Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity
Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity
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DOI：
10.1016/j.immuni.2007.12.015
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发表时间：
2008-02-01
期刊：
影响因子：
32.4
通讯作者：
Perlman, Harris
中科院分区：
文献类型：
--
作者：
Hutcheson, Jack;Scatizzi, John C.;Perlman, Harris
Bcl - 2和Fas凋亡通路成员之间化学计量平衡的改变可能导致系统性红斑狼疮（SLE）的发病机制。我们发现，SLE患者分离的单核细胞中Bcl - 2和Fas凋亡通路的抗凋亡成员表达增加。此外，缺乏Bcl - 2促凋亡成员Bim（Bcl2l11（-/-））且编码Fas的基因存在lpr突变（Fas（lpr/lpr））的小鼠（Bcl2l11（-/-）Fas（lpr/lpr））在16周龄时会发展出严重的SLE样疾病，而Bcl2l11（-/-）或Fas（lpr/lpr）小鼠则不会。Bcl2l11（-/-）Fas（lpr/lpr）抗原呈递细胞（APCs）明显活化，其在淋巴组织和肾脏中的数量增加，然而在Bcl2l11（-/-）Fas（lpr/lpr）小鼠的肾小球中观察到大量TUNEL阳性细胞。这些数据表明，Bcl - 2或Fas通路的失调可改变APCs的功能，从而导致SLE的发病机制。
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.