Inflammation control in rheumatoid arthritis: Modulating Toll-like receptor responses

Rheumatoid arthritis (RA) is a systemic autoimmune disease mainly characterized by chronic inflammation in the joints. Dendritic cells (DCs) and macrophages play an important role in the initiation and continuation of the inflammatory process. These cells express a wide array of receptors to sample their environment, including Toll-like Receptors (TLRs), Fc gamma receptors (FcγRs) and integrins. These receptors can all be involved in cellular activation which needs to be strictly controlled. In this thesis we focused on the interaction between different receptor systems and how they modulate cellular activation and cytokine production. We found that a specific group of RA patients that managed to control their disease activity without further need of medication had a highly increased expression of the inhibitory FcγRIIb, which upon triggering was able to dampen TLR induced DC and macrophage activation. Along with TLRs also activated T cells are involved in macrophage activation in RA, which synergistically increased inflammatory cytokine production by macrophages. Both FcγRIIb and the drug abatacept were able to modulate T cell induced macrophage activation. Cellular interaction can also be important for dampening inflammation and we showed that the accumulation of macrophages and DCs, which is likely to happen at a site of inflammation, decreased their proinflammatory potential. In addition to this the synovial fluid present in RA joints also contains factors, including lipids, that can dampen DC activation via TLRs. On the other hand we see a decreased response of DCs from RA patients to Porphyromonas gingivalis, which might result in reduced clearance of this bacterium in RA patients. A balanced immune system is crucial to prevent over activation of the immune system leading to chronic inflammation, but to respond sufficiently to bacterial stimulation to clear an infection. To do this multiple receptor systems and cells interact with each other to fine-tune inflammatory responses, which could be disturbed at many levels in disease.