Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis

Shao, Lan; Fujii, Hiroshi; Colmegna, Inés; Oishi, Hisashi; Goronzy, Jörg J.; Weyand, Cornelia M.

doi:10.1083/jcb1855oia11

Cited by 15 publications

(27 citation statements)

References 32 publications

(32 reference statements)

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“…6,10 Several studies have shown that such inflammation is associated with systemic genotoxicity, which may be a mechanistic factor linking such inflammation with known associations of chronic inflammation to a variety of systemic diseases. 13,[32][33][34][35] In our study, we characterized the systemic effects of intestinal inflammation by determining genotoxic sensitivity of multiple cell types in different anatomical locations to gain insights into the consequences of chronic mucosal inflammation on extraintestinal tissues.…”

Section: Discussionmentioning

confidence: 99%

Intestinal inflammation induces genotoxicity to extraintestinal tissues and cell types in mice

Westbrook

Wei

Braun

et al. 2011

Intl Journal of Cancer

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Chronic intestinal inflammation leads to increased risk of colorectal and small intestinal cancers, and is also associated with extraintestinal manifestations such as lymphomas, other solid cancers, and autoimmune disorders. We have previously found that acute and chronic intestinal inflammation causes DNA damage to circulating peripheral leukocytes, manifesting a systemic effect in genetic and chemically-induced models of intestinal inflammation. This study addresses the scope of tissue targets and genotoxic damage induced by inflammation-associated genotoxicity. Using several experimental models of intestinal inflammation, we analyzed various types of DNA damage in leukocyte subpopulations of the blood, spleen, mesenteric and peripheral lymph nodes; and, in intestinal epithelial cells, hepatocytes, and the brain. Genotoxicity in the form of DNA single and double stranded breaks accompanied by oxidative base damage was found in leukocyte subpopulations of the blood, diverse lymphoid organs, intestinal epithelial cells, and hepatocytes. The brain did not demonstrate significant levels of DNA double strand breaks as measured by γ-H2AX immunostaining. CD4+ and CD8+ T-cells were most sensitive to DNA damage versus other cell types in the peripheral blood. In vivo measurements and in vitro modeling suggested that genotoxicity was induced by increased levels of systemically circulating proinflammatory cytokines. Moreover, genotoxicity involved increased damage rather than reduced repair, since it not associated with decreased expression of the DNA double-strand break recognition and repair protein, ataxia telangiectasia mutated (ATM). These findings suggest that levels of intestinal inflammation contribute to the remote tissue burden of genotoxicity, with potential effects on non-intestinal diseases and cancer.

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Section: Discussionmentioning

confidence: 99%

Intestinal inflammation induces genotoxicity to extraintestinal tissues and cell types in mice

Westbrook

Wei

Braun

et al. 2011

Intl Journal of Cancer

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“…As a consequence, DNA damage responses to genotoxic stress are impaired in these cells with reduced serine phosphorylation of ataxia telangiectasia mutated (ATM) and p53. Also, naïve CD4 T cells from patients with rheumatoid arthritis have reduced expression of the ATM-MRE complex, which causes increased frequencies of DNA double-strand breaks and impaired p53 activation in T cells from these patients (23). Functional consequences are increased apoptosis susceptibility and a decreased replicative capacity, which dampens T cell responses.…”

Section: Difference In the Immune Response In The Elderlymentioning

confidence: 98%

The Gracefully Aging Immune System

Aguado²,

et al. 2013

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Prolonged life expectancy in the 20th century has been one of humankind's greatest triumphs. However, the substantial increase in the human life span has ushered in a new concern: healthy aging. Because infectious diseases prominently contribute to morbidity in the particularly vulnerable elderly population, strategies for preventing these diseases would have a clear impact on improving healthy aging. Thus, vaccines and immunization strategies tailored for the elderly population are needed, and vaccines should be developed to take into consideration the peculiar age-induced variations of immune responsiveness. The conference "Ageing and Immunity" recently held in Siena, Italy, has reviewed and discussed several possible causes of immune senescence, as well as strategies for counteracting this waning of immune responsiveness and for restoring immunocompetence. In addition, examples of diseases that should be targeted by vaccination in the senior population were considered.

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“…Chronic DNA damage responses are apparent in all hematopoietic lineages in older people including T cells. In part, they are explained by telomeric dysfunction; an increase in frequency of double-strand breaks is also found in peripheral T cells during aging 100 . Of note, DNA damage in memory T cells far exceeds that found in naïve T cells, at any age.…”

Section: Intrinsic T Cell Defects -A Consequence Of Resource Allocationmentioning

confidence: 99%

“…Such a defect certainly is one of the major driving forces in the accelerated immune aging seen in patients with rheumatoid arthritis. In addition, to expressing reduced telomerase activity similar to healthy immune aging 104 , expression and function of molecules in the ATM-dependent DNA repair pathway are reduced, leading to increased nontelomeric DNA damage, a failure in p53 activation and the activation of alternative DNA repair pathways 100,105 . It will be interesting to examine whether similar mechanisms can also be identified with normal aging.…”

Section: Intrinsic T Cell Defects -A Consequence Of Resource Allocationmentioning

confidence: 99%

Understanding immunosenescence to improve responses to vaccines

2013

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In the older adult the benefits of vaccination to prevent infectious disease are limited, mainly due to the adaptive immune system’s inability to generate protective immunity. Age-dependent decline in immune competence, often referred to as immunosenescence, results from progressive deterioration of innate and adaptive immune responses and most of the insights into mechanisms of immune aging have derived from studies in murine models. In this Review, we explore how well these models are applicable to understand the aging process throughout the 80–100 years of human life and discuss recent advances in uncovering and characterizing the mechanisms underlying age-associated defective adaptive immunity in humans.

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Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis

Cited by 15 publications

References 32 publications

Intestinal inflammation induces genotoxicity to extraintestinal tissues and cell types in mice

Intestinal inflammation induces genotoxicity to extraintestinal tissues and cell types in mice

The Gracefully Aging Immune System

Understanding immunosenescence to improve responses to vaccines

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