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Open Access Research article

Novel self-epitopes derived from aggrecan, fibrillin, and matrix metalloproteinase-3 drive distinct autoreactive T-cell responses in juvenile idiopathic arthritis and in health

Sylvia Kamphuis12, Kolbrún Hrafnkelsdóttir1, Mark R Klein1, Wilco de Jager1, Margje H Haverkamp1, Jolanda HM van Bilsen3, Salvatore Albani45, Wietse Kuis1, Marca HM Wauben36 and Berent J Prakken1*

Author Affiliations

1 Department of Paediatric Immunology and IACOPO, Institute for Translational Medicine, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands

2 Department of Paediatric Immunology and Rheumatology, Erasmus MC Sophia, PO Box 2060, 3000 CB Rotterdam, The Netherlands

3 Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands

4 Department of Medicine and Pediatrics and IACOPO Institute for Translational Medicine, University of California San Diego, 9500 Gilmandrive, La Jolla CA 92093-0663, USA

5 Androclus Therapeutics, Via Carducci 15, 92100 Milan, Italy

6 Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands

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Arthritis Research & Therapy 2006, 8:R178  doi:10.1186/ar2088

Published: 27 November 2006

Abstract

Juvenile idiopathic arthritis (JIA) is a heterogeneous autoimmune disease characterized by chronic joint inflammation. Knowing which antigens drive the autoreactive T-cell response in JIA is crucial for the understanding of disease pathogenesis and additionally may provide targets for antigen-specific immune therapy. In this study, we tested 9 self-peptides derived from joint-related autoantigens for T-cell recognition (T-cell proliferative responses and cytokine production) in 36 JIA patients and 15 healthy controls. Positive T-cell proliferative responses (stimulation index ≥2) to one or more peptides were detected in peripheral blood mononuclear cells (PBMC) of 69% of JIA patients irrespective of major histocompatibility complex (MHC) genotype. The peptides derived from aggrecan, fibrillin, and matrix metalloproteinase (MMP)-3 yielded the highest frequency of T-cell proliferative responses in JIA patients. In both the oligoarticular and polyarticular subtypes of JIA, the aggrecan peptide induced T-cell proliferative responses that were inversely related with disease duration. The fibrillin peptide, to our knowledge, is the first identified autoantigen that is primarily recognized in polyarticular JIA patients. Finally, the epitope derived from MMP-3 elicited immune responses in both subtypes of JIA and in healthy controls. Cytokine production in short-term peptide-specific T-cell lines revealed production of interferon-γ (aggrecan/MMP-3) and interleukin (IL)-17 (aggrecan) and inhibition of IL-10 production (aggrecan). Here, we have identified a triplet of self-epitopes, each with distinct patterns of T-cell recognition in JIA patients. Additional experiments need to be performed to explore their qualities and role in disease pathogenesis in further detail.