Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency
Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency
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DOI：
10.1038/nature01063
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发表时间：
2002-09-26
期刊：
影响因子：
64.8
通讯作者：
Lenardo, MJ
中科院分区：
文献类型：
--
作者：
Chun, HJ;Zheng, LX;Lenardo, MJ
细胞凋亡是一种程序性细胞死亡的形式，其由称为半胱天冬酶的谷氨酸特异性半胱氨酸蛋白酶控制。在免疫系统中，细胞凋亡对抗淋巴细胞的增殖，以实现稳态平衡，这允许对病原体的有效反应，但避免自身免疫（1，2）。CD 95（Fas、Apo-1）受体通过将Fas相关死亡结构域（FADD）、半胱天冬酶-8和半胱天冬酶-10蛋白募集到死亡诱导信号复合物中来触发淋巴细胞凋亡（3，4）。CD 95、CD 95配体或半胱天冬酶-10的杂合突变是大多数自身免疫性淋巴增生综合征（ALPS）病例的基础，ALPS是一种以淋巴细胞凋亡缺陷、淋巴结病、脾肿大和自身免疫为特征的人类疾病（5-14）。在ALPS中还没有描述半胱天冬酶-8的突变，并且纯合子半胱天冬酶-8缺陷导致小鼠胚胎死亡。在这里，我们描述了一个人类亲属与遗传性基因缺陷的半胱天冬酶-8。纯合子个体表现出淋巴细胞凋亡和稳态缺陷，但与受ALPS影响的个体不同，其T淋巴细胞、B淋巴细胞和自然杀伤细胞的活化也存在缺陷，这导致免疫缺陷。因此，人类的半胱天冬酶-8缺陷与正常发育相容，并表明半胱天冬酶-8在幼稚淋巴细胞的免疫激活中具有出生后的作用。
Apoptosis is a form of programmed cell death that is controlled by aspartate-specific cysteine proteases called caspases. In the immune system, apoptosis counters the proliferation of lymphocytes to achieve a homeostatic balance, which allows potent responses to pathogens but avoids autoimmunity(1,2). The CD95 (Fas, Apo-1) receptor triggers lymphocyte apoptosis by recruiting Fas-associated death domain (FADD), caspase-8 and caspase-10 proteins into a death-inducing signalling complex(3,4). Heterozygous mutations in CD95, CD95 ligand or caspase-10 underlie most cases of autoimmune lymphoproliferative syndrome (ALPS), a human disorder that is characterized by defective lymphocyte apoptosis, lymphadenopathy, splenomegaly and autoimmunity(5-14). Mutations in caspase-8 have not been described in ALPS, and homozygous caspase-8 deficiency causes embryonic lethality in mice. Here we describe a human kindred with an inherited genetic deficiency of caspase-8. Homozygous individuals manifest defective lymphocyte apoptosis and homeostasis but, unlike individuals affected with ALPS, also have defects in their activation of T lymphocytes, B lymphocytes and natural killer cells, which leads to immunodeficiency. Thus, caspase-8 deficiency in humans is compatible with normal development and shows that caspase-8 has a postnatal role in immune activation of naive lymphocytes.