van Eden W, van der Zee R, Taams L S, Prakken A B, van Roon J, Wauben M H
Institute of Infectious Diseases and Immunology, Veterinary Faculty, University of Utrecht, The Netherlands.
Immunol Rev. 1998 Aug;164:169-74. doi: 10.1111/j.1600-065x.1998.tb01218.x.
Adjuvant arthritis (AA) in Lewis rats is T-cell mediated and seems to depend on T cells recognising the 180-188 epitope of mycobacterial heat-shock protein (hsp) 60. Analysis of arthritogenic T-cell clone A2b has revealed a mimicry of this particular epitope with an articular cartilage-associated target T-cell epitope. Nasal administration of synthetic peptides covering this 180-188 sequence led to epitope-specific tolerance and resistance to AA. Since this tolerisation protocol also inhibited avridine arthritis, one may conclude that this form of epitope-specific tolerance had effectuated a spreading tolerisation at the level of target antigens that included a diverse set of possible arthritis-associated antigens. In vitro anergised T cells exhibited suppressive activity in a co-culture system. As in this case--depending on the presence of the antigen of the anergic T cell--such T cells suppressed responder T cells of a different antigenic specificity, we postulated that anergic T cells may be responsible for a spreading of tolerance. It seemed that such spreading of tolerance was channelled through the antigen-presenting cells (APC) and was dependent on direct cell-cell contact. This and additional forms of spreading of tolerance could be responsible for specific nasal tolerance, causing inhibition of the development of an arthritogenic inflammatory response. This can be similarly the case for the arthritis protection that resulted from immunisation with hsps. Analysis of T-cell responses following hsp immunisations revealed that the arthritis inhibitory activity resided in T cells with specificity for a conserved part of microbial hsp 60. The same T cells cross-responded to rat self-hsp60. Low level expression of the latter molecule on non-professional APC could possibly have induced a suppressive anergic state in these autoreactive cells. Thus, immunisation with microbial hsp would have led to an expansion of such T cells, leading to raised disease-suppressive potential when selectively trapped and activated in the inflamed self-hsp-overexpressing joint. Alternatively, the cross-recognised self-hsp epitope could have the regulatory qualities of an altered peptide ligand or a partial agonist for T cells that see the microbial homologue as the full agonist.
刘易斯大鼠的佐剂性关节炎（AA）是由T细胞介导的，似乎取决于识别分枝杆菌热休克蛋白（hsp）60的180 - 188表位的T细胞。对致关节炎T细胞克隆A2b的分析揭示了该特定表位与一种关节软骨相关靶T细胞表位的模拟。经鼻给予覆盖该180 - 188序列的合成肽导致表位特异性耐受和对AA的抗性。由于这种耐受方案也抑制了阿夫立定关节炎，因此可以得出结论，这种形式的表位特异性耐受在包括多种可能的关节炎相关抗原的靶抗原水平上实现了扩展性耐受。体外无反应性T细胞在共培养系统中表现出抑制活性。在这种情况下，取决于无反应性T细胞抗原的存在，此类T细胞抑制了具有不同抗原特异性的反应性T细胞，我们推测无反应性T细胞可能是耐受性扩展的原因。似乎这种耐受性扩展是通过抗原呈递细胞（APC）介导的，并且依赖于细胞间的直接接触。这种及其他形式的耐受性扩展可能是特异性鼻内耐受的原因，导致抑制致关节炎炎症反应的发展。用热休克蛋白免疫导致的关节炎保护情况可能类似。对热休克蛋白免疫后的T细胞反应分析表明，关节炎抑制活性存在于对微生物hsp 60保守部分具有特异性的T细胞中。相同的T细胞对大鼠自身hsp60产生交叉反应。非专职APC上该分子的低水平表达可能在这些自身反应性细胞中诱导了抑制性无反应状态。因此，用微生物热休克蛋白免疫会导致此类T细胞的扩增，当在炎症性自身hsp过表达的关节中被选择性捕获并激活时，导致疾病抑制潜力增强。或者，交叉识别的自身hsp表位可能具有改变的肽配体或部分激动剂的调节特性，对于将微生物同源物视为完全激动剂的T细胞而言。
