Lehmann P V, Forsthuber T, Miller A, Sercarz E E
Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90024.
Nature. 1992 Jul 9;358(6382):155-7. doi: 10.1038/358155a0.
Immunization with myelin basic protein (MBP) induces experimental allergic encephalomyelitis (EAE), a prototype of CD4+ T-cell mediated autoimmune disease. In rodents, MBP-reactive T-cell clones are specific for a single, dominant determinant on MBP and use a highly restricted number of T-cell receptor genes. Accordingly, EAE has been prevented by various receptor-specific treatments, suggesting similar strategies may be useful for therapy of human autoimmune disease. Here we report that in (SJL x B10.PL)F1 mice, immune dominance of a single determinant, MBP:Ac1-11, is confined to the inductive phase of EAE. In mice with chronic EAE, several additional determinants of MBP in peptides 35-47, 81-100 and 121-140 recall proliferative responses. Most importantly, reactivity to the latter determinants was also detected after induction of EAE with MBP peptide Ac1-11 alone; this demonstrates priming by endogenous MBP determinants. Thus, determinants of MBP that are cryptic after primary immunization can become immunogenic in the course of EAE. Diversification of the autoreactive T-cell repertoire due to 'determinant spreading' has major implications for the pathogenesis of, and the therapeutic approach to, T-cell driven autoimmune disease.
用髓鞘碱性蛋白（MBP）进行免疫可诱发实验性自身免疫性脑脊髓炎（EAE），这是一种CD4 + T细胞介导的自身免疫性疾病的原型。在啮齿动物中，MBP反应性T细胞克隆对MBP上的单个主要决定簇具有特异性，并使用数量高度受限的T细胞受体基因。因此，通过各种受体特异性治疗可预防EAE，这表明类似的策略可能对人类自身免疫性疾病的治疗有用。在此我们报告，在（SJL×B10.PL）F1小鼠中，单个决定簇MBP:Ac1 - 11的免疫显性仅限于EAE的诱导阶段。在患有慢性EAE的小鼠中，肽段35 - 47、81 - 100和121 - 140中的MBP的几个其他决定簇可引发增殖反应。最重要的是，在用单独的MBP肽段Ac1 - 11诱导EAE后，也检测到了对后一种决定簇的反应性；这证明了内源性MBP决定簇的启动作用。因此，初次免疫后隐匿的MBP决定簇在EAE过程中可变得具有免疫原性。由于“决定簇扩展”导致的自身反应性T细胞库的多样化对T细胞驱动的自身免疫性疾病的发病机制和治疗方法具有重要意义。
