Cleavage by granzyme B is strongly predictive of autoantigen status: implications for initiation of autoimmunity.
Cleavage by granzyme B is strongly predictive of autoantigen status: implications for initiation of autoimmunity.
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Granzyme B的切割是对自身抗原状态的强烈预测：对自身免疫的影响。
DOI：
10.1084/jem.190.6.815
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发表时间：
1999-09-20
影响因子：
15.3
通讯作者：
Rosen, A
中科院分区：
文献类型：
--
作者：
Casciola-Rosen, L;Andrade, F;Ulanet, D;Wong, W B;Rosen, A
全身性自身免疫性疾病是一组遗传上复杂、异质性的疾病，免疫系统针对的是一组不同但高度特异的细胞内自身抗原。靶向分子在对照细胞中并不是通过共同的结构、功能或分布来统一的，而是在细胞发生凋亡时聚集并集中在表面的气泡中。我们在这里表明，在体外和细胞毒性淋巴细胞颗粒诱导的死亡过程中，大多数针对人类系统性自身免疫性疾病的自身抗原都能被颗粒酶B有效地切割，产生在任何其他形式的凋亡中没有观察到的独特片段。这些分子不被caspase-8切割，尽管这种酶具有与颗粒酶B非常相似的特异性。自身抗原中的颗粒酶B裂解位点在P2和P3位置含有氨基酸，这些氨基酸是颗粒酶B所偏好的，但不被caspase-8所耐受。与自身抗原不同的是，非自身抗原要么不被颗粒酶B切割，要么被切割产生与其他形式的细胞凋亡相同的片段。因此，颗粒酶B产生独特片段的惊人能力是自身抗原的独有特性，并统一了这一疾病谱中的大多数靶分子。这些结果集中在细胞毒性淋巴细胞颗粒诱导的死亡通路在系统自身免疫的启动和传播中的作用。
Systemic autoimmune diseases are a genetically complex, heterogeneous group of disorders in which the immune system targets a diverse but highly specific group of intracellular autoantigens. The molecules targeted are not unified by common structure, function, or distribution in control cells but become clustered and concentrated in surface blebs when cells undergo apoptosis. We show here that the majority of autoantigens targeted across the spectrum of human systemic autoimmune diseases are efficiently cleaved by granzyme B in vitro and during cytotoxic lymphocyte granule–induced death, generating unique fragments not observed during any other form of apoptosis. These molecules are not cleaved by caspase-8, although this protease has a very similar specificity to granzyme B. The granzyme B cleavage sites in autoantigens contain amino acids in the P2 and P3 positions that are preferred by granzyme B but are not tolerated by caspase-8. In contrast to autoantigens, nonautoantigens are either not cleaved by granzyme B or are cleaved to generate fragments identical to those formed in other forms of apoptosis. The striking ability of granzyme B to generate unique fragments is therefore an exclusive property of autoantigens and unifies the majority of molecules targeted in this spectrum of diseases. These results focus attention on the role of the cytotoxic lymphocyte granule–induced death pathway in the initiation and propagation of systemic autoimmunity.