Article

Kamphuis, S. et al. Novel self-epitopes derived from aggrecan, fibrillin, and matrix metalloproteinase-3 drive distinct autoreactive T-cell responses in juvenile idiopathic arthritis and in health. Arthritis Res. Ther. 8, R178

Department of Paediatric Immunology and IACOPO, Institute for Translational Medicine, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands.
Arthritis research & therapy (Impact Factor: 3.75). 02/2006; 8(6):R178. DOI: 10.1186/ar2088
Source: PubMed

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 > or =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-gamma (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.

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    • "The association between susceptibility to oligoarticular JIA and HLA class II alleles implicates CD4 + T cells in the pathogenesis of chronic arthritis [3]. This is supported by the fact that activated CD4 + T cells clustered around dendritic cells are found in the synovia of the inflamed joint in oligoarticular JIA patients [4]. There exist two hypotheses for the development of autoimmune phenomena in oJIA: Massa et al. reported that T cell cross-recognition (molecular mimicry) of exogenous and self HLA-derived antigens generates an abnormal regulatory circuit which maintains and expands T cells, which may participate in autoimmune inflammation by generation of pro-inflammatory cytokines [5]. "

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    • "Both T-and B-cells are detected in synovial infiltrates from JIA and Rheumatoid Arthritis (RA) patients. Evidence of autoreactive T-cells as well as autoantibodies reacting with several tissue autoantigens has been provided in both diseases [5] [6]. Beside their wellknown function as antibody secreting cells, an antibodyindependent role for B-cells in disease pathogenesis has been documented by experimental data as well as the promising results of B-cell depleting therapies in RA [7] [8] [9]. "
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    ABSTRACT: Juvenile Idiopathic Arthritis (JIA) is the most common cause of chronic arthritis in childhood and adolescents and encompasses a heterogeneous group of different diseases. Due to the promising results of B-cell depleting therapies in rheumatoid arthritis the role of B-cells in autoimmune diseases has to be discussed in a new context. Additionally, experiments in mouse models have shed new light on the antibody-independent role of B-cells in the development of autoimmune diseases. In this review we will discuss the importance of B-cells in the pathogenesis of JIA appraising the question for an immunological basis of B-cell targeted therapy in JIA.
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