Title: Increased DNA damage in Rheumatoid arthritis
Introduction:
Rheumatoid arthritis (RA) is a chronic, debilitating inflammatory disease that causes pain, swelling, stiffness, and loss of function in the joints. The onset usually begins in middle-age, but also affects children and young adults. The ratio of women to men affected by RA is 3:1. In India, RA affects close to 1% of the population, which means around 10 million Indians suffer from RA.
Although the patho-physiological basis of RA is not yet fully understood, reactive oxygen species (ROS) have been implicated in its pathogenesis. Normal cellular metabolism appears to be a primary source for endogenous ROS, However, when the production of damaging ROS exceeds the capacity of the body’s antioxidant defenses to detoxify them, a condition known as oxidative stress occurs.
Ros produced by activated neutrophils during the inflammatoty response play important role in elevation oxidative stress and thereby in the pathogenesis of RA.
Oxidative stress leads oxidative damage of the cellular macromolecules (lipids, proteins and nucleic acids), DNA is a particular target for oxidation as damage may lead to important alterations. It has been proposed that DNA damage induced by ROS may contribute to increased mutation rates, genome instability, apoptosis and associated tissue regeneration and cell proliferation.
Review of literature:
Rheumatoid arthritis RA) is a chronic inflammatory disease with persistent synovial hyperplasia and progressive joint damage (1) immune dysfunction is a characteristic of RA and linked with lymphocyte DNA metabolism. In particular, DNA damage may impair lymphocyte function and induce increased cell turnover; such changes are of relevance to the pathogenesis of RA (2).
DNA can be damaged by many agents such as drugs, radiation, free radicals, and enzymes (3). Various forms of chemical damage have been described, including the disruption of phosphodiester bonds, the formation of DNA- DNA and DNA –protein cross links. And base modification (4). It has been suggested that high level of DNA damage induced by oxidative stress was observed in human auto immune diseases including RA.(5). Enhance production of inflammatory cytokines induces various enzymes such as NADPH oxidase, nitric oxide synthase, myeloperoxidase, and eosinophil peroxidase, these enzymes which produce free radicals may contribute to increased cancer risk in relation to oxidative DNA damage in inflammation (6).
Endogenous nucleases can also damage DNA (7) by forming internucleosomal breaks. Endonuclease activation can be triggered by a number of stimuli which increase intracellular calcium levels (8) and can be inhibited by interleukin 1 and 2. Some studies suggest that in patients with RA there are less interleukin 2 receptors on peripheral blood lymphocytes (9) and therefore a lack of endonuclease inhibition may be a mechanism causing increased DNA damage.
