Rheumatoid Arthritis: Wenink MH

Wenink MH, Han W, Toes RE, Radstake TR. · Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. · Handb Exp Pharmacol. · Pubmed #19031022 No free full text.

Abstract: Dendritic cells (DC) are the professional antigen presenting cells that protect us against invading organisms. On the other hand, they uphold tolerance thereby avoiding the initiation of autoimmunity. In performing these contrasting but essential tasks DC are unique and divide these processes in time and space. It is often thought that a loss of separation of these tasks underlies the breakthrough of tolerance leading to autoimmune conditions such as rheumatoid arthritis. In this review, we will focus on the evidence which points towards the implication of DC in the inflammatory process observed in RA and in experimental models of arthritis. Finally, we will conclude on future programs exploiting the capacity of DC to cure conditions such as RA.

Wenink MH, van den Berg WB, van Riel PL, Radstake TR. · Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. · Neth J Med. · Pubmed #16609156 links to  free full text

Abstract: Autoimmune diseases such as rheumatoid arthritis (RA) result from a deregulation of immune responses culminating in immune-mediated tissue injury. In RA, this tissue injury is mainly reflected by synovitis and subsequent joint damage, although involvement of visceral organs (heart, lungs and kidneys) often leads to severe comorbidity. Accumulating evidence points towards dendritic cells (DC) as the principal regulators of the balance between immunity and tolerance. Recently, a large body of evidence has demonstrated that the balance between activating and inhibitory Fc gamma receptor (Fc gammaR) subtypes is intricately involved in the regulation of DC behaviour. In this overview we summarise recent findings from our group and others that suggest an important role for Fc gammaR in arthritis. Furthermore, we postulate novel mechanisms of how triggering of Fc gammaR might be used to manipulate DC function and combat autoimmunity. When DC are envisaged as useful targets in the light of DC immunotherapy in RA, detailed knowledge on the regulatory pathways of Fc gammaR in RA is of paramount importance.

Roelofs MF, Wenink MH, Toonen EJ, Coenen MJ, Joosten LA, van den Berg WB, van Riel PL, Radstake TR. · Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. · J Rheumatol. · Pubmed #18381796 No free full text.

Abstract: OBJECTIVE: To investigate functional consequences of the Toll-like receptor 4 (TLR4) variant (Asp299Gly) in rheumatoid arthritis (RA). METHODS: Peripheral blood mononuclear cells from 28 patients with RA carrying or not carrying the TLR4 variant were incubated with lipopolysaccharide (LPS) and heat shock protein B8 (HSPB8). Concentrations of interleukin 6 (IL-6), tumor necrosis factor-alpha(TNF-alpha), and IL-10 were determined along with TLR4 and CD14 expression. RESULTS: TLR4 expression was similar in patients carrying or not carrying the variant. In contrast, both LPS and HSPB8 resulted in significantly lower secretion of IL-6, TNF-alpha, and IL-10 in those who carried the variant, whereas the frequency of CD14+ cells was higher in these individuals. CONCLUSION: TLR4 variant clearly reduces its potency to mediate signaling. Correction for CD14+ cells is necessary in comparable experiments.

Radstake TR, Franke B, Wenink MH, Nabbe KC, Coenen MJ, Welsing P, Bonvini E, Koenig S, van den Berg WB, Barrera P, van Riel PL. · Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. · Arthritis Rheum. · Pubmed #17133580 links to  free full text

Abstract: OBJECTIVE: Fcgamma receptors (FcgammaRs) recognize immune complexes (ICs) and coordinate the immune response by modulating the functions of dendritic cells (DCs). The purpose of this study was to unravel the role of the inhibitory FcgammaRIIb in rheumatoid arthritis (RA) by studying the effect of the FCGR2B 695T>C polymorphism on susceptibility to RA, severity of the disease, and DC function. METHODS: Genotyping was performed in RA patients (n = 246) and healthy blood donors (n = 269). The patients' demographic data, disease severity, and disease progression were assessed over a followup of 6 years. DCs were cultured for flow cytometry to determine the expression of FcgammaRs. For detection of FcgammaRIIb (CD32B), a unique anti-FcgammaRIIb antibody (2B6-fluorescein isothiocyanate [FITC]) was used. The capacity for antigen uptake by DCs was studied by assessing the uptake of FITC-labeled ICs. Levels of cytokine production by DCs were measured during lipopolysaccharide-mediated cell activation in the presence and absence of ICs. RESULTS: Although no role of the FCGR2B variant in RA susceptibility was demonstrated, this variant was associated with a nearly doubled rate of radiologic joint damage during the first 6 years of RA. Multiple regression analysis showed that FCGR2B was by far the strongest predictor of joint damage identified to date. DCs from patients carrying this variant failed to display the inhibitory phenotype normally observed upon IC-mediated triggering of inflammation and displayed diminished FcgammaRII-mediated antigen uptake compared with wild-type DCs. However, the levels of FcgammaRs were not affected, suggesting that the FCGR2B variant alters the function rather than regulation of proteins. CONCLUSION: This study is the first to show that a single genetic variant, the FCGR2B 695T>C polymorphism, is a critical determinant of disease severity in RA and radically changes DC behavior. Our results underscore the key role of DCs in the progression of RA and reveal FcgammaRIIb as an important potential therapeutic target in RA and other autoimmune conditions.

Radstake TR, Nabbe KC, Wenink MH, Roelofs MF, Oosterlaar A, van Lieshout AW, Barrera P, van Lent PL, van den Berg WB. · Geert Grooteplein 8, 6500 HB Nijmegen, The Netherlands. · Ann Rheum Dis. · Pubmed #15878907 links to  free full text

Abstract: BACKGROUND: Dendritic cell (DC) function is largely tailored by Fc gamma receptors (Fc gamma R) and is critical for every immune response. OBJECTIVE: To compare interleukin (IL) 13 mediated regulation of Fc gamma RII and its related DC function between healthy controls and patients with rheumatoid arthritis (RA). METHODS: DC were derived from peripheral blood mononuclear cells according to standardised protocols. F cgammaRI, II, and III expression and DC phenotype were assessed by FACS analysis. The level of cytokine production and chemokine expression was measured by Luminex and real time quantitative polymerase chain reaction techniques. Antigen uptake capacity was studied by DC fluorescent heat aggregated immunoglobulins and FACS analysis. RESULTS: Replacement of IL4 by IL13 clearly increased the expression of Fc gamma RII on DC from healthy controls (CDC), but had no effect on DC from patients with RA (RADC). The lower production of inflammatory mediators by IL13 CDC upon Fc gamma R mediated triggering suggests that IL13 induces up regulation of specifically Fc gamma RII. RADC co-cultured with IL4 already displayed an inhibitory DC phenotype, but this inhibitory phenotype was not augmented by the addition of IL13. The defective Fc gamma RII regulation was further substantiated by the finding that IL13 CDC increased antigen uptake capacity, whereas IL13 RADC did not. CONCLUSION: IL13 regulates the expression of inhibitory Fc gamma RII in normal subjects but not in RA, potentially resulting in a chronic proinflammatory immune reaction in RA. Unravelling the underlying mechanisms of Fc gamma RII regulation might lead to new therapeutic targets in RA.