Diversification of T cell responses to carboxy-terminal determinants within the 65-kD heat-shock protein is involved in regulation of autoimmune arthritis.
Diversification of T cell responses to carboxy-terminal determinants within the 65-kD heat-shock protein is involved in regulation of autoimmune arthritis.
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DOI：
10.1084/jem.185.7.1307
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发表时间：
1997-04-07
影响因子：
15.3
通讯作者：
Sercarz, E E
中科院分区：
文献类型：
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作者：
Moudgil, K D;Chang, T T;Eradat, H;Chen, A M;Gupta, R S;Brahn, E;Sercarz, E E
T细胞对65-kD分枝杆菌热休克蛋白（Bhsp 65）的反应与自身免疫性关节炎的发病机制有关。通过注射结核分枝杆菌在刘易斯大鼠（RT-1 l）中诱导的佐剂性关节炎（AA）用作人类类风湿性关节炎（RA）的实验模型。然而，调节急性AA或对AA的易感性/抗性的免疫学基础尚不清楚。我们已经确定了增殖性T细胞反应的特异性BHSP 65在过程中的AA在刘易斯大鼠。在疾病的早期阶段（AA发作后6-9天），刘易斯大鼠提高了T细胞对Bhsp 65内许多决定簇的反应，这些决定簇遍布整个分子。重要的是，在疾病的晚期（AA发作后8-10周），有证据表明T细胞对Bhsp 65羧基末端决定簇（BCTD）（即417-431、441-455、465-479、513-527和521-535）的应答多样化。此外，在AA的晚期阶段的关节炎大鼠也提出了有力的T细胞反应的那些羧基末端决定簇内的自我（大鼠）热休克蛋白65（Rhsp 65），对应于上述BCTD的位置。这些结果表明，所观察到的多样化可能是在体内引发的诱导自身（Rhsp 65）反应性T细胞。有趣的是，另一种大鼠品系Wistar京都（WKY/NHsd）大鼠（RT-1 l）与刘易斯大鼠具有相同的主要组织相容性复合体II类分子，发现其对AA具有抗性。在WKY大鼠中，在注射M后10天，观察到对BCTD的强烈反应，而刘易斯大鼠仅在AA的晚期反应。结核引人注目的是，用包含BCTD组而不是其氨基末端决定簇的肽预处理，为幼稚刘易斯大鼠提供了显著的保护，使其免于随后诱导AA。因此，对BCTD的T细胞应答参与调节刘易斯大鼠的炎性关节炎和赋予WKY大鼠对AA的抗性。这些结果对于理解RA的发病机制和设计针对这种疾病的新的免疫策略具有重要意义。
The T cell response to the 65-kD mycobacterial heat-shock protein (Bhsp65) has been implicated in the pathogenesis of autoimmune arthritis. Adjuvant arthritis (AA) induced in the Lewis rat (RT-1l) by injection of Mycobacterium tuberculosis serves as an experimental model for human rheumatoid arthritis (RA). However, the immunological basis of regulation of acute AA, or of susceptibility/resistance to AA is not known. We have defined the specificity of the proliferative T cell responses to Bhsp65 during the course of AA in the Lewis rat. During the early phase of the disease (6–9 d after onset of AA), Lewis rats raised T cell responses to many determinants within Bhsp65, spread throughout the molecule. Importantly, in the late phase of the disease (8–10 wk after onset of AA), there was evidence for diversification of the T cell responses toward Bhsp65 carboxy-terminal determinants (BCTD) (namely, 417–431, 441–455, 465–479, 513–527, and 521–535). Moreover, arthritic rats in the late phase of AA also raised vigorous T cell responses to those carboxy-terminal determinants within self(rat) hsp65 (Rhsp65) that correspond in position to the above BCTD. These results suggest that the observed diversification is possibly triggered in vivo by induction of self(Rhsp65)-reactive T cells. Interestingly, another strain of rat, the Wistar Kyoto (WKY/NHsd) rat (RT-1l), with the same major histocompatibility complex class II molecules as the Lewis rat, was found to be resistant to AA. In WKY rats, vigorous responses to the BCTD, to which the Lewis rat responded only in the late phase of AA, were observed very early, 10 d after injection of M. tuberculosis. Strikingly, pretreatment with the peptides comprising the set of BCTD, but not its amino-terminal determinants, provided significant protection to naive Lewis rats from subsequent induction of AA. Thus, T cell responses to the BCTD are involved in regulating inflammatory arthritis in the Lewis rat and in conferring resistance to AA in the WKY rat. These results have important implications in understanding the pathogenesis of RA and in devising new immunotherapeutic strategies for this disease.