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Autoaggressive CD8 T cells in polymyositis

多发性肌炎中的自身攻击性 CD8 T 细胞

基本信息

批准号：
13670452
负责人：
KOHSAKA Hitoshi
金额：
$ 0.9万
依托单位：
Tokyo Medical & Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670452/
关键词：
polymiositis CD8T cells autoimmunity

项目摘要

Polymyositis (PM) involves destruction of striated muscles by autoaggressive CD8 T cells, which accumulate and secrete cytotoxic effecter molecules in the affected muscles. On the other hand, studies of peripheral T cell repertoires from normal individuals and patients with viral infections have shown that primed CD8 T cells, unlike CD4 T cells are prone to expand clonally and persist as large populations in the peripheral blood. This made us assume that autoaggressive myocytotoxic CD8 T cells would be expanded clonally in the peripheral blood from patients with PM. By clonal analyzes of peripheral T cells from patients and age-matched controls, we show here that clonal expansion of CD8 T cells, but not that of CD4 T cells, was significantly more frequent in patients. In analogy to virus-specific T cells, the expanded T cells persisted as large populations over time. Analysis of the muscle biopsy specimens revealed that some of the expanded clones were infiltrating in the affected muscles from the same patients. These results provide the first evidence that local autoimmune reaction directly elicits significant biases in peripheral T cell repertoire. Since the expanded cells, which should be candidate autoaggressive T cells, are readily isolated from peripheral blood, our findings should give us an immediate clue to analysis of the pathogenic T cells in PM.Following studies failed to show that the expanded cells recognize human C-protein that is responsible for a rodent model of PM. The future studies will be focused on the antigen specificity of the expanded cells.

多发性肌炎(PM)涉及自身侵袭性CD8 T细胞对横纹肌的破坏，CD8 T细胞在受影响的肌肉中积聚和分泌细胞毒效应分子。另一方面，对正常人和病毒感染患者的外周T细胞库的研究表明，CD8T细胞与CD4T细胞不同，容易克隆性扩张，并在外周血中作为大量群体持续存在。这让我们推测PM患者外周血中的自攻性肌细胞毒性CD8 T细胞会克隆性扩增。通过对患者和年龄匹配的对照组的外周T细胞的克隆性分析，我们发现CD8T细胞的克隆性增殖在患者中明显更频繁，而CD4T细胞的克隆性增殖则不明显。与病毒特异性T细胞类似，随着时间的推移，扩大的T细胞以大量群体的形式持续存在。对肌肉活检标本的分析表明，一些扩大的克隆正在从同一患者的受影响肌肉中渗透。这些结果首次证明局部自身免疫反应直接导致外周T细胞谱系的显著偏向。由于扩增的细胞应该是候选的自身侵袭性T细胞，很容易从外周血中分离出来，我们的发现应该会给我们提供分析PM中致病T细胞的直接线索。以下研究未能表明扩增的细胞识别导致PM啮齿动物模型的人类C蛋白未来的研究将集中在扩增细胞的抗原特异性上。