Dendritic cells play several roles in RA

Dendritic cells are the major antigen-presenting and antigenpriming cells of the immune system. We review the antigenpresenting and proinflammatory roles played by dendritic cells in the initiation of rheumatoid arthritis (RA) and atherosclerosis, which complicates RA. Various signals that promote the activation of NF-κB and the secretion of TNF and IL-1 drive the maturation of dendritic cells to prime self-specific responses, and drive the perpetuation of synovial inflammation. These signals may include genetic factors, infection, cigarette smoking, immunostimulatory DNA and oxidized low-density lipoprotein, with major involvement of autoantibodies. We propose that the pathogenesis of RA and atherosclerosis is intimately linked, with the vascular disease of RA driven by similar and simultaneous triggers to NF-κB. Introduction Rheumatoid arthritis (RA) is characterized by systemic and synovial tissue chronic inflammation, and by bone and cartilage erosion and destruction [1]. Autoimmune diseases such as RA result from a process involving three distinct but related components – a break in self-tolerance, development of chronic inflammation in one or several organs, and, if ongoing, tissue destruction and its resultant detrimental effects. Dendritic cells (DC) are essential regulators of both innate and acquired arms of the immune system [2]. Their capacity to prime naïve T lymphocytes for helper and cytotoxic function distinguishes them from other antigen-presenting cells (APC). DC are also essential accessory cells in the generation of primary antibody responses, and are powerful enhancers of natural killer T cells and of natural killer cell cytotoxicity [3]. On the other hand, DC are also involved in the maintenance of tolerance to antigens. Along with the medullary thymic epithelial cells, DC contribute to thymic central tolerance and shaping of the T-cell repertoire by presenting endogenous self-antigens to T cells and deleting those T cells that exhibit strong autoreactivity [4]. In the periphery, resting DC delete autoreactive lymphocytes and expand the population of regulatory T cells. DC therefore have potential use in protective and therapeutic strategies for tolerance restoration in autoimmune diseases (for review see [5]). Dendritic cells play several roles in RA DC are likely to contribute in several ways to the pathogenesis of RA. First, it is clear from autoimmune models that DC are able to prime MHC-restricted autoimmune responses in lymphoid organs [6-8]. Through this process, DC orchestrate the development of the autoantibody and chronic inflammatory pathology on which the clinical features of RA are based. Second, DC infiltrate synovial tissue and synovial fluid and here are able to take up, process and present antigen locally, contributing to disease perpetuation [9,10]. Animal models and histological evidence show that DC drive the generation of ectopic lymphoid tissue in inflammatory environments, probably including the synovium [8,11]. Furthermore DC, along with synoviocytes and macrophages, produce innate immune inflammatory mediators, and these mediators drive inflammatory pathology in RA [7,12]. Finally, evidence is accumulating that DC also contribute to the complications of RA, including atherosclerosis. In the present review we consider each of these activities of DC in RA. In any human systemic condition, evidence for these activities relies on in vitro analysis of patient cells and tissues, and on animal models of RA and other autoimmune diseases. Each of these experimental approaches contributes to our current overall understanding of RA pathogenesis. In the near future, approaches developed to image DC in situ in patients, and to use DC therapeutically, will help to validate in Review Cells of the synovium in rheumatoid arthritis Dendritic cells Viviana Lutzky, Suad Hannawi and Ranjeny Thomas Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia Corresponding author: Ranjeny Thomas, [email protected] Published: 7 September 2007 Arthritis Research & Therapy 2007, 9:219 (doi:10.1186/ar2200) This article is online at http://arthritis-research.com/content/9/4/219 © 2007 BioMed Central Ltd anti-CCP = anticyclic citrullinated peptide; APC = antigen-presenting cells; CRP = C-reactive protein; DC = dendritic cells; EC = endothelial cells; Fc = crystallizable fragment; IFN = interferon; IL = interleukin; LDL = low-density lipoprotein; MHC = major histocompatability complex; NF = nuclear factor; RA = rheumatoid arthritis; TLR = Toll-like receptor; TNF = tumour necrosis factor.