Hogervorst E J, Boog C J, Wagenaar J P, Wauben M H, Van der Zee R, Van Eden W
Department of Immunology, Faculty of Veterinary Medicine, University of Utrecht, The Netherlands.
Eur J Immunol. 1991 May;21(5):1289-96. doi: 10.1002/eji.1830210529.
Adjuvant arthritis (AA) can be induced in genetically susceptible rats by immunization with heat-killed mycobacteria suspended in mineral oil. From our analysis of arthritogenic T cell clone A2b, obtained from an arthritic Lewis rat and specific for the 180-188 epitope of mycobacterial 65-kDa heat-shock protein (hsp 65), the possible origin of AA was explained by the existence of a molecular mimicry of the 180-188 epitope with a cartilage-associated self antigen. We now have shown that Lewis rats respond to the 180-188 epitope after Mycobacterium tuberculosis immunization and that arthritis-resistant Fisher and (Lewis x Fisher)F1 rats, although major histocompatibility complex class II identical with Lewis, do not respond to this epitope. However, in rare cases of arthritis in Fisher rats, responses to the epitope were seen. We obtained no evidence for a defect at the level of antigen processing and presentation or for suppression in Fisher rats. Thus, non-responsiveness in Fisher rats was likely due to a difference at the level of the T cell repertoire. Previously, we have reported that pretreatment with hsp 65 in experimental arthritis, and not only in AA, caused resistance to arthritis induction. We now present evidence that immunization with hsp 65 or in vitro stimulation with hsp 65 may lead to inhibition of responses specific for epitope 180-188. Thus the hsp 65-induced resistance to arthritis is probably caused by the induction of regulatory control specifically targeted at the 180-188 epitope. Especially in rats that tend to focus their responses on the critical 180-188 sequence, such as Lewis, regulation seems to develop following immunization with hsp 65. Since recent evidence suggests that hsp 65 and also the 180-188 epitope have a role in human arthritic conditions, the present findings are expected to contribute to further experimentation directed at exploiting hsp 65 or its epitopes for the development of new therapeutical approaches in humans.
通过用悬浮在矿物油中的热灭活分枝杆菌免疫，可在基因易感大鼠中诱发佐剂性关节炎（AA）。根据我们对从患有关节炎的Lewis大鼠中获得的、对分枝杆菌65-kDa热休克蛋白（hsp 65）的180-188表位具有特异性的致关节炎T细胞克隆A2b的分析，AA可能的起源可通过180-188表位与一种软骨相关自身抗原存在分子模拟来解释。我们现已表明，Lewis大鼠在接种结核分枝杆菌后会对180-188表位产生反应，而关节炎抗性的Fisher大鼠和（Lewis×Fisher）F1大鼠，尽管其主要组织相容性复合体II类与Lewis大鼠相同，但对该表位无反应。然而，在Fisher大鼠罕见的关节炎病例中，可观察到对该表位的反应。我们没有获得证据表明Fisher大鼠在抗原加工和呈递水平存在缺陷或存在抑制作用。因此，Fisher大鼠的无反应性可能是由于T细胞库水平的差异。此前，我们曾报道，在实验性关节炎中，不仅是在AA中，用hsp 65进行预处理可导致对关节炎诱导产生抗性。我们现在提供的证据表明，用hsp 65免疫或用hsp 65进行体外刺激可能会导致对180-188表位特异性反应的抑制。因此，hsp 65诱导的对关节炎的抗性可能是由针对180-188表位的调节性控制的诱导所引起的。特别是在倾向于将反应集中在关键的180-188序列上的大鼠中，如Lewis大鼠，在用hsp 65免疫后似乎会产生调节作用。由于最近的证据表明hsp 65以及180-188表位在人类关节炎病症中起作用，预计目前的研究结果将有助于进一步开展实验，旨在利用hsp 65或其表位开发针对人类的新治疗方法。
