Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis

Author:

Shao Lan1,Fujii Hiroshi1,Colmegna Inés1,Oishi Hisashi1,Goronzy Jörg J.1,Weyand Cornelia M.1

Affiliation:

1. The Kathleen B. and Mason I. Lowance Center for Human Immunology and Rheumatology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322

Abstract

In rheumatoid arthritis (RA), dysfunctional T cells sustain chronic inflammatory immune responses in the synovium. Even unprimed T cells are under excessive replication pressure, suggesting an intrinsic defect in T cell regeneration. In naive CD4 CD45RA+ T cells from RA patients, DNA damage load and apoptosis rates were markedly higher than in controls; repair of radiation-induced DNA breaks was blunted and delayed. DNA damage was highest in newly diagnosed untreated patients. RA T cells failed to produce sufficient transcripts and protein of the DNA repair kinase ataxia telangiectasia (AT) mutated (ATM). NBS1, RAD50, MRE11, and p53 were also repressed. ATM knockdown mimicked the biological effects characteristic for RA T cells. Conversely, ATM overexpression reconstituted DNA repair capabilities, response patterns to genotoxic stress, and production of MRE11 complex components and rescued RA T cells from apoptotic death. In conclusion, ATM deficiency in RA disrupts DNA repair and renders T cells sensitive to apoptosis. Apoptotic attrition of naive T cells imposes lymphopenia-induced proliferation, leading to premature immunosenescence and an autoimmune-biased T cell repertoire. Restoration of DNA repair mechanisms emerges as an important therapeutic target in RA.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

Reference44 articles.

1. T-cell-targeted therapies in rheumatoid arthritis;Weyand;Nat. Clin. Pract. Rheumatol.,2006

2. Citrullinated proteins: sparks that may ignite the fire in rheumatoid arthritis;Vossenaar;Arthritis Res. Ther.,2004

3. Rheumatoid arthritis;Goronzy;Immunol. Rev.,2005

4. T cell homeostasis in patients with rheumatoid arthritis;Koetz;Proc. Natl. Acad. Sci. USA.,2000

5. DNA damage checkpoints: from initiation to recovery or adaptation;Bartek;Curr. Opin. Cell Biol.,2007

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3