McRae B L, Vanderlugt C L, Dal Canto M C, Miller S D
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
J Exp Med. 1995 Jul 1;182(1):75-85. doi: 10.1084/jem.182.1.75.
The role of epitope spreading in the pathology of relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) was examined. Using peripherally induced immunologic tolerance as a probe to analyze the neuropathologic T cell repertoire, we show that the majority of the immunopathologic reactivity during the acute phase of R-EAE in SJL/J mice induced by active immunization with the intact proteolipid (PLP) molecule is directed at the PLP139-151 epitope and that responses to secondary encephalitogenic PLP epitopes may contribute to the later relapsing phases of disease. Intermolecular epitope spreading was demonstrated by showing the development of T cell responses to PLP139-151 after acute disease in mice in which R-EAE was initiated by the transfer of T cells specific for the non-cross-reactive MBP84-104 determinant. Intramolecular epitope spreading was demonstrated by showing that endogenous host T cells specific for a secondary encephalitogenic PLP epitope (PLP178-191) are demonstrable by both splenic T cell proliferative and in vivo delayed-type hypersensitivity responses in mice in which acute central nervous system damage was initiated by T cells reactive with the immunodominant, non-cross-reactive PLP139-151 sequence. The PLP178-191-specific responses are activated as a result of and correlate with the degree of acute tissue damage, since they do not develop in mice tolerized to the initiating epitope before expression of acute disease. Most importantly, we show that the PLP178-191-specific responses are capable of mediating R-EAE upon adoptive secondary transfer to naive recipient mice. Furthermore, induction of tolerance to intact PLP (which inhibits responses to both the initiating PLP139-151 epitope and to the PLP178-191 epitope) after the acute disease episode is sufficient to prevent relapsing disease. These results strongly support a contributory role of T cell responses to epitopes released as a result of acute tissue damage to the immunopathogenesis of relapsing clinical episodes and have important implications for the design of antigen-specific immunotherapies for the treatment of chronic autoimmune disorders in humans.
研究了表位扩展在复发缓解型实验性自身免疫性脑脊髓炎（R-EAE）病理过程中的作用。我们以外周诱导的免疫耐受作为分析神经病理T细胞库的探针，结果显示，在用完整蛋白脂质（PLP）分子主动免疫诱导的SJL/J小鼠R-EAE急性期，大多数免疫病理反应针对PLP139-151表位，对继发性致脑炎性PLP表位的反应可能促成疾病后期的复发阶段。通过在由针对非交叉反应性MBP84-104决定簇的T细胞转移引发R-EAE的小鼠急性疾病后，显示对PLP139-151的T细胞反应的发展，证实了分子间表位扩展。通过显示在由与免疫显性、非交叉反应性PLP139-151序列反应的T细胞引发急性中枢神经系统损伤的小鼠中，脾T细胞增殖和体内迟发型超敏反应均能证实针对继发性致脑炎性PLP表位（PLP178-191）的内源性宿主T细胞，证实了分子内表位扩展。PLP178-191特异性反应是由于急性组织损伤而被激活的，并且与急性组织损伤的程度相关，因为在急性疾病表达之前对起始表位耐受的小鼠中它们不会产生。最重要的是，我们表明PLP178-191特异性反应在过继性二次转移至未致敏受体小鼠后能够介导R-EAE。此外，在急性疾病发作后诱导对完整PLP的耐受（这会抑制对起始PLP139-151表位和PLP178-191表位的反应）足以预防复发性疾病。这些结果有力地支持了T细胞对急性组织损伤释放的表位的反应在复发性临床发作的免疫发病机制中的作用，并且对设计用于治疗人类慢性自身免疫性疾病的抗原特异性免疫疗法具有重要意义。
