Date: Monday, November 9, 2015
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Production of anti-CCP autoantibodies, the hallmark of rheumatoid arthritis (RA), is dependent on T cell help, positioning T cells into a pinnacle position in the breakdown of self-tolerance. Such RA T cells have features of premature senescence and age-inappropriately erode their telomeric sequences. It has been speculated that senescence and telomere erosion result from increased proliferative pressure, but the underlying mechanism is not understood. To explore why RA T cells lose telomeric sequences, we have analyzed the structure and function of telomere-residing proteins in CD4 T cells, focusing on DNA repair molecules involved in telomeric maintenance.
Methods: Naïve CD4+CD45RA+ T cells were purified from anti-CCP+ RA patients and age-matched controls and stimulated by T cell receptor triggering. The length and structural intactness of the telomeric cap of individual telomeres was examined by fluorescence-in-situ-hybridization in metaphase nuclei. DNA repair molecules were mapped to the telomere by multicolor confocal microscopy, utilizing the shelterin protein TRF2 as a telomere-specific marker. To investigate the function of individual DNA damage proteins in telomere protection, we employed siRNA knockdown technology.
Results: Metaphase nuclei from RA T cells consistently had structurally damaged telomeres. Almost 70% of nuclei had structural abnormalities, including telomere fragility products, end apposition, telomere fusion and signal free ends (p=0.001 compared to age-matched controls). Confocal analysis demonstrated that the protein complexes recruited to duplicating telomeres were significantly different in RA and control T cells, with RA telomeres lacking the MRN complex (p=0.002). Knockdown of the MRN component MRE11 in healthy T cells promptly produced telomeric damage, quantified by the telomeric localization of the damage-sensing protein 53BP1 (p=0.0001). Also, forced MRE11 loss rapidly induced T cell senescence, as demonstrated by the induction of the cyclin-dependent kinase inhibitor 2A (p=0.01) and the cell surface marker CD57 (p=0.04).
Conclusion: Telomeres in RA T cells are not only shortened, but are structurally damaged. The protein complex surrounding RA telomeres lacks the repair molecule MRE11, and knockdown of MRE11 in healthy T cells promptly reproduces the telomere damage phenotype of RA T cells. MRE11 loss is mechanistically linked to T cell senescence. Telomeric erosion and premature senescence in RA T cells results from insufficiencies in the DNA repair machinery.
To cite this abstract in AMA style:Li Y, Ju J, Bush TM, Genovese MC, Goronzy J, Weyand CM. Telomere Damage in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/telomere-damage-in-rheumatoid-arthritis/. Accessed October 24, 2021.
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