Identification of self-epitopes recognized by T cells in rheumatoid arthritis demonstrates matrix metalloproteinases as a novel T cell target

OBJECTIVE: To identify novel arthritis-associated and/or cartilage-specific self-epitopes recognized by T cells in patients with rheumatoid arthritis (RA). METHODS: Human analogs of several self-epitopes recognized in the rat adjuvant arthritis (AA) model (n = 13) were tested for T cell recognition in patients with RA and healthy controls. Recognition was assessed by proliferative activity of peripheral blood mononuclear cells (PBMC). In addition, cytokine production was determined. RESULTS: Six out of the 13 peptides recognized during AA were also recognized by more than 20% of the RA patients, in contrast to only one out of the 16 control peptides that were not recognized during AA. The highest proliferative responses were to matrix metalloproteinase (MMP)-derived peptides. The response to a MMP-1 epitope was significantly higher in RA patients than in healthy controls. Moreover, this MMP-1 epitope increased interleukin 4 (IL-4) production of RA PBMC and decreased IL-4 production by control PBMC. The proliferative response to a MMP-3 epitope was similar in RA patients and controls; however, the MMP-3 epitope increased IL-4, and concomitantly IL-1beta and tumor necrosis factor-a production of RA PBMC, whereas these cytokines were unaffected in control PBMC. CONCLUSION: This study shows the presence of immune reactions to MMP-derived T cell epitopes that are associated with RA, suggesting a novel role of MMP in RA.