A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis

Abstract

IntroductionInterleukin (IL)-21 is a member of type I cytokine family. Recent studies indicate that IL-21 can promote T follicular helper (Tfh) cell differentiation and survival, a specialized T cell subset which provides help for B cell. It can also regulate the activation, proliferation and differentiation of human B cell and immunoglobulin (Ig) production as well as isotype switching of plasma cell. Rheumatoid arthritis (RA) is characterized by auto-antibodies overproduction such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody, suggesting a pivotal role of Tfh cell and B cell in the pathogenesis of RA. This study aimed to investigate whether IL-21 had a regulatory effect on Tfh cell and B cell in RA.MethodsSerum IL-21 concentrations were measured by ELISA. The correlations between serum IL-21 levels and clinical features of RA patients were analyzed by Spearman's rank test. The percentages of Tfh-like cells, IL-21 receptor (R) expression on Tfh-like cells and B cells in peripheral blood (PB) were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) were stimulated by rIL-21 (100 ng/ml) in the presence or absence of anti-CD40 and/or anti-IgM, and changes of IL-21R, activation-associated surface markers (CD25, CD69 and CD40), the proliferation, apoptosis and differentiation of B cells were analyzed by flow cytometry. Production of IgG and IgM in the culture supernatants was determined by ELISA.ResultsThe results showed that the serum IL-21 levels in RA patients were significantly higher than that of healthy controls (HC). IL-21 concentrations were positively correlated with 28-joint count disease activity score (DAS28) and anti-CCP antibody in RA patients with high IL-21 levels. Furthermore, the frequencies of peripheral CXCR5+PD-1+CD4+ Tfh-like cells markedly increased in RA patients and the percentages of Tfh-like cells were positively correlated with DAS28 and anti-CCP antibody levels. Moreover, elevated IL-21 levels were also correlated with the frequencies of Tfh-like cells. IL-21R expression on both Tfh-like cells and B cells were significantly enhanced in RA patients. In cultures vitro, exogenous IL-21 upregulated IL-21R expression and activation-associated surface markers on B cells and promoted more B cell proliferation in RA than in HC. This IL-21-mediated effect could be reversed by IL-21R-specific neutralizing antibody. Importantly, IL-21 promoted more differentiation of B cell into plasmablast and higher levels of IgG and IgM production in RA than in HC.ConclusionsIncreased serum IL-21 levels in RA patients correlate with DAS28, anti-CCP antibody and frequencies of Tfh-like cells. IL-21 supports B cell activation, proliferation and antibody secretion via IL-21R pathway. Thus, IL-21 may be involved in the pathogenesis of RA and antagonizing IL-21 could be a novel strategy for the therapy of RA.

High frequencies of activated B cells and T follicular helper cells are correlated with disease activity in patients with new-onset rheumatoid arthritis

“…We found that the levels of serum IL-21 were significantly higher in the RA patients than that in the HC. These results were in agreement with a previous observation showing that IL-21 regulates Tfh and B cell function [41]. We are interested in investigating further how IL-21 regulates B and Tfh cell activation and differentiation in RA patients.…”

Follicular helper T cells in rheumatoid arthritis

“…Similarly, the percentages of circulating PD-1 + CD4 + CXCR5 + and ICOS + CD4 + CXCR5 + are significantly higher in RA patients than in healthy controls [3]. Furthermore, the concentrations of serum IL-21 in RA patients are significantly higher than that in healthy controls [25]. Functionally, circulating TFH cells can be divided into three subsets [22,23].…”

Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia

“…Supporting the role of TFHs in the generation of GC, we demonstrated that TFHs were the major source of IL-21 in ITP spleen, a key cytokine involved in B-cell stimulation and differentiation. 42 44 has been demonstrated and has justified the use of anti-IL-21 therapy in clinical trials. 45 However, the fact that bone marrow PCs, contrary to secondary lymphoid organ PCs, do not depend on IL-21 to survive, 46 argues for a blockade of the IL-21 axis early in the disease, before the establishment of long-lived PCs.…”