title: Interleukin-21 is increased in active systemic lupus erythematosus patients and contributes to the generation of plasma B cells.
abstract: OBJECTIVE
  Excessive interleukin- (IL-) 21 production by T cells has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). We explored the expression and function of IL-21 in human SLE.
  
  
  METHODS
  IL-21 and IL-21 receptor (IL-21R) expression was assessed by real-time PCR and flow cytometry in peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy controls. PBMCs, purified CD19+CD27- naïve and CD19+CD27+ memory B cells were stimulated with IL-21 and CpG-ODN2006 (TLR-9 agonist) to examine generation of memory and plasma (CD19+CD38highIgD-) B cells. Apoptosis was assessed by 7AAD staining.
  
  
  RESULTS
  Active SLE patients had 4-fold higher IL-21 mRNA and increased levels of intracellular IL-21 in peripheral blood CD4+ T cells (mean±SD fluorescence intensity, 1.7±0.1 in active versus 0.9±0.3 in inactive SLE and controls, p=0.035). IL-21R mRNA was comparable between SLE and healthy controls. Stimulation of PBMCs with IL-21 increased the proportion of memory and plasma cells; addition of CpG-ODN2006 enhanced these effects. Both naïve and memory B cells responded to IL-21/TLR-9 by increased generation of memory and plasma B cells, respectively; an anti-apoptotic effect was observed. In active SLE, PBMCs stimulation with IL-21 and/or CpG-ODN increased memory and plasma B cells, comparable to healthy controls. Addition of IL-21 to lupus autologous mixed lymphocyte cultures induced significant IgG production, and treatment with IL-21R.Fc to block IL-21/IL-21R interaction reduced the proportion of plasma cells.
  
  
  CONCLUSIONS
  Increased IL-21 may synergise with TLR-9 signalling and contributes to generation of plasma cells in active SLE patients.
authors.affiliation: University of Crete, Greece. mnakou@hotmail.com
authors.forename: Magdalene
authors.initials: M
authors.lastname: Nakou
authors.forename: Eva D
authors.initials: ED
authors.lastname: Papadimitraki
authors.forename: Antonios
authors.initials: A
authors.lastname: Fanouriakis
authors.forename: George K
authors.initials: GK
authors.lastname: Bertsias
authors.forename: Christianna
authors.initials: C
authors.lastname: Choulaki
authors.forename: Nektaria
authors.initials: N
authors.lastname: Goulidaki
authors.forename: Prodromos
authors.initials: P
authors.lastname: Sidiropoulos
authors.forename: Dimitrios T
authors.initials: DT
authors.lastname: Boumpas
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D018941:Antigens, CD19 / Q000097:blood; D017209:Apoptosis; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D053738:Interleukin-21 Receptor alpha Subunit / Q000097:blood; D007378:Interleukins / Q000097:blood* / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000097:blood; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000097:blood; D015854:Up-Regulation; D000098546:Interleukin-21
chemical_list: D000276:Adjuvants, Immunologic; D018941:Antigens, CD19; D015415:Biomarkers; C513533:CpG ODN 2006; C508117:IL21R protein, human; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D009838:Oligodeoxyribonucleotides; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D000098546:Interleukin-21