Dendritic cells: The driving force behind autoimmunity in rheumatoid arthritis?

Abstract

IntroductionDendritic cells (DC) are the professional APC of the immune system. As such, they are the only APC capable of priming the immune response and the most efficient stimulators of memory responses. In addition, their role in the generation of central tolerance is well known and recent evidence implicates DC in various forms of peripheral tolerance. [1][2][3][4][5][6][7] The DC function as effective APC because of their efficient antigen capture and processing functions, migratory and cell surface remodelling ability and potent T cell stimulatory capacity. 4,[8][9][10][11][12][13] In addition, DC are likely to play a role in the regulation of B cell growth, differentiation and immunoglobulin class switching that is separate to that of follicular DC. 4,[14][15][16][17] Two DC subsets, the classical myeloid-related DC and a novel lymphoid-related DC, have been identified and recent evidence suggests that each of these subsets may have different roles in the generation of peripheral tolerance or immunity and in the type of T cell response. [18][19][20][21][22] It has been proposed that DC are the critical decision-making cells in the immune system. Thus, DC respond to local factors that facilitate decisions about the nature of the T cell response. The various signals that influence the DC are not yet fully elucidated, but these signals are likely to depend on the type and dose of antigen, the micro-environment of the DC-antigen encounter, the number, subset and phenotype of the DC involved and the micro-environment of the secondary lymphoid organs where the antigen is presented. 4,8,9,23,24 Functional differentiation of DC Myeloid-related DC (to be referred to as DC for the remainder of this paper) are found in most tissues, solid organs and blood as immature sentinel cells that are continually sampling the environment for self and non-self antigens. The DC can capture and present antigen at picomolar and nanomolar concentrations. 25 These immature DC also process antigen efficiently and produce large amounts of MHC class II molecules that are localized to specialised MHC class II-rich late-endosomal compartments (MIIC). The MIIC contain all the necessary machinery required to edit and load peptides into MHC class II molecules and efficiently transport the peptide-loaded molecules to the cell surface for interaction with T cells. 4,13,[26][27][28][29][30][31][32] The combination of antigen and inflammatory signals, including granulocyte-macrophage colony stimulating factor (GM-CSF), LPS, TNF-α and IL-1, stimulates differentiation and migration of peripheral DC via the afferent lymphatics to draining lymph node (LN). During this differentiation process, DC down-regulate their antigen capture and processing ability, while up-regulating the expression of molecules required for efficient antigen presentation, including peptide-loaded MHC class I and II, costimulatory molecules CD80 and CD86, CC-chemokine receptor (CCR)7 and adhesion molecules that are involved in the direct interaction of DC with T cells. In the...

Co‐stimulatory and adhesion molecules of dendritic cells in rheumatoid arthritis

“…Correspondingly, infiltration of ST by macrophages and the expression of macrophage-derived cytokines in ST of patients with RA have been noted [39][40][41]. A recent study demonstrates a close correlation between differentiated DCs infiltration, lymphocytic infiltration and vascularity in ST from patients not only with RA, but also with osteoarthritis and spondyloarthropathy, suggesting common factors mediating the migration of DCs and lymphocytes into damaged joints [42].…”

FcγR expression on NK cells influences disease severity in rheumatoid arthritis

“…Abnormalities in DC phenotype and function have been reported in RA. 46,47 DC precursors readily migrate into the rheumatoid synovial tissue where they can undergo maturation. 47,48 Recent studies demonstrated that the culture of monocytes with cytokines found in RA synovial fluid led to the generation of a DC subset with strong Th1 stimulatory capacity.…”

“…46,47 DC precursors readily migrate into the rheumatoid synovial tissue where they can undergo maturation. 47,48 Recent studies demonstrated that the culture of monocytes with cytokines found in RA synovial fluid led to the generation of a DC subset with strong Th1 stimulatory capacity. 49 Interestingly, a CD16 þ DC subset with an increased capacity to secrete inflammatory cytokines has been identified.…”

Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine

“…Previously, we have demonstrated that IFN-α enhances enzymatic activity of IDO1, which was critically required in the sensitization phase for IFN-α protective effect and also pDC that have been shown to express IDO1 (Refer to Fig. 8 in paper III) were essential for IFN-α mediated protection [32]. Because IDO1 is known to induce Tregs, we wanted to test if IDO1 was associated with the observed increase in suppressive capacity conferred by IFN-α on Tregs during AIA (Fig.…”

“…DCs initiate and direct adaptive immune responses against the encountered pathogen. DCs also contribute to ongoing inflammation in RA by production of pro-inflammatory factors and also by regulating B cells [31,32].…”