FUNCTIONAL EVIDENCE FOR EPITOPE SPREADING IN THE RELAPSING PATHOLOGY OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
FUNCTIONAL EVIDENCE FOR EPITOPE SPREADING IN THE RELAPSING PATHOLOGY OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
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DOI：
10.1084/jem.182.1.75
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发表时间：
1995-07-01
影响因子：
15.3
通讯作者：
MILLER, SD
中科院分区：
文献类型：
--
作者：
MCRAE, BL;VANDERLUGT, CL;MILLER, SD
研究了表位扩散在复发-缓解型实验性自身免疫性脑脊髓炎（R-EAE）病理学中的作用。利用外周诱导的免疫耐受作为探针来分析神经病理性T细胞库，我们表明，在用完整蛋白脂质（PLP）分子主动免疫诱导的SJL/J小鼠中，R-EAE急性期期间的大多数免疫病理反应性针对PLP 139- 151表位，并且对次级致脑炎PLP表位的反应可能导致疾病的后期复发。通过显示小鼠急性疾病后对PLP 139 -151的T细胞应答的发展来证明分子间表位扩散，其中R-EAE由对非交叉反应性MBP 84 -104决定簇特异性的T细胞的转移引发。分子内表位扩散通过显示特异于继发性致脑炎PLP表位（PLP 178 -191）的内源性宿主T细胞可通过小鼠中脾T细胞增殖和体内迟发型超敏反应来证明，其中急性中枢神经系统损伤由与免疫显性的、非交叉反应性PLP 139 -151序列反应的T细胞引发。PLP 178 -191特异性应答由于急性组织损伤的程度而被激活，并且与急性组织损伤的程度相关，因为它们在急性疾病表达之前在对起始表位耐受的小鼠中不发展。最重要的是，我们表明PLP 178 -191特异性应答能够介导过继性二次转移至幼稚受体小鼠后的R-EAE。此外，在急性疾病发作后诱导对完整PLP（其抑制对起始PLP 139 -151表位和PLP 178 -191表位的应答）的耐受性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导致的表位的应答对复发性临床发作的免疫发病机制的贡献作用，并且对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的设计具有重要意义。
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.