T-helper (Th) cells positive for the chemokine receptor CCR6 are implicated in the pathogenesis of rheumatoid arthritis (RA). In this thesis, we explored the role and modulation of these pathogenic CCR6+ Th cells in RA.

As a first implication of their role, higher proportions of CCR6+ Th cells were identified in ACPA+ patients with RA, who have a more severe and erosive disease in comparison to ACPA- patients.

Next we explored the mechanisms underlying the pathogenic behavior of CCR6+ Th cells by using a functional Th cell-synovial fibroblast (RASF) co-culture system. Herein, the COX-2/PGE2 pathway was identified to be critically involved, by inducing autocrine IL-17A production.

However, the CCR6+ Th population is heterogeneous and several subpopulations can be identified. In the exploration towards their RA relevance, we found that IL-17A producing Th17 cells and not IL-22 producing Th22 cells were potent inducers of RASF activation. Moreover, we found that murine Th17-mediated inflammation was IL-22 independent. In contrast, the remaining IL-17Alow CCR6+ Th cell populations, including Th17.1 cells, were potent inducers of RASF. Interestingly, RA Th17.1 cells expressed the multidrug transporters MDR1 and MRP1, which are able to efflux the commonly used RA therapeutics methotrexate and glucocorticoids. From preliminary studies, we found evidence that expression and function of these transporters may be associated with the clinical response to these drugs.

When taken together the findings described in this thesis shed light on the pathogenic role and modulation of CCR6+ Th cells and identifies possibilities for future therapeutic applications in RA.

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J.M.W. Hazes (Mieke) , E.W. Lubberts (Erik)
Erasmus University Rotterdam
Erasmus MC: University Medical Center Rotterdam

Paulissen, S. (2015, December 9). The Role and Modulation of Pathogenic CCR6 Positive T Helper Cells in Rheumatoid Arthritis. Retrieved from http://hdl.handle.net/1765/79229