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

被引:182
作者
Hutcheson, Jack [1 ,2 ]
Scatizzi, John C. [1 ,3 ]
Siddiqui, Akbar M. [1 ]
Haines, G. Kenneth, III [4 ]
Wu, Tianfu [2 ]
Li, Quan-Zhen [2 ]
Davis, Laurie S. [2 ]
Mohan, Chandra [2 ]
Perlman, Harris [1 ]
机构
[1] St Louis Univ, Sch Med, Dept Mol Microbiol & Immunol, St Louis, MO 63104 USA
[2] Univ Texas SW Med Ctr Dallas, Ctr Immunol, Dept Rheumatol & Internal Med, Dallas, TX 75390 USA
[3] Univ Calif San Diego, Sch Med, Dept Rheumatol Allergy & Immunol, La Jolla, CA 92093 USA
[4] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA
关键词
D O I
10.1016/j.immuni.2007.12.015
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 weeks of age unlike Bcl2l11(-/-) or Fas(lpr/lpr) mice. Bcl2l11(-/-)Fas(lpr/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(-/-)Fas(lpr/lpr) mice. These data demonstrate that dysreaulation of the Bcl-2 or Fas pathways can alter the function of APCs, thereby leading to SLE pathogenesis.
引用
收藏
页码:206 / 217
页数:12
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