T cell homeostasis and autoreactivity in rheumatoid arthritis.

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease that prima-rily aVects the synovial membrane and causes irreversible joint damage. Theprevailing pathogenetic model of RA assumes an autoimmune mechanism.Considerable evidence exists that the disease is mediated or at least regulatedby abnormal T cell responses. The most important and, so far, the onlyuniversallyimplicateddiseaseriskgenesareallelicpolymorphismsoftheHLA-DRB1 genes that serve as ligands for the T cell receptor (TCR) of CD4 T cells[1–3]. CD4 T cells are a major component of the inflammatory infiltrate inthe rheumatoid synovium. In many patients, CD4 T cells and B cells inthe synovial infiltrates are organized into lymphoid structures that resemblegerminal centers [4, 5]. Clonally expanded T cell populations are easily detect-able within synovial lesions and identical TCR sequences have been identifiedin distinct joints of the same patient, strongly suggesting that CD4 T cellsrecognize antigens in the synovium [6, 7].In spite of this unequivocal evidence of antigen-driven T cell responses, itappearsincreasinglyunlikelythatRAisanantigen-specificautoimmunedisease.In the strictest sense, autoimmunity is defined as the loss of tolerance and thegeneration of an adaptive immune response to an autoantigen. Such a singleautoantigen has not been identified in RA. In contrast, recent data suggest thatrecognitionofamultitudeofself-antigensmaybeinvolvedinthediseaseprocess.RA patients have global abnormalities in the peripheral T cell repertoire thatare associated with increased T cell turnover and a contraction of repertoirediversity.Theseaberrationsmaynotonlyreflecttherecognitionofmultipleself-antigens but by themselves are likely to have a negative impact on peripheral