Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals.
Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals.
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DOI：
10.4049/jimmunol.145.2.540
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发表时间：
1990-07
影响因子：
4.4
通讯作者：
R. Martin;D. Jaraquemada;M. Flerlage;J. Richert;J. Whitaker;Eric O Long;D. McFarlin;H. McFarland
中科院分区：
文献类型：
--
作者：
R. Martin;D. Jaraquemada;M. Flerlage;J. Richert;J. Whitaker;Eric O Long;D. McFarlin;H. McFarland
髓鞘碱性蛋白（MBP）是一种候选抗原的自身免疫过程中被认为是参与多发性硬化症（MS）的发病机制。为探讨人MBP特异性CTL的特异性和HLA限制性，用抗原再刺激法从22例MS患者和16例健康人中建立了长期T细胞系（TCL）。通过使用这种方法，MBP特异性细胞毒性TCL产生的81%的MS患者和69%的那些从控制线。两组TCL均表达CD 3+、CD 4+、CD 8-表型，并分泌大量IFN-γ。通过使用MBP的大的酶促和小的合成肽，TCL主要特异于分子的C-末端部分，并且在较小程度上特异于N-末端部分。分子的两个区域，MBP肽87-106和MBP肽154-172，分别被大多数多特异性细胞系和14个单特异性TCL中的4个和3个识别。这些高度免疫原性的区域是令人感兴趣的，因为它们包括在其他物种中致脑炎的序列。通过使用抗体阻断以及各种靶细胞（包括EBV转化的B细胞、纯合分型细胞和用DR-α和DR-β基因的cDNA转染的成纤维细胞）来确定每个细胞系的HLA限制。所有TCL均受HLA-DR Ag限制。几种HLA-DR分子限制多种组织蛋白酶D衍生的和合成的MBP肽，包括肽87-106和154-172的区域，其分别与四种和三种HLA-DR类型结合识别。这些HLA-DR类型中的三种在不同地理区域的MS患者中过度代表。总之，这些发现表明，MBP特异性细胞毒性T细胞反应，虽然不足以疾病，可能是重要的MS的发病机制。
Myelin basic protein (MBP) is a candidate Ag for the autoimmune process believed to be involved in the pathogenesis of multiple sclerosis (MS). To investigate the fine specificity and HLA restriction of human MBP-specific CTL, long term T cell lines (TCL) were established from 22 MS patients and 16 healthy individuals by repeated antigenic restimulation. By using this approach, MBP-specific cytotoxic TCL were generated from 81% of the lines from MS patients and 69% of those from controls. TCL from both groups expressed the CD3+, CD4+, CD8- phenotype and secreted substantial amounts of IFN-gamma. By using large enzymatic and small synthetic peptides of MBP, TCL were primarily specific for the C-terminal part of the molecule and to a lesser extent for the N-terminal portion. Two regions of the molecule, MBP peptide 87-106 and MBP peptide 154-172, were recognized by the majority of the polyspecific lines and by four and three of 14 monospecific TCL, respectively. These highly immunogenic regions are of interest because they include sequences encephalitogenic in other species. The HLA restriction of each line was determined by using antibody blocking as well as various target cells including EBV-transformed B cells, homozygous typing cells, and fibroblasts transfected with cDNA for DR-alpha and DR-beta genes. All TCL were restricted by HLA-DR Ag. Several HLA-DR molecules restricted multiple cathepsin D-derived and synthetic MBP peptides, including the regions of peptides 87-106 and 154-172 which, respectively, were recognized in conjunction with four and three HLA-DR types. Three of these HLA-DR types are overrepresented in MS patients in different geographic regions. Together, these findings suggest that the MBP-specific cytotoxic T cell response, although not sufficient for disease, may be important for the pathogenesis of MS.