van Eden W
Institute of Infectious Diseases and Immunology, Veterinary Faculty, University of Utrecht, The Netherlands.
Immunol Rev. 1991 Jun;121:5-28. doi: 10.1111/j.1600-065x.1991.tb00821.x.
Heat-shock proteins are ubiquitous and surprisingly immunogenic bacterial proteins. Due to their extensive evolutionary conservation, development of immune reactivity directed at hsp is expected to jeopardize the maintenance of tolerance for "self". The experimental model of adjuvant arthritis in rats has been illustrative in this respect. In this model disease is induced by immunization to mycobacteria, and by T-cell cloning it appeared that T cells with specificity for the 180-188 sequence of the mycobacterial hsp65 were capable of both inducing the disease or inducing resistance to the disease. Although the exact molecular mimicry relationship of this 180-186 epitope with the proteoglycan moiety of cartilage remains to be elucidated, the crucial significance of hsp65 immunity has been substantiated further, not only in adjuvant arthritis, but also in other models of experimentally induced arthritis. Development of disease is seen to coincide with development of hsp65 reactivity, and in AA to the 180-186 epitope in particular. There is now experimental evidence that responses to hsp65 are subject to regulatory T-cell control, and that such regulatory control may explain the observations that preimmunization with hsp65 induces protection against subsequent development of arthritis. In human arthritis, responses to hsp65 have been seen to occur at the level of synovial fluid-derived T lymphocytes. Especially, in children with juvenile chronic arthritis such responsiveness was seen to be directed at the endogenous "self" hsp60, as it was also found to be expressed at a raised level in the synovial lining cells. Altogether, both from the experimental models and from the human disease, evidence is being collected for hsp65 as a critical antigen which has, in the experimental models, the potential of inducing protective regulatory T-cell control. AA has now offered us some initial possibilities for exploiting this feature of hsp65 in inducing remission of disease. We may hope that, ultimately, such specific immunological intervention in disease will also become a reality in the management of human autoimmune arthritis. The exploitation of the regulatory control mechanisms that normally contain the dangerously autoimmune reactive elements in the system seems to be most attractive for such a purpose. We should not try to modify the outside non-self; however, we should use our understanding of the mechanisms involved in order to stimulate the immune system of the unfortunate to resume control over the management of responses directed at the endogenous "self". It is possible that further analysis of the role of hsp65 in arthritis will lead to such necessary understanding.
热休克蛋白是普遍存在且具有惊人免疫原性的细菌蛋白。由于它们在进化上具有广泛的保守性，针对热休克蛋白产生免疫反应预计会危及自身耐受性的维持。大鼠佐剂性关节炎的实验模型在这方面具有启发性。在该模型中，疾病是通过对分枝杆菌进行免疫诱导的，通过T细胞克隆发现，对分枝杆菌热休克蛋白65的180 - 188序列具有特异性的T细胞既能诱发疾病，也能诱导对疾病的抵抗力。尽管该180 - 186表位与软骨蛋白聚糖部分的确切分子模拟关系仍有待阐明，但热休克蛋白65免疫的关键意义不仅在佐剂性关节炎中得到了进一步证实，在其他实验性诱导关节炎模型中也是如此。疾病的发展与热休克蛋白65反应性的发展同时出现，在佐剂性关节炎中尤其与针对180 - 186表位的反应相关。现在有实验证据表明，对热休克蛋白65的反应受调节性T细胞控制，这种调节性控制可能解释了热休克蛋白65预免疫可诱导对随后关节炎发展的保护作用这一观察结果。在人类关节炎中，已观察到滑膜液来源的T淋巴细胞对热休克蛋白65有反应。特别是在幼年慢性关节炎儿童中，这种反应性被发现是针对内源性“自身”热休克蛋白60的，因为在滑膜衬里细胞中也发现其表达水平升高。总之，无论是从实验模型还是从人类疾病中，都在收集证据证明热休克蛋白65是一种关键抗原，在实验模型中它具有诱导保护性调节性T细胞控制的潜力。佐剂性关节炎现在为我们利用热休克蛋白65的这一特性诱导疾病缓解提供了一些初步可能性。我们可能希望，最终这种针对疾病的特异性免疫干预在人类自身免疫性关节炎的治疗中也能成为现实。利用通常控制系统中危险的自身免疫反应性元素的调节控制机制似乎最适合这一目的。我们不应试图改变外部的非自身；然而，我们应该利用我们对所涉及机制的理解，来刺激不幸患者的免疫系统重新控制针对内源性“自身”的反应管理。对热休克蛋白65在关节炎中作用的进一步分析有可能带来这种必要的理解。
