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Identification of Self-Epitopes Recognized by T Cells in Rheumatoid Arthritis Demonstrates Matrix Metalloproteinases as a Novel T Cell Target
JESSICA ter STEEGE, MARIEKE VIANEN, JOLANDA van BILSEN, JOHANNES BIJLSMA, FLORIS LAFEBER, and MARCA WAUBEN
ABSTRACT. 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-1ß 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. (J Rheumatol 2003;30:1147-56) Key Indexing Terms:
RHEUMATOID ARTHRITIS
From the Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht; and the Institute of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. Supported by a grant from the Dutch Organization for Scientific Research (NWO 940-35-035), Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Japan, and Upither BV, Utrecht, The Netherlands. Dr. Wauben was supported by a fellowship of the Royal Netherlands Academy of Arts and Sciences. J.C.A. ter Steege, PhD; M.E. Vianen, BA; J.W.J. Bijlsma MD, PhD; F.P.J.G. Lafeber, PhD, Department of Rheumatology and Clinical Immunology; J. van Bilsen, PhD; M.H.M. Wauben, PhD, Institute of Infectious Disease and Immunology. Address reprint request to Dr. F.P.J.G. Lafeber, Rheumatology and Clinical Immunology, UMC Utrecht, F02.127, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail: f.lafeber@digd.azu.nl Submitted July 15, 2002; revision accepted November 28, 2002. |