Dendritic cells in rheumatoid arthritis: Which subset should be used as a tool to induce tolerance?
Introduction
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, but also to the maintenance of both central and peripheral tolerance. As such, DC have been implicated in the initiation and perpetuation of chronic autoimmune disease through the abolition of self-tolerance and subsequent emergence of self-reactive lymphocytes. It has recently been demonstrated that the aberrant accumulation of DC in tissue, but not of T cells or B cells, may be sufficient in itself to induce symptoms of autoimmunity, including the production of antinuclear antibodies [1].
Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with the destruction of affected joints and represents one of the most common autoimmune-related diseases, affecting as much as 1% of Western populations. Clinically, RA manifests as a symmetric polyarthritis associated with swelling and pain in multiple joints, often initially occurring in the joints of the hands, wrists, and feet. RA is characterized by synovial hyperplasia and progressive joint destruction [2]. In this respect, there is increased proliferation of fibroblast-like synoviocytes and a massive influx of T cells, B cells, macrophages, and DC into the synovial tissue (ST) [3].
Section snippets
Human DC subsets
DC play a pivotal role in the orchestration of T-cell immunity and tolerance due to their ability to stimulate naive T cells and direct effector cell function [4]. Moreover, plasmacytoid DC (pDC) induce T-cell-dependent [5] and T-cell-independent [6] B-cell differentiation into antibody-producing plasma cells.
Antigen presentation in RA
Most of the studies performed with human DC subsets in RA have indicated that DC play a role in the initiation and perpetuation of inflammatory arthritis by the presentation of arthritogenic antigens to autoreactive T cells [23], [24], [25]. This presentation may drive aberrant memory T-cell responses, promoting B-cell activation and immunoglobulin class switching. T cells recognize specific antigenic peptide combined with MHC molecules by virtue of their specific T-cell receptor (TCR). The
DC as a therapeutic tool to induce tolerance in RA: Which subset?
Most of the present studies regarding the use of DC as a therapeutic tool to ameliorate arthritis have been performed in experimental arthritis (reviewed in [10]). However, it remains unclear which DC subset should be the target of therapy or which DC subset is the best to induce tolerance. Nevertheless, it is tempting to speculate that both mDC and pDC might be important and worth investigating with regard to their potential capacity to induce tolerance; we also speculate that mDC rather than
Concluding remarks
DC comprise a complex network of heterogeneous APC that are critical not only to the initiation and regulation of adaptive immunity, but also to the maintenance of both central and peripheral tolerance. As such, DC have been implicated in the initiation and perpetuation of chronic autoimmune disease through the abolition of self-tolerance and the subsequent emergence of self-reactive lymphocytes.
Further research aimed at elucidating the specific and possibly complementary roles of DC subsets in
Acknowledgments
The authors acknowledge Saïda Aarrass for excellent technical assistance and EULAR for providing financial support (EULAR Young Investigator Award 2005, to M.C.L.), as well as the Dutch Arthritis Association (2008, No. 0701014, to P.P.T. and M.C.L.).
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