Telomere dysfunction, autoimmunity and aging.
Telomere dysfunction, autoimmunity and aging.
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DOI：
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发表时间：
2011-06
影响因子：
7.4
通讯作者：
P. Hohensinner;J. Goronzy;C. Weyand
中科院分区：
文献类型：
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作者：
P. Hohensinner;J. Goronzy;C. Weyand
免疫老化与关键免疫功能的丧失有关，例如宿主对感染和恶性肿瘤的保护。出乎意料的是，免疫衰老也使宿主对炎症易感，这可能转化为组织损伤性疾病，因为衰老的免疫系统失去了其最大化炎症保护同时最小化炎症损伤的能力。另一方面，与免疫介导的疾病相关的慢性炎症代表免疫系统的深刻应激因素，影响细胞的周转、复制和衰竭。免疫细胞的寿命与端粒的功能完整性密切相关，端粒的功能完整性受细胞增殖、氧化应激和DNA修复机制的影响。淋巴细胞是少数可以通过端粒酶作用主动延长端粒的细胞类型之一。在自身免疫性疾病类风湿性关节炎（RA）患者中，端粒酶缺乏与免疫老化的过早发生有关。RA患者在DNA修复机制中存在其他缺陷，包括激酶共济失调毛细血管扩张突变（ATM），其关键参与DNA双链断裂的修复。RA中ATM缺陷缩短淋巴细胞存活。端粒长度和结构的动力学开始被理解，并在不同的自身免疫性疾病中具有不同的模式，这表明了定义慢性免疫刺激和免疫系统进行性衰老之间界面的多种分子机制。
Immune aging is associated with loss of critical immune functions, such as host protection from infection and malignancy. Unexpectedly, immunosenescence also renders the host susceptible to inflammation, which may translate into tissue-damaging disease as the senescent immune system loses its ability to maximize inflammatory protection while minimizing inflammatory injury. On the other hand, chronic inflammation associated with immune-mediated disease represents a profound stress factor for the immune system, affecting cellular turn-over, replication and exhaustion. Immune cell longevity is tightly connected to the functional integrity of telomeres which are regulated by cell multiplication, exposure to oxidative stress and DNA repair mechanisms. Lymphocytes are amongst the few cell types that can actively elongate telomeres through the action of telomerase. In patients with the autoimmune disease rheumatoid arthritis (RA), telomerase deficiency is associated with prematurity of immune aging. Patients with RA have other defects in DNA repair mechanisms, including the kinase Ataxia telangiectasia mutated (ATM), critically involved in the repair of DNA double strand breaks. ATM deficiency in RA shortens lymphocyte survival. Dynamics of telomeric length and structure are beginning to be understood and have distinct patterns in different autoimmune diseases, suggesting a multitude of molecular mechanisms defining the interface between chronic immune stimulation and progressive aging of the immune system.