Ellmerich Stephan, Mycko Marcin, Takacs Katalin, Waldner Hanspeter, Wahid Faisal N, Boyton Rosemary J, King Rosalind H M, Smith Paul A, Amor Sandra, Herlihy Amy H, Hewitt Rachel E, Jutton Mark, Price David A, Hafler David A, Kuchroo Vijay K, Altmann Daniel M
Human Disease Immunogenetics Group, Department of Infectious Diseases and Transplantation Biology Group, Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London, United Kingdom.
J Immunol. 2005 Feb 15;174(4):1938-46. doi: 10.4049/jimmunol.174.4.1938.
Multiple sclerosis (MS) is thought to involve CD4 T cell recognition of self myelin, many studies focusing on a pathogenic role for anti-myelin, HLA-DR15-restricted T cells. In experimental allergic encephalomyelitis, it is known which epitopes trigger disease and that disease is associated with determinant spread of T cell reactivity. Characterization of these events in human MS is critical for the development of peptide immunotherapies, but it has been difficult to define the role of determinant spread or define which epitopes might be involved. In this study, we report humanized transgenic mice, strongly expressing HLA-DR15 with an MS-derived TCR; even on a RAG-2 wild-type background, mice spontaneously develop paralysis. Disease, involving demyelination and axonal degeneration, correlates with inter- and intramolecular spread of the T cell response to HLA-DR15-restricted epitopes of myelin basic protein, myelin oligodendrocyte glycoprotein, and alphaB-crystallin. Spread is reproducible and progressive, with two of the epitopes commonly described in responses of HLA-DR15 patients. The fact that this pattern is reiterated as a consequence of CNS tissue damage in mice demonstrates the value of the transgenic model in supplying an in vivo disease context for the human responses. This model, encompassing pathologically relevant, spontaneous disease with the presentation of myelin epitopes in the context of HLA-DR15, should offer new insights and predictions about T cell responses during MS as well as a more stringent test bed for immunotherapies.
多发性硬化症（MS）被认为涉及CD4 T细胞对自身髓磷脂的识别，许多研究聚焦于抗髓磷脂、HLA - DR15限制性T细胞的致病作用。在实验性自身免疫性脑脊髓炎中，已知哪些表位引发疾病，且疾病与T细胞反应性的决定簇扩展相关。在人类MS中表征这些事件对于肽免疫疗法的发展至关重要，但一直难以确定决定簇扩展的作用或确定可能涉及哪些表位。在本研究中，我们报告了人源化转基因小鼠，其在MS来源的TCR作用下强烈表达HLA - DR15；即使在RAG - 2野生型背景下，小鼠也会自发出现麻痹。涉及脱髓鞘和轴突退变的疾病与T细胞对髓磷脂碱性蛋白、髓鞘少突胶质细胞糖蛋白和αB - 晶状体蛋白的HLA - DR15限制性表位的分子间和分子内反应扩展相关。这种扩展是可重复且渐进的，其中两个表位常见于HLA - DR15患者的反应中。这种模式因小鼠中枢神经系统组织损伤而反复出现这一事实，证明了转基因模型在为人类反应提供体内疾病背景方面的价值。该模型涵盖了具有病理相关性的自发性疾病，并在HLA - DR15背景下呈现髓磷脂表位，应该能为MS期间的T细胞反应提供新的见解和预测，以及为免疫疗法提供更严格的试验平台。
