Mountz J D, Zhou T, Su X, Cheng J, Pierson M, Bluethmann H, Edwards C K
University of Alabama at Birmingham 35294-0007, USA.
Behring Inst Mitt. 1996 Oct(97):200-19.
Activation induced cell death (AICD) plays a critical role in eliminating autoimmune cells and limiting inflammation after activation. The two major signaling molecules for AICD are the Fas and TNF-R pathways of apoptosis. Defective Fas apoptosis in lpr/lpr mice results in a compensatory increase in TNF-R/TNF-mediated apoptosis. TNF/TNF-R has been shown to be a compensatory pathway of apoptosis in T cells and macrophages of lpr/lpr mice. Therefore, early production of TNF/TNF-R limit an immune response by inducing AICD in the absence of an intact Fas/Fas ligand apoptosis pathway. However, increased TNF production in lpr mice also lead to increased susceptibility to septic shock and autoimmune disease such as arthritis. Therefore TNF production during an inflammatory response can downmodulate this response, but this also results in the failure to downmodulate TNF production leading to septic shock and arthritis. A second pathway of AICD is mediated by Nur77 after T cell stimulation through the CD3 molecule. Mice with defective Nur77 signaling undergo AICD using the Fas-Fas ligand pathway to eliminate autoreactive T cells. A third defect of AICD is observed in HCP-mutant me/me (motheaten) mice which develop autoimmune disease related to defective Fas apoptosis signaling. Therefore, multiple interactive pathways play a role in limiting development of autoimmunity.
活化诱导的细胞死亡（AICD）在清除自身免疫细胞和限制活化后的炎症反应中起关键作用。AICD的两个主要信号分子是凋亡的Fas和TNF-R途径。lpr/lpr小鼠中Fas凋亡缺陷导致TNF-R/TNF介导的凋亡代偿性增加。TNF/TNF-R已被证明是lpr/lpr小鼠T细胞和巨噬细胞中凋亡的代偿途径。因此，在缺乏完整的Fas/Fas配体凋亡途径时，TNF/TNF-R的早期产生通过诱导AICD来限制免疫反应。然而，lpr小鼠中TNF产生增加也导致对败血症性休克和自身免疫性疾病（如关节炎）的易感性增加。因此，炎症反应期间TNF的产生可下调这种反应，但但这也导致无法下调TNF的产生，从而导致败血症性休克和关节炎。AICD的第二条途径由T细胞通过CD3分子刺激后Nur77介导。Nur77信号缺陷的小鼠利用Fas-Fas配体途径进行AICD以消除自身反应性T细胞。在HCP突变的me/me（食母生）小鼠中观察到AICD的第三个缺陷，这些小鼠会发生与Fas凋亡信号缺陷相关的自身免疫性疾病。因此，多种相互作用的途径在限制自身免疫的发展中起作用。
