T-cell aging in rheumatoid arthritis.
T-cell aging in rheumatoid arthritis.
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DOI：
10.1097/bor.0000000000000011
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发表时间：
2014-01
影响因子：
5.1
通讯作者：
Goronzy JJ
中科院分区：
文献类型：
--
作者：
Weyand CM;Yang Z;Goronzy JJ
随着年龄的增长，免疫系统和免疫异常的倾向发生了根本性的变化。50岁的人更容易感染和癌症，但患慢性炎症和免疫介导的组织损伤的风险也更高。类风湿性关节炎患者的免疫衰老过程加快。T细胞早衰不仅发生在类风湿关节炎中，它还与慢性HIV感染的发病率和死亡率有关。衰老细胞获得“衰老相关分泌表型(SASP)”，促进和维持组织炎症。人们开始了解T细胞衰老的分子机制。衰老的T细胞除了由于克隆扩增不均衡而导致T细胞多样性收缩外，还存在着平衡胞浆蛋白激酶和磷酸酶活性的缺陷，改变了它们的激活阈值。此外，修复DNA损伤和未封顶的端粒的泄漏会施加基因组压力。年龄引起的组织微环境的改变可能改变T细胞的反应。衰老T细胞功能的获得和丧失破坏了保护性免疫，并创造了慢性组织炎症的条件，这是RA常见的一种组合。涉及T细胞信号和DNA修复的遗传程序在寻找潜在的分子缺陷方面具有很高的兴趣。
With progressive age, the immune system and the propensity for abnormal immunity change fundamentally. Individuals >50 years of age are more susceptible to infection and cancer, but also at higher risk for chronic inflammation and immune-mediated tissue damage. The process of immunosenescence is accelerated in rheumatoid arthritis. Premature T cell senescence occurs not only in RA, it has also been involved in morbidity and mortality of chronic HIV infection. Senescent cells acquire the “senescence associated secretory phenotype (SASP)”, which promotes and sustains tissue inflammation. Molecular mechanisms underlying T cell aging are beginning to be understood. Besides the contraction of T cell diversity due to uneven clonal expansion, senescent T cells have defects in balancing cytoplasmic kinase and phosphatase activities, changing their activation thresholds. Also, leakiness in repairing DNA lesions and uncapped telomeres imposes genomic stress. Age-induced changes in the tissue microenvironment may alter T cell responses. Gain- and loss-of-function in senescent T cells undermine protective immunity and create the conditions for chronic tissue inflammation, a combination typically encountered in RA. Genetic programs involved in T cell signaling and DNA repair are of high interest in the search for underlying molecular defects.