Dendritic cells, Fc{gamma} receptors, and Toll-like receptors: potential allies in the battle against rheumatoid arthritis

Abstract

Recent findings suggest an important role for Fcgamma receptors and Toll-like receptors expressed by dendritic cells (DC) in the pathogenesis of rheumatoid arthritis (RA). Possibly, DC behaviour might be tuned to counteract the misbalanced immune system in RA. Understanding the precise mechanisms that determine the skewed immune response in RA may provide new clues for the therapeutic use of DC in RA.

Figure 1

Phenotype and functional behaviour of DC during development. iDC and mDc express a distinct repertoire of surface molecules and produce a different set of inflammatory mediators. iDC express high levels of antigen uptake receptors (FcγR, TLR, and DC-SIGN) and produce low levels of inflammatory mediators. Expression of the chemokine receptors CCR1, CCR5, and CCR6 results in chemoattraction to inflammatory sites. mDC, in contrast, express low levels of antigen receptors but express molecules which are involved in the presentation of antigen (MHC) and stimulation of T cells (CD80, CD86). Moreover, mDC secrete high quantities of proinflammatory mediators such as TNFα, IL12, and chemokines to attract and activate neighbouring T cells with utmost efficiency. mDC express particularly CCR7 for homing towards the T cell-rich areas in the lymph nodes.

Figure 2

Immune response by DC upon TLR mediated pathways in healthy people and patients with RA. (A) TLR are triggered by a multitude of stimuli (1), leading to activation of DC and production of various proinflammatory mediators (TNFα, IL12, chemokines) to eliminate the potentially harmful trigger. The presence of IC in this phase leads to additional activation of DC because the balance between activation and inhibitory FcγR is skewed towards the former (2). During the late phase of the immune response anti-inflammatory cytokines, designed to dampen the immune response, lead to a skewing of the FcγR balance toward the inhibitory subtype (3). Local production of IC now results in abrogation of the proinflammatory response and perhaps even a restoration of tolerance mediated by DC (4). In patients with RA (B), more TLR agonists are present in the synovial compartment, leading to an increased activation state of DC (1). This leads to an higher production of cytokines and chemokines by DC upon triggering both specific and aspecific stimuli (2). Although it was found that DC from patients with RA express a high level of inhibitory FcγR subtype, DC from patients with RA still produce higher amounts of proinflammatory mediators even upon stimulation with IC (2). Levels of IL13 and IL10 are increased during synovial inflammation. However, we have shown that the increase of the inhibitory FcγRIIb is impaired upon stimulation with IL13. Although IC are abundantly present in the patients with RA (3), this leads to an inefficient up regulation of FcγRIIb, and thus dampening of the immune response as seen in healthy subjects (4).