IL-17A-Low CCR6+ Th Cell Populations of Patients with Rheumatoid Arthritis Are Pathogenic, Multidrug Resistant and Associated with DMARD and Glucocorticoid Treatment Response

Jan Piet van Hamburg¹, Sandra M.J. Paulissen², Nadine Davelaar¹, Mieke Hazes³ and Erik Lubberts¹, ¹Rheumatology and Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, ²Room Nb-84, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, ³Rheumatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: DMARDs, interleukins (IL) and rheumatoid arthritis (RA), T cells

Session Information

Date: Monday, November 9, 2015

Title: T cell Biology and Targets in Autoimmune Disease Poster I

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: CCR6+ T-helper (Th) cells and their pro-inflammatory cytokines including IL-17A are implicated in the pathogenesis of rheumatoid arthritis (RA). However, within the CCR6+ Th population various subpopulations are present and the clinical relevance of each subpopulation in RA is unclear. Therefore, we characterized CCR6+ Th subpopulations with regard to pathogenic potential and treatment outcome in RA.

Methods: Within total CCR6+ Th cells from patients with RA, CCR4+CXCR3- (Th17), CCR4-CXCR3+ (Th17.1), CCR4/CXCR3 double-positive (DP) and double-negative (DN) cells were distinguished and/or sorted by flow cytometry. These subpopulations were: analyzed for Th17/Th1-associated factors; co-cultured with RA-derived synovial fibroblasts (RASF); related to disease-modifying antirheumatic drugs (DMARDs) and glucocorticoid (GC) therapy response; analyzed regarding the expression of multidrug transporters MDR1 and MRP1 and drug efflux potential.

Results: All CCR6+ Th subpopulations expressed the Th17 associated transcription factor, RORC+ and were present in RA peripheral blood and synovial fluid. Despite differential IL-17A, IL-17F, IFNγ and TBX21 expression, all CCR6+ Th subpopulations, including IL-17A low-producing Th17.1, DP and DN cells, showed pathogenic activity in the induction of IL-1β, IL-6, IL-8, COX-2 and MMP-3 expression by RASF. MDR1 expression levels and MDR1 efflux activity were significantly higher in Th17.1 and DN cells, in comparison to the other CCR6+ Th subpopulations and Th1 cells. In contrast, MRP1 expression and efflux activity was present in all CCR6+ Th subpopulations and increased upon DMARD/GC therapy. Moreover, the lack of response of DMARD/GC therapy was accompanied with increased drug efflux potential by CCR6+ Th cell populations.

Conclusion: Despite distinct differences in Th17/Th1 characteristics, including IL-17A production, all CCR6+ Th subpopulations of patients with RA display pathogenic activity. Future treatment strategies towards CCR6+ Th cells in RA may therefore focus on targets shared by all subpopulations. Furthermore, personalized treatment strategies may be improved by using drug efflux potential of CCR6+ Th cells to monitor DMARD/GC therapy response.

Disclosure: J. P. van Hamburg, None; S. M. J. Paulissen, None; N. Davelaar, None; M. Hazes, None; E. Lubberts, None.

To cite this abstract in AMA style:

van Hamburg JP, Paulissen SMJ, Davelaar N, Hazes M, Lubberts E. IL-17A-Low CCR6+ Th Cell Populations of Patients with Rheumatoid Arthritis Are Pathogenic, Multidrug Resistant and Associated with DMARD and Glucocorticoid Treatment Response [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/il-17a-low-ccr6-th-cell-populations-of-patients-with-rheumatoid-arthritis-are-pathogenic-multidrug-resistant-and-associated-with-dmard-and-glucocorticoid-treatment-response/. Accessed .

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