The T cells specific for the carboxyl-terminal determinants of self (rat) heat-shock protein 65 escape tolerance induction and are involved in regulation of autoimmune arthritis
The T cells specific for the carboxyl-terminal determinants of self (rat) heat-shock protein 65 escape tolerance induction and are involved in regulation of autoimmune arthritis
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DOI：
10.4049/jimmunol.172.5.2795
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发表时间：
2004-03-01
影响因子：
4.4
通讯作者：
Moudgil, KD
中科院分区：
文献类型：
--
作者：
Durai, M;Gupta, RS;Moudgil, KD
用热灭活的结核分枝杆菌 H37Ra 对 Lewis 大鼠进行免疫会导致多关节炎（佐剂诱导性关节炎；AA）的发展，其与人类类风湿性关节炎（RA）有一些共同特征。据信，对 65 kDa 分枝杆菌热休克蛋白 (Bhsp65) 的免疫反应参与 AA 的诱导以及该疾病的实验调节。然而，由于缺乏关于 Bhsp65、65-kDa 大鼠热休克蛋白 (Rhsp65) 的哺乳动物自身（大鼠）同源物的耐受水平和表位特异性的信息，以及关于该自身蛋白特异的 T 细胞库的功能属性的信息，严重阻碍了对 Lewis 大鼠 AA 发病机制的几个关键方面的理解。在这项研究中，我们确定Lewis大鼠对Rhsp65的耐受性是不完全的，并且在用这种自身hsp65攻击时引发的残留T细胞本质上具有疾病调节作用。我们还定义了 Rhsp65 C 端区域的 T 细胞表位，这些表位主要有助于免疫反应性以及该自身蛋白的 AA 保护作用。此外，由包含这些C末端决定簇的肽引发的T细胞可以被内源性Rhsp65自然产生的表位有效地再刺激，这表明自身hsp65也可能参与急性AA的自然缓解。这些对 AA 中自身 hsp65 定向调节 T 细胞库的首次实验性见解将有助于开发更好的自身免疫性关节炎免疫治疗方法。
Immunization of Lewis rats with heat-killed Mycobacterium tuberculosis H37Ra leads to development of polyarthritis (adjuvant-induced arthritis; AA) that shares several features with human rheumatoid arthritis (RA). Immune response to the 65-kDa mycobacterial heat-shock protein (Bhsp65) is believed to be involved in induction of AA as well as in experimental modulation of this disease. However, the understanding of several critical aspects of the pathogenesis of AA in the Lewis rat has severely been hampered by the lack of information both regarding the level as well as epitope specificity of tolerance to the mammalian self (rat) homologue of Bhsp65, 65-kDa rat heat-shock protein (Rhsp65), and about the functional attributes of the T cell repertoire specific for this self protein. In this study, we established that tolerance to Rhsp65 in the Lewis rat is incomplete, and that the residual T cells primed upon challenge with this self hsp65 are disease regulating in nature. We also have defined the T cell epitopes in the C-terminal region within Rhsp65 that contribute predominantly to the immune reactivity as well as the AA-protective effect of this self protein. Furthermore, the T cells primed by peptides comprising these C-terminal determinants can be efficiently restimulated by the naturally generated epitopes from endogenous Rhsp65, suggesting that self hsp65 might also be involved in natural remission from acute AA. These novel first experimental insights into the self hsp65-directed regulatory T cell repertoire in AA would help develop better immunotherapeutic approaches for autoimmune arthritis.