
Summary
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.
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