Telomerase insufficiency in rheumatoid arthritis

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

doi:10.1073/pnas.0811332106

Cited by 161 publications

(162 citation statements)

References 44 publications

(46 reference statements)

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“…Increased proliferative turnover would cause cell divisioninduced shortening. We have recently found that naive RA T cells fail to up-regulate telomerase (38). Telomeric DNA is highly susceptible to DNA damage, even more so than nontelomeric DNA.…”

Section: Methodsmentioning

confidence: 99%

Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis

Shao¹,

Fujii²,

Colmegna³

et al. 2009

J Cell Biol

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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.

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Section: Methodsmentioning

confidence: 99%

Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis

Shao¹,

Fujii²,

Colmegna³

et al. 2009

J Cell Biol

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“…The mechanisms leading to prematurity of telomeric erosion in RA T cells are not understood. One cause lies in the impaired induction of telomerase activity in RA T cells (32). Telomerase activity in CD4 T cells is directly related to their survival and with reduced telomerase activity RA T cells are apoptosis sensitive.…”

Section: Dna Damage and Immune Agingmentioning

confidence: 99%

Aging of the Immune System. Mechanisms and Therapeutic Targets

2016

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Beginning with the sixth decade of life, the human immune system undergoes dramatic aging-related changes, which continuously progress to a state of immunosenescence. The aging immune system loses the ability to protect against infections and cancer and fails to support appropriate wound healing. Vaccine responses are typically impaired in older individuals. Conversely, inflammatory responses mediated by the innate immune system gain in intensity and duration, rendering older individuals susceptible to tissue-damaging immunity and inflammatory disease. Immune system aging functions as an accelerator for other age-related pathologies. It occurs prematurely in some clinical conditions, most prominently in patients with the autoimmune syndrome rheumatoid arthritis (RA); and such patients serve as an informative model system to study molecular mechanisms of immune aging. T cells from patients with RA are prone to differentiate into proinflammatory effector cells, sustaining chronic-persistent inflammatory lesions in the joints and many other organ systems. RA T cells have several hallmarks of cellular aging; most importantly, they accumulate damaged DNA. Because of deficiency of the DNA repair kinase ataxia telangiectasia mutated, RA T cells carry a higher burden of DNA double-strand breaks, triggering cell-indigenous stress signals that shift the cell's survival potential and differentiation pattern. Immune aging in RA T cells is also associated with metabolic reprogramming; specifically, with reduced glycolytic flux and diminished ATP production. Chronic energy stress affects the longevity and the functional differentiation of older T cells. Altered metabolic patterns provide opportunities to therapeutically target the immune aging process through metabolic interference.

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“…It would be of particular interest to determine whether the defective ability of naive CD4 + T cells in patients with this disease to upregulate telomerase activity is related to increased p38 signaling in these cells (61). In addition, CD4 + EMRA T cells that are specific for particular immunodominant epitopes of persistent viruses such as CMV accumulate in older humans (7,62,63).…”

Section: Cd27mentioning

confidence: 99%

Reversible Senescence in Human CD4+CD45RA+CD27− Memory T Cells

Mitri

Azevedo

Henson

et al. 2011

The Journal of Immunology

195

170

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Persistent viral infections and inflammatory syndromes induce the accumulation of T cells with characteristics of terminal differentiation or senescence. However, the mechanism that regulates the end-stage differentiation of these cells is unclear. Human CD4+ effector memory (EM) T cells (CD27−CD45RA−) and also EM T cells that re-express CD45RA (CD27−CD45RA+; EMRA) have many characteristics of end-stage differentiation. These include the expression of surface KLRG1 and CD57, reduced replicative capacity, decreased survival, and high expression of nuclear γH2AX after TCR activation. A paradoxical observation was that although CD4+ EMRA T cells exhibit defective telomerase activity after activation, they have significantly longer telomeres than central memory (CM)-like (CD27+CD45RA−) and EM (CD27−CD45RA−) CD4+ T cells. This suggested that telomerase activity was actively inhibited in this population. Because proinflammatory cytokines such as TNF-α inhibited telomerase activity in T cells via a p38 MAPK pathway, we investigated the involvement of p38 signaling in CD4+ EMRA T cells. We found that the expression of both total and phosphorylated p38 was highest in the EM and EMRA compared with that of other CD4+ T cell subsets. Furthermore, the inhibition of p38 signaling, especially in CD4+ EMRA T cells, significantly enhanced their telomerase activity and survival after TCR activation. Thus, activation of the p38 MAPK pathway is directly involved in certain senescence characteristics of highly differentiated CD4+ T cells. In particular, CD4+ EMRA T cells have features of telomere-independent senescence that are regulated by active cell signaling pathways that are reversible.

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Telomerase insufficiency in rheumatoid arthritis

Abstract: telomere ͉ immunosenescence ͉ pathogenesis ͉ autoimmunity ͉ apoptosis

Cited by 161 publications

References 44 publications

Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis

Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis

Aging of the Immune System. Mechanisms and Therapeutic Targets

Reversible Senescence in Human CD4+CD45RA+CD27− Memory T Cells

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