Unraveling the role of human endogenous retroviruses in rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic and painful joint inflammation that can lead to bone erosion and significant disability if not treated promptly. The etiology of this disease is not fully defined. Multiple genetic, epigenetic, environmental, and immunological factors have been associated with the development and perpetuation of this autoimmune and inflammatory phenomenon. Human endogenous retroviruses (HERVs), retroelements that comprise approximately 8% of the human genome, have been proposed as potential contributors to the loss of immune tolerance and may contribute to the development of RA. Exposure to certain environmental risk factors, cellular activation processes, and inflammation promotes HERV gene expression. Compared with healthy individuals, RA patients exhibit increased transcripts of particular HERVs in blood and synovium, mainly of the HERV-K family. In addition, autoantibodies targeting distinct HERV epitopes have been identified in patients with RA. A better understanding of the role of HERVs in RA, including their epigenetic dysregulation and their activation of the immune system, could be a relevant basis for developing new tools for the detection, diagnosis, and follow-up of patients, as well as for identifying alternative therapeutic targets in those individuals who are refractory to conventional treatments. This review examines the general features of HERVs and their potential role in the immune dysregulation of patients with RA.