DNA Repair Mechanisms in Rheumatoid Arthritis

The immune system plays a crucial role in inflammatory processes; however, prolonged or misguided activation of immune cells can have detrimental effects. The effect of a misguided immune response can be particularly seen in diseases such as rheumatoid arthritis (RA) or atherosclerosis. Recent evidence points out that patients with rheumatoid arthritis have fundamental defects in building and rebuilding their immune system. As a consequence, RA patients have a high turn-over immune system, prone to premature immunosenescence and the functional abnormalities associated with the decline of adaptive immunity. Furthermore, acceleration of cardiovascular disease is now recognized as a major complication in RA. The process of atherosclerosis emerges as being a closely, if not integral component of RA defining autoimmunity. T-cells of RA patients exhibit a signature of accelerated immune aging, including deficiencies in maintaining and repairing telomeres and insufficiencies in guarding the integrity of the chromosomal DNA. We therefore propose to study specific DNA repair mechanisms in T-cells from patients with RA to determine if there is an alteration or shift in the two main DNA repair pathways, namely non homologues end joining and homology directed repair. Furthermore, we will investigate apoptotic mechanisms in RA T-cells. We will especially focus on p53 independent apoptotic processes, as p53 is diminished in T-cells from patients with RA. Finally, we will investigate how well telomeres are protected in RA T-cells including the components of the shelterin complex. In conclusion, within this proposal we plan to study the molecular mechanisms of the alteration of DNA repair, to determine the function and organization of telomeres in T-cells from RA patients and to delineate possible therapeutic strategies to reduce apoptosis.