Background/Purpose Rheumatoid Arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovium, causing progressive joint destruction and reduction in quality of life for patients. Auto-antibodies in RA patients appear prior to the onset of clinic disease, and are responsible for disease progression. Our previous study showed that follicular helper T (Tfh) cells are increased in peripheral blood of RA patients and correlate with anti-citrullinated protein antibodies (ACPAs) production and disease activity score (DAS-28). IL-21 is the signature cytokine produced by Tfh cells. Through its receptor (IL-21R), IL-21 induces B cell differentiation into antibody producing plasma cells, and also promotes T cell differentiation in an autocrine manner. To dissect the role of IL-21 and IL-21R in RA, we examined the IL-21 and IL-21R expression on different subsets of B cells and T cells in RA patients and healthy donors, and determined their correlation with autoantibody level and disease activity.

Methods Peripheral blood was collected from 50 subjects (25 RA patients meeting 2010 ACR/EULAR RA classification criteria and 25 age/gender matched healthy donors). Tonsils were surgically derived from non-RA donors and used as positive controls. Clinical disease activity was assessed using DAS-28 score. RA patients were divided into four groups based on DAS-28 score ranging from remisson, low, moderate and high disease activity. Serum laboratory measurements including Rheumatoid factor (RF), ACPA, Erythrocyte sedimentation rate (ESR) and C Reactive Protein (CRP) levels were obtained. IL-21 and IL-21R expression on T cell subsets (Tfh, Th1, and Th2 cells) and B cell subsets (naïve B cell, memory B cell, and pre-plasmablast) in peripheral blood and tonsils (naïve B cells, memory B cells, germinal center B cells, and plasma cells) were determined via flow cytometry.  Pearson correlation coefficient was determined in the analysis of correlation between IL-21R expression and clinic parameters.

Results ICOS⁺CXCR5⁺ Tfh cells were identified in peripheral blood of RA patients. These circulating Tfh cells are the dominant T cell subset producing IL-21. We found that Tfh cells were significantly elevated in RA patients with moderate/high disease activity (P<0.05). IL-21R was expressed on naïve B cells, germinal center B cells, and plasma cells in tonsillar lymphoid follicles. As compared to healthy donors, the level of IL-21R expression on naïve B cells, pre-plasma cells, and T cells was significantly elevated in peripheral blood of RA patients and correlated with disease activity.

Conclusion RA patients with moderate/high disease activity have elevated levels of IL-21 expression on Tfh cells and IL-21R expression on B cell subsets, similar to that seen in tonsillar lymphoid follicles. Our results indicate that IL-21/IL-21R pathway is involved in RA pathogenesis.  Interruption of IL-21/IL-21R interaction may be a potential therapeutic target for RA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/follicular-helper-t-cells-control-autoimmunity-through-il-21il-21-receptor-interaction-in-ra-patients/