CDR3 sequence motifs shared by oligoclonal rheumatoid arthritis synovial T cells. Evidence for an antigen-driven response.
CDR3 sequence motifs shared by oligoclonal rheumatoid arthritis synovial T cells. Evidence for an antigen-driven response.
复制标题
寡克隆类风湿关节炎滑膜 T 细胞共有 CDR3 序列基序。
DOI：
10.1172/jci117624
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Friedman,SM
中科院分区：
文献类型：
--
作者：
Li,Y;Sun,GR;Tumang,JR;Crow,MK;Friedman,SM
T淋巴细胞与尚未确定的关节局部外来或自身抗原反应可能是重要的RA的发病机制。分子研究表明，倾斜的T细胞抗原受体（TCR）可变基因的使用和选择性扩增特定的T细胞克隆内滑膜隔室支持这一观点。基于我们最近记录RA中V β 17+ T细胞选择性扩增的研究，我们通过将新鲜外植RA滑液组织V β 17 TCR转录本的分子分析与体外结合，在信息丰富的患者中鉴定与疾病过程相关的T细胞。V β 17+滑液组织T细胞克隆的扩增。外周血V β 17 cDNA转录证明异质性。相比之下，两个密切相关的序列，没有发现在外周血中，占主导地位的滑膜组织V β 17的成绩单，这表明选择性定位和寡克隆扩增的病理部位。发现分离并在体外生长的CD 4+、V β 17+滑膜组织衍生的T细胞克隆表达与显性V β 17滑膜组织序列同源的TCR β链转录物。一个克隆与显性滑膜组织序列共享高度多样性抗原结合CDR 3区中的4/5氨基酸（IGQ-N）的保守簇，表明这些转录物所来源的T细胞可以识别相同的抗原。这些发现允许在RA中由脓毒症致病性T细胞克隆表达的α/β TCR的完整表征。功能分析表明，保守的CDR 3序列可以赋予特异性，或限制，MHC II类抗原，DR 4。
T lymphocytes reactive with as yet undefined joint-localized foreign or autoantigens may be important in the pathogenesis of RA. Molecular studies demonstrating skewed T cell antigen receptor (TCR) variable gene usage and selective expansion of particular T cell clones within the synovial compartment support this view. Based on our recent study documenting selective expansion of V beta 17+ T cells in RA, we have pursued the identification of T cells relevant to the disease process, in an informative patient, by combining molecular analysis of freshly explanted RA synovial tissue V beta 17 TCR transcripts with in vitro expansion of V beta 17+ synovial tissue T cell clones. Peripheral blood V beta 17 cDNA transcripts proved heterogeneous. In contrast, two closely related sequences, not found in the peripheral blood, dominated synovial tissue V beta 17 transcripts, suggesting selective localization and oligoclonal expansion at the site of pathology. CD4+, V beta 17+ synovial tissue-derived T cell clones, isolated and grown in vitro, were found to express TCR beta chain transcripts homologous to the dominant V beta 17 synovial tissue sequences. One clone shares with a dominant synovial tissue sequence a conserved cluster of 4/5 amino acids (IGQ-N) in the highly diverse antigen binding CDR3 region, suggesting that the T cells from which these transcripts derive may recognize the same antigen. These findings have permitted a complete characterization of the alpha/beta TCR expressed by putatively pathogenic T cell clones in RA. Functional analysis suggests that the conserved CDR3 sequence may confer specificity for, or restriction by, the MHC class II antigen, DR4.