Expansion and functional relevance of high-avidity myelin-specific CD4+ T cells in multiple sclerosis
Expansion and functional relevance of high-avidity myelin-specific CD4+ T cells in multiple sclerosis
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DOI：
10.4049/jimmunol.172.6.3893
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发表时间：
2004-03-15
影响因子：
4.4
通讯作者：
Martin, R
中科院分区：
文献类型：
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作者：
Bielekova, B;Sung, MH;Martin, R
多发性硬化症（MS）是一种自身免疫性疾病，髓磷脂特异性T细胞被认为在其中起着至关重要的致病作用。然而，到目前为止，证明多发性硬化症患者和对照组之间T细胞对髓磷脂Ag的反应性差异是极其困难的。我们认为，通过使用非生理性的高银浓度，以前的研究错过了自身免疫反应的一个高度相关的方面，即T细胞以高功能贪婪度识别银。因此，我们重点研究了大量MS患者和对照人群中高密度髓磷脂特异性CD4(+) T细胞的特征，这些患者和对照在人口统计学上与MHC II类等位基因的表达相匹配。我们证明，它们的频率在MS患者中显着更高，而在两个队列中，流感血凝素特异性对照T细胞的数量几乎相同；高亲和性T细胞富集于先前在体内激活的细胞，并且明显偏向于促炎表型。此外，MS患者和对照组之间最具区别性的免疫显性表位与先前描述的表位不同，并且明显偏向于与HLA-DR分子结合亲和力较低的表位，这表明胸腺选择对自身免疫T细胞库生成的重要性。选定的免疫学参数和磁共振成像标志物之间的相关性表明，这些细胞的特异性和功能影响表型疾病的表达。这些数据对自身免疫研究具有重要意义，在开发针对多发性硬化症的ag特异性疗法时应予以考虑。
Multiple sclerosis (MS) is an autoimmune disease in which myelin-specific T cells are believed to play a crucial pathogenic role. Nevertheless, so far it has been extremely difficult to demonstrate differences in T cell reactivity to myelin Ag between MS patients and controls. We believe that by using unphysiologically high Ag concentrations previous studies have missed a highly relevant aspect of autoimmune responses, i.e., T cells recognizing Ag with high functional avidity. Therefore, we focused on the characterization of high-avidity myelin-specific CD4(+) T cells in a large cohort of MS patients and controls that was matched demographically and with respect to expression of MHC class II alleles. We demonstrated that their frequency is significantly higher in MS patients while the numbers of control T cells specific for influenza hemagglutinin are virtually identical between the two cohorts; that high-avidity T cells are enriched for previously in vivo-activated cells and are significantly skewed toward a proinflammatory phenotype. Moreover, the immunodominant epitopes that were most discriminatory between MS patients and controls differed from those described previously and were clearly biased toward epitopes with lower predicted binding affinities to HLA-DR molecules, pointing at the importance of thymic selection for the generation of the autoimmune T cell repertoire. Correlations between selected immunological parameters and magnetic resonance imaging markers indicate that the specificity and function of these cells influences phenotypic disease expression. These data have important implications for autoimmunity research and should be considered in the development of Ag-specific therapies in MS.