Rheumatoid Arthritis: Lebre MC

Lebre MC, Tak PP. · Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands. · Hum Immunol. · Pubmed #19236901 No free full text.

Abstract: Dendritic cells (DC) comprise a complex network of heterogeneous antigen-presenting cells (APC) that are critical not only to the initiation and regulation of adaptive immunity (Th1/Th2/Th17 responses), but also to the maintenance of both central and peripheral tolerance (regulatory T cells, peripheral T-cell deletion). Previous work has clearly indicated a role for DC subsets in the pathogenesis of rheumatoid arthritis (RA). Therefore, utilizing these cells as therapeutic agents could be beneficial in the treatment of RA. However, it remains unclear which DC should be used for tolerance-inducing immunotherapy: myeloid, plasmacytoid, or both? This review summarizes the data obtained thus far concerning the functional characterization of several DC subsets in human RA and accordingly explores their potential use for immunotherapy.

Lebre MC, Tak PP. · Academic Medical Center, University of Amsterdam, Division of Clinical Immunology and Rheumatology, Amsterdam, The Netherlands. · Acta Reumatol Port. · Pubmed #18344920 links to  free full text

Abstract: Dendritic cells (DC) are now known to influence many different classes of lymphocytes (T, B, NK cells) and many types of T cell responses (Th1/Th2/Th17, regulatory T cells, peripheral T cell deletion). In rheumatoid arthritis (RA) DC have been described and their roles in RA pathogenesis have been implicated. This review summarizes the data obtained so far concerning the functional characterization of several DC subsets in human RA. Moreover, the effect of TNF-alpha blockade on DC phenotype and function is also discussed. As most of the studies on DC in experimental arthritis have been conducted using (immunomodulated/tolerogenic) DC as tools to ameliorate experimental arthritis, we give some examples of how these cells may induce tolerance in vivo. Although a lot of work has been performed so far, the specific and functional roles of DC subsets in human RA and in CIA remain to be established. Achieving a detailed understanding of specific DC functions in RA holds potential for modulating DC for immunotherapy by down-regulating the autoimmune response.

Vergunst CE, van de Sande MG, Lebre MC, Tak PP. · Division of Clinical Immunology and Rheumatology, Academic Medical Centre/University of Amsterdam, the Netherlands. · Scand J Rheumatol. · Pubmed #16393761 No free full text.

Abstract: The directed movement of immune cells is highly dependent on the chemokine network. Chemokines are key molecules early in the embryogenesis of lymph nodes and throughout adult life, where they regulate immune responses against pathogens. Although immune cells are best known for expressing chemokine receptors, through which they can respond to matching chemokines, endothelial cells also express chemokine receptors. The directed movement of endothelial cells facilitates angiogenesis. In chronic inflammatory conditions, such as rheumatoid arthritis (RA), chemokines are abundantly present at the site of inflammation and form a group of potential therapeutic targets. Some agents that block chemokine-chemokine receptor interaction are already under clinical investigation. The expression of chemokine receptors has also been found in cell types other than immune cells and endothelial cells. Chondrocytes, for instance, express several chemokine receptors. Elucidating their function may provide new insights into joint degradation in RA as well as in other conditions, including osteoarthritis (OA).

van Maanen MA, Lebre MC, van der Poll T, LaRosa GJ, Elbaum D, Vervoordeldonk MJ, Tak PP. · Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Arthritis Rheum. · Pubmed #19116908 No free full text.

Abstract: OBJECTIVE: The parasympathetic nervous system, through the vagus nerve, can down-regulate inflammation in vivo by decreasing the release of cytokines, including tumor necrosis factor alpha (TNFalpha), by activated macrophages. The vagus nerve may exert antiinflammatory actions via a specific effect of its principal neurotransmitter, acetylcholine, on the alpha7 subunit of nicotinic acetylcholine receptors (alpha7nAChR) on macrophages. The present study was undertaken to obtain insight into the role of the cholinergic antiinflammatory pathway in arthritis. METHODS: To inhibit the cholinergic antiinflammatory pathway, mice were subjected to unilateral cervical vagotomy or sham surgery, after which arthritis was induced with type II collagen. In a separate study, nicotine was added to the drinking water of mice with collagen-induced arthritis (CIA). In addition, we investigated the effects of intraperitoneally (IP)-injected nicotine and the specific alpha7nAChR agonist AR-R17779. RESULTS: Clinical arthritis was exacerbated by vagotomy and ameliorated by oral nicotine administration. Moreover, oral nicotine inhibited bone degradation and reduced TNFalpha expression in synovial tissue. Both IP-injected nicotine and AR-R17779 ameliorated clinical arthritis and reduced synovial inflammation. This was accompanied by a reduction of TNFalpha levels in both plasma and synovial tissue. The effect of AR-R17779 was more potent compared with that of nicotine and was associated with delayed onset of the disease as well as with protection against joint destruction. CONCLUSION: These data provide the first evidence of a role of the cholinergic antiinflammatory pathway in the murine CIA model of rheumatoid arthritis.

Lebre MC, Jongbloed SL, Tas SW, Smeets TJ, McInnes IB, Tak PP. · Academic Medical Center/University of Amsterdam, Division of Clinical Immunology and Rheumatology, Amsterdam, The Netherlands. · Am J Pathol. · Pubmed #18292234 links to  free full text

Abstract: Dendritic cells (DCs) have been proposed to play a pivotal role in the initiation and perpetuation of rheumatoid arthritis (RA) by presentation of arthritogenic antigens to T cells. We investigated the in vivo characteristics of two major DC subsets, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), in RA synovial tissue (ST) by measuring their frequency, phenotype, distribution, and cytokine expression. ST was obtained by arthroscopy from 20 RA, 8 psoriatic arthritis, and 10 inflammatory osteoarthritis patients. Levels of CD1c(+) mDCs and CD304(+) pDCs present in ST were quantified by digital image analysis, and their distribution was assessed by double immunolabeling with antibodies against CD3 and CD8. The maturation status and cytokine profile of mDCs and pDCs were quantified by double-immunofluorescence microscopy. In RA patients, the number of CD304(+) pDCs exceeded that of CD1c(+) mDCs, with the majority of infiltrating DCs being CD83(-) or DC-LAMP(-). Synovial pDC numbers were especially increased in RA patients who were positive for rheumatoid factor and anti-citrullinated peptide antibody. mDCs and pDCs were localized adjacent to lymphocyte aggregates. In ST from RA patients, both mDCs and pDCs expressed interleukin (IL)-15. IL-18 and interferon (IFN)-alpha/beta were mainly expressed by pDCs whereas IL-12p70 and IL-23p19 expression was predominant in mDCs. These data characterize the phenotypes of mDCs and pDCs in inflammatory synovitis and define for the first time the cytokine expression profile of these DC subsets.

Jongbloed SL, Lebre MC, Fraser AR, Gracie JA, Sturrock RD, Tak PP, McInnes IB. · Division of Immunology, Infection and Inflammation, 10 Alexandra Parade, Glasgow, G31 2ER, UK. · Arthritis Res Ther. · Pubmed #16507115 links to  free full text

Abstract: Dendritic cells (DCs) comprise heterogeneous subsets of professional antigen-presenting cells, linking innate and adaptive immunity. Analysis of DC subsets has been hampered by a lack of specific DC markers and reliable quantitation assays. We characterised the immunophenotype and functional characteristics of psoriatic arthritis (PsA)-derived and rheumatoid arthritis (RA)-derived myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) to evaluate their potential role in arthritis. Circulating peripheral blood (PB) pDC numbers were significantly reduced in PsA patients (P = 0.0098) and RA patients (P = 0.0194), and mDCs were significantly reduced in RA patients (P = 0.0086) compared with healthy controls. The number of circulating mDCs in RA PB was significantly inversely correlated to C-reactive protein (P = 0.021). The phenotype of both DC subsets in PsA PB and RA PB was immature as compared with healthy controls. Moreover, CD62L expression was significantly decreased on both mDCs (PsA, P = 0.0122; RA, P = 0.0371) and pDCs (PsA, P = 0.0373; RA, P = 0.0367) in PB. Both mDCs and pDCs were present in PsA synovial fluid (SF) and RA SF, with the mDC:pDC ratio significantly exceeding that in matched PB (PsA SF, P = 0.0453; RA SF, P = 0.0082). pDCs isolated from RA SF and PsA SF displayed an immature phenotype comparable with PB pDCs. RA and PsA SF mDCs, however, displayed a more mature phenotype (increased expression of CD80, CD83 and CD86) compared with PB mDCs. Functional analysis revealed that both SF DC subsets matured following toll-like receptor stimulation. pDCs from PB and SF produced interferon alpha and tumour necrosis factor alpha on TLR9 stimulation, but only SF pDCs produced IL-10. Similarly, mDCs from PB and SF produced similar tumour necrosis factor alpha levels to TLR2 agonism, whereas SF mDCs produced more IL-10 than PB controls. Circulating DC subset numbers are reduced in RA PB and PsA PB with reduced CD62L expression. Maturation is incomplete in the inflamed synovial compartment. Immature DCs in SF may contribute to the perpetuation of inflammation via sampling of the inflamed synovial environment, and in situ presentation of arthritogenic antigen.