The regulatory C-terminal determinants within mycobacterial heat shock protein 65 are cryptic and cross-reactive with the dominant self homologs: Implications for the pathogenesis of autoimmune arthritis
The regulatory C-terminal determinants within mycobacterial heat shock protein 65 are cryptic and cross-reactive with the dominant self homologs: Implications for the pathogenesis of autoimmune arthritis
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DOI：
10.4049/jimmunol.173.1.181
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发表时间：
2004-07-01
影响因子：
4.4
通讯作者：
Mondgil, KD
中科院分区：
文献类型：
--
作者：
Durai, M;Kim, HR;Mondgil, KD
65-kDa分枝杆菌热休克蛋白（Bhsp 65）在刘易斯大鼠（RT. 1（1））的佐剂性关节炎（AA）和人类类风湿性关节炎的发病机制中均被调用。处于AA晚期的关节炎刘易斯大鼠显示T细胞对Bhsp 65 C-末端决定簇（BCTD）的应答的多样化，并且用代表这些新表位的肽的混合物预处理幼稚刘易斯大鼠提供针对AA的保护。然而，精细的特异性和生理意义的BCTD-指导的T细胞库，和同源的自我（大鼠）热休克蛋白65（Rhsp 65）的作用，如果有的话，在传播的T细胞应答Bhsp 65尚未被检查。我们观察到由包含BCTD的肽引发的T细胞可以过继性地将针对AA的保护转移到受体刘易斯大鼠。然而，这些T细胞可以被预处理的（肽）形式的BCTD激活，而不是天然的Bhsp 65，表明BCTD是隐蔽表位。BCTD反应性T细胞可以被外源性和内源性Rhsp 65的天然产生的（显性）C末端表位激活，反之亦然。此外，构成BCTD的某些单独的肽及其自身同源物也可以诱导针对AA的保护。这些结果支持了一个模型的多样化的T细胞反应Bhsp 65在AA的过程中，涉及上调的隐蔽BCTD的显示加上自发诱导的T细胞反应的交叉反应性的显性C-末端表位的Rhsp 65。在关节炎相关抗原中发现疾病调节的隐蔽决定簇，为类风湿关节炎的免疫治疗提供了新的途径。
The 65-kDa mycobacterial heat shock protein (Bhsp65) has been invoked in the pathogenesis of both adjuvant arthritis (AA) in the Lewis rat (RT.1(1)) and human rheumatoid arthritis. Arthritic Lewis rats in the late phase of AA show diversification of the T cell response to Bhsp65 C-terminal determinants (BCTD), and pretreatment of naive Lewis rats with a mixture of peptides representing these neoepitopes affords protection against AA. However, the fine specificity and physiologic significance of the BCTD-directed T cell repertoire, and the role of homologous self (rat) hsp65 (Rhsp65), if any, in spreading of the T cell response to Bhsp65 have not yet been examined. We observed that T cells primed by peptides comprising BCTD can adoptively transfer protection against AA to the recipient Lewis rats. However, these T cells can be activated by preprocessed (peptide) form of BCTD, but not native Bhsp65, showing that BCTD are cryptic epitopes. The BCTD-reactive T cells can be activated by the naturally generated (dominant) C-terminal epitopes of both exogenous and endogenous Rhsp65 and vice versa. Furthermore, certain individual peptides constituting BCTD and their self homologs can also induce protection against AA. These results support a model for the diversification of T cell response to Bhsp65 during the course of AA involving up-regulation of the display of cryptic BCTD coupled with spontaneous induction of T cell response to the cross-reactive dominant C-terminal epitopes of Rhsp65. The identification of disease-regulating cryptic determinants in Ags implicated in arthritis provides a novel approach for immunotherapy of rheumatoid arthritis.