Voskuhl R R, Farris R W, Nagasato K, McFarland H F, Dalcq M D
Laboratory of Viral and Molecular Pathogenesis, NINDS, National Institutes of Health, Bethesda, MD 20892, USA.
J Neuroimmunol. 1996 Nov;70(2):103-11. doi: 10.1016/s0165-5728(96)00054-9.
Using experimental allergic encephalomyelitis, EAE, as a model for the study of autoimmune demyelinating disease in the CNS, previous studies have indicated that spread may occur with respect to the specificity of T cell responses during disease. This phenomenon, known as epitope spreading, is central to therapeutic strategies in multiple sclerosis (MS). However, in EAE, the clinical course, neuropathology and immunopathogenesis vary depending upon host factors and the method of disease induction. Since passive EAE in SJL/J mice resembles MS clinically and neuropathologically, this model was chosen to study the immune phenomenon of epitope spreading. T cells specific for whole 18.5 kDa MBP were used to initiate disease since MBP or one of its naturally occurring cleavage fragments may initiate a more physiological immune response than one generated to an artificially designed synthetic peptide. While a progressive increase in T cell responsiveness specific for the immunodominant MBP 87-106 region was observed during disease, there was no evidence of either intermolecular epitope spreading to the immunodominant region of proteolipid protein (PLP) 139-151 or of intramolecular epitope spreading to the exon 2 encoded region of MBP, which is spliced out of 18.5 kDa MBP. In addition there was no shift in immunodominance toward the subdominant MBP 16-35 region during disease. In contrast during active EAE induced by MBP, epitope spreading to the immunodominant epitope of PLP, 139-151, was observed. These data demonstrate that immune responses generated during passive versus active EAE may differ, and suggest that significant epitope spreading does not occur in chronic relapsing demyelinating disease initiated with T cells specific for whole MBP in the absence of exogenous antigen, complete Freund's adjuvant and pertussis. Implications of these findings with regard to epitope spreading in MS are discussed.
以往研究利用实验性自身免疫性脑脊髓炎（EAE）作为中枢神经系统自身免疫性脱髓鞘疾病的研究模型，表明疾病过程中T细胞反应的特异性可能会发生扩散。这种现象被称为表位扩展，是多发性硬化症（MS）治疗策略的核心。然而，在EAE中，临床病程、神经病理学和免疫发病机制因宿主因素和疾病诱导方法而异。由于SJL/J小鼠的被动EAE在临床和神经病理学上类似于MS，因此选择该模型来研究表位扩展的免疫现象。使用对完整18.5 kDa髓鞘碱性蛋白（MBP）特异的T细胞来引发疾病，因为MBP或其天然存在的裂解片段之一可能引发比人工设计的合成肽更生理性的免疫反应。虽然在疾病过程中观察到对免疫显性MBP 87 - 106区域特异的T细胞反应性逐渐增加，但没有证据表明分子间表位扩展到蛋白脂蛋白（PLP）139 - 151的免疫显性区域，也没有证据表明分子内表位扩展到从18.5 kDa MBP中剪接出来的MBP外显子2编码区域。此外，疾病过程中免疫显性没有向次显性MBP 16 - 35区域转移。相比之下，在由MBP诱导的主动EAE中，观察到表位扩展到PLP的免疫显性表位139 - 151。这些数据表明，被动EAE与主动EAE期间产生的免疫反应可能不同，并表明在没有外源性抗原、完全弗氏佐剂和百日咳的情况下，用对完整MBP特异的T细胞引发的慢性复发性脱髓鞘疾病中不会发生显著的表位扩展。讨论了这些发现对MS中表位扩展的意义。
