Apoptosis and autoimmunity: two sides to the coin
Apoptosis and autoimmunity: two sides to the coin
复制标题
细胞凋亡和自身免疫：硬币的两面
DOI：
10.1038/sj.cdd.4400471
复制
发表时间：
1999
影响因子：
12.4
通讯作者：
M. Piacentini
中科院分区：
文献类型：
--
作者：
M. Piacentini
细胞死亡稳态的改变是表征许多疾病发病机制的重要事件。越来越多的人认为，自身免疫是细胞凋亡过程中信号通路、执行通路和清除通路发生缺陷的结果。1凋亡细胞中细胞蛋白发生广泛的翻译后修饰，不仅导致死亡细胞的结构发生显著变化，而且导致其抗原特性发生显著变化。然而，这一事件固有的有害后果被邻近的吞噬细胞迅速清除凋亡细胞所阻止。因此，对凋亡细胞产生和清除之间的动态平衡的任何扰动都会使免疫系统暴露于有害的凋亡产生的自身抗原。在这一期的《细胞死亡与分化》中，Rosen和Casciola-Rosen4概述了细胞凋亡的损伤，以及随之而来的隐性决定因素的暴露，可能导致导致系统性自身免疫性疾病发展的致病事件。在随后的综述中，Ohsako和Elkon5批判性地描述了被认为在器官特异性自身免疫性疾病（甲状腺炎、多发性硬化症和胰岛素依赖性糖尿病）中导致细胞凋亡信号通路失败的分子事件，特别是TNF受体家族。细胞凋亡和自身免疫之间潜在联系的第一个分子证据是lpr和gold小鼠（众所周知的自身免疫性疾病动物模型）分别是CD95和CD95配体基因的功能缺失突变体。这些发现的相关性最近被自身免疫性淋巴细胞增生性疾病患者也被发现携带CD95基因突变的事实所证实。这些发现表明CD95-CD95配体系统在人类和小鼠的自我耐受性维持中起着重要作用。我们现在知道，有效的细胞凋亡是维持外周淋巴细胞稳态和减少自身反应性淋巴细胞积累的关键因素。在过去的一年中，在了解各种分子，特别是一组半胱氨酸蛋白酶在细胞凋亡过程中的关键作用方面取得了重要进展。这些蛋白酶似乎是负责细胞凋亡的主要效应分子，它们的功能可能对外周免疫耐受至关重要。最近，其他凋亡相关基因（如Nurr779和组织转谷氨酰胺酶）的功能与耐受性的破坏和自身免疫性疾病的发展有关。特别是，由组织转谷氨酰胺酶催化的蛋白质的谷氨酰胺和赖氨酸残基的翻译后修饰可能在凋亡相关的自身免疫中起重要作用。10 tTG的过表达减少了表征tnfa诱导的L929细胞死亡的大分子（dsDNA和LDH）的释放。10这表明ttg催化的细胞内蛋白交联在稳定凋亡小体和防止其含量泄漏中起重要作用。这一现象可能代表了体内细胞凋亡的一个关键特征，因为有控制地处置交联凋亡小体对于防止炎症反应以及可能导致自身免疫发展的自身抗原暴露是必要的。虽然CD95/CD95L系统中介导细胞凋亡的缺陷已被证明是自身免疫性糖尿病、甲状腺炎和前列腺癌的重要因素。
Alteration of cell death homeostasis is an essential event characterizing the pathogenesis of many diseases. There is growing consensus on the fact that autoimmunity is a consequence of defects occurring in the signaling, execution and clearance pathways involved in apoptosis. 1 Extensive post-translational modifications of cellular proteins occur in apoptotic cells, resulting in notable changes not only in the structure of the dying cells, but also in their antigenic properties. 2 However, the harmful consequences intrinsic of this event are prevented by the rapid clearance of cells undergoing apoptosis by neighboring phagocytes. 3 As a consequence, any perturbation of the dynamic equilibrium between the generation and clearance of apoptotic cells will expose the immune system to harmful apoptosis-generated autoantigens. In this issue of Cell Death and Differentiation Rosen and Casciola-Rosen4 provide an overview of how the impairment of apoptosis, with the consequent exposition of cryptic determinants, might result in pathogenic events leading to the development of systemic autoimmune disorders. In an accompanying review, Ohsako and Elkon5 critically describe the molecular events thought to be responsible for the failure of apoptosis signaling pathways, in particular of the TNF receptor family, in organ-specific autoimmune diseases (thyroiditis, multiple sclerosis and insulin-dependent diabetes mellitus). The first molecular evidence of the potential link between apoptosis and autoimmunity was the demonstration that lpr and gld mice, well known animal models of autoimmune diseases, are loss-of-function mutants of the CD95 and CD95 ligand genes respectively. 6 The relevance of these findings was recently confirmed by the fact that patients with autoimmune lymphoproliferative disorders have also been found to bear mutations of the CD95 gene. 7 These findings indicate that the CD95-CD95 ligand system plays an important role in the maintenance of self-tolerance among both humans and mice. We now know that efficient apoptosis is a key element in maintaining peripheral lymphocyte homeostasis and in minimizing the accumulation of autoreactive lymphocytes. 8 Important progress has been made during the past year in understanding the critical roles of a variety of molecules, especially a group of cysteine proteases, in the execution of apoptosis. 2 These proteases appear to be the primary effector molecules responsible for apoptosis and their function may be critical for peripheral immunological tolerance. More recently, the functions of other apoptotic-related genes, such as Nurr779 andtissue'transglutaminase, 10 have been linked to breakdown of tolerance and development of autoimmune diseases. In particular, the post-translational modification of glutamine and lysine residues of proteins catalyzed bytissue'transglutaminase might play an important role in apoptosis-related autoimmunity. 10 Overexpression of tTG reduces the release of macromolecules (dsDNA and LDH) characterizing TNFa-induced death of L929 cells. 10 This suggests that tTG-catalyzed intracellular protein crosslinking plays an important role in stabilizing apoptotic bodies and preventing the leakage of their content. 11 This phenomenon might represent a key feature of apoptosis in vivo, since a controlled disposal of cross-linked apoptotic bodies is necessary to prevent the inflammatory response as well as the exposure of autoantigens which may lead to the development of autoimmunity. Although defects in the CD95/CD95L system that mediates apoptosis have been shown to be an important factor in autoimmune diabetes, thyroiditis and in the …