Date: Monday, November 9, 2015
Session 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.
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 September 30, 2020.
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ACR Meeting Abstracts - 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/