Rivellese, Felice (2016) CONTROVERSIAL ROLES OF MAST CELLS IN RHEUMATOID ARTHRITIS. [Tesi di dottorato]

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Background Mast cells are tissue-resident cells of the innate immunity implicated in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). In fact, they are present in synovia and their activation has been linked to the inflammatory responses driving the development of RA. However, their exact contribution to the development of RA is still unclear. In particular, their interactions with other immune cells at synovial levels and their correlation to disease outcomes have never been investigated in a systematic fashion. Objective Aim of this PhD project was to elucidate the role of mast cells in rheumatoid arthritis, by studying their cellular interaction at synovial levels, their influence on the activation of immune cells and, finally, their correlation with disease outcomes. Results In the synovia of RA patients, mast cells correlated with the degree of local inflammations and cellular infiltration. In particular, higher numbers of mast cells were associated with the presence of lymphoid aggregates, and mast cells were localized in close proximity of cellular aggregates of B and T cells. In vitro, mast cells were able to modulate the responses of immune cells, suppressing the pro-inflammatory activation of monocytes and supporting B cells survival, differentiation and antibody production. In patients with early RA, high numbers of synovial mast cells were associated with antibody positive disease and with systemic inflammatory markers. At the 12 months follow-up, baseline mast cells represented an independent predictor of radiographic progression. Conclusions Mast cells, as part of the inflammatory infiltrate in the synovia of RA patients, are able to induce both pro- and anti-inflammatory immune responses, which might explain the conflicting results obtained so far with experimental models not taking into account their tunable immunomodulatory properties. The ex vivo analysis performed in the synovia of early RA patients indicate that mast cell presence can be used to further dissect the disease heterogeneity, as mast cells clustered with antibody positivity and with a higher degree of local and system inflammation. Interestingly, independently from these associations, mast cell presence at baseline represented a predictor of radiographic progression at 1 year. Overall, our data suggest that mast cells play a multifaceted role in the pathogenesis of RA, warranting additional investigations to further assess their involvement in disease development, progression and response to therapy.

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