title: A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis.
abstract: BACKGROUND
  Interleukin (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.
  
  
  METHODS
  Serum 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  Increased 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.forename: Dinglei
authors.initials: D
authors.lastname: Su
authors.forename: Nan
authors.initials: N
authors.lastname: Che
authors.forename: Haifeng
authors.initials: H
authors.lastname: Chen
authors.forename: Linyu
authors.initials: L
authors.lastname: Geng
authors.forename: Jinyun
authors.initials: J
authors.lastname: Chen
authors.forename: Wanjun
authors.initials: W
authors.lastname: Chen
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Lingyun
authors.initials: L
authors.lastname: Sun
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D018501:Antirheumatic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D053655:Receptors, Interleukin-21 / Q000276:immunology / Q000378:metabolism; D012720:Severity of Illness Index; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000098546:Interleukin-21; D000099192:CD69 Antigens
chemical_list: D000305:Adrenal Cortex Hormones; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018501:Antirheumatic Agents; D001323:Autoantibodies; D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins; D037181:Lectins, C-Type; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21; D000099192:CD69 Antigens