Rheumatoid Arthritis: van Bilsen JH

van Aken J, van Bilsen JH, Allaart CF, Huizinga TW, Breedveld FC. · Leiden University Medical Center, Leiden, The Netherlands. · Clin Exp Rheumatol. · Pubmed #14969059 No free full text.

Abstract: In 1993 a special Early Arthritis Clinic (EAC) was established at the Department of Rheumatology of the Leiden University Medical Center in order to detect and treat inflammatory disorders early in the disease state, especially early rheumatoid arthritis. Patients with confirmed arthritis of recent onset (less than 2 years) were included by rheumatologists and trained research nurses. Parameters of first and follow-up visits (3, 6 and 9 months and yearly) that were entered in the EAC-database include the medical history, physical-diagnostic examination, laboratory tests, questionnaires, radiographic joint scores and diagnosis. This database enables us to conduct research on arthritis, with an emphasis on rheumatoid arthritis, in many ways. Physicians and basic scientists have studied cellular immunology and genetic, environmental and clinical risk factors in order to determine the pathophysiologic mechanisms of inflammatory arthritis. The present article is a review on reports published from the EAC. Over the past ten years, these reports have been highly relevant for both daily clinical practice and research. Present and planned future studies, as described in this article, reconfirm the importance of an EAC framework to ensure that research continues on this disease in the Leiden EAC area.

Kamphuis S, Hrafnkelsdóttir K, Klein MR, de Jager W, Haverkamp MH, van Bilsen JH, Albani S, Kuis W, Wauben MH, Prakken BJ. · Department of Paediatric Immunology and IACOPO, Institute for Translational Medicine, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands. · Arthritis Res Ther. · Pubmed #17129378 links to  free full text

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.

van Bilsen JH, van Dongen H, Lard LR, van der Voort EI, Elferink DG, Bakker AM, Miltenburg AM, Huizinga TW, de Vries RR, Toes RE. · Departments of Rheumatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. · Proc Natl Acad Sci U S A. · Pubmed #15569925 links to  free full text

Abstract: The class of immune response against autoantigens could profoundly influence the onset and/or outcome of autoimmune diseases. Until now, there is only limited information on the antigen-specific balance between proinflammatory and regulatory responses in humans. Here we analyzed the natural immune response against a candidate autoantigen in rheumatoid arthritis, human cartilage glycoprotein-39 (HC gp-39). Peripheral blood mononuclear cells from healthy individuals reacted against HC gp-39 with the production of IL-10 but not IFN-gamma. Ex vivo assays indicated that the naturally occurring HC gp-39-specific immune response in bulk is powerful enough to suppress antigen-specific recall responses, demonstrating that rather than being unresponsive, the HC gp-39-directed immune response in healthy individuals shows a strong bias toward a regulatory phenotype. Moreover, CD4(+) T cell lines directed against HC gp-39 expressed CD25, glucocorticoid-induced tumor necrosis factor receptor, and Foxp3 molecules and were capable of suppressing antigen-specific T cell responses. Cell-cell contact was required for this suppression. As opposed to healthy individuals, the HC gp-39-directed immune response in 50% of patients with rheumatoid arthritis exhibits polarization toward a proinflammatory T helper 1 phenotype and is significantly less powerful in suppressing antigen-specific recall responses. Together these findings indicate that the presence of HC gp-39-specific immune responses in healthy individuals may have an inhibitory effect on inflammatory responses in areas where HC gp-39 is present. Furthermore, these data indicate that the class of HC gp-39-directed immune response in rheumatoid arthritis patients has shifted from an antiinflammatory toward a proinflammatory phenotype.

van Bilsen JH, Wagenaar-Hilbers JP, Grosfeld-Stulemeijer MC, van der Cammen MJ, van Dijk ME, van Eden W, Wauben MH. · Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. · J Immunol. · Pubmed #15067089 links to  free full text

Abstract: Novel therapies for rheumatoid arthritis aiming at intervention in the inflammatory process by manipulation of autoreactive T and B lymphocytes receive major interest. However, the development of such therapies is largely hampered by the lack of knowledge of self-Ags recognized during the disease process. Recently, we predicted putative T cell self-epitopes based on a computer search profile. In the present study, the predicted self-epitopes were tested for T cell recognition in two experimental arthritis models, and their arthritogenic capacity was analyzed. Fourteen of n = 51 predicted self-epitopes were recognized during experimental arthritis of which six were able to actively induce arthritis. Interestingly, three of these six peptides were derived from matrix metalloproteinases (MMP), and only T cells responsive to MMP-derived epitopes were able to passively transfer arthritis to naive rats. Moreover, we demonstrate the presence of Abs to MMP-3 during the course of adjuvant arthritis. Together these data indicate that MMPs play a pivotal role as target for T and B cells during the development of inflammatory arthritis. This finding sheds new light on the pathophysiological role of MMPs during arthritis and opens novel possibilities for Ag-specific immunotherapy.