Interleukin-21 is increased in active systemic lupus erythematosus patients and contributes to the generation of plasma B cells

Clin Exp Rheumatol. Mar-Apr 2013;31(2):172-9. Epub 2012 Nov 6.

Abstract

Objectives: 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.

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Adult
  • Antigens, CD19 / blood
  • Apoptosis
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology*
  • Biomarkers / blood
  • CD4-Positive T-Lymphocytes / immunology
  • Case-Control Studies
  • Cells, Cultured
  • Female
  • Flow Cytometry
  • Humans
  • Immunologic Memory
  • Interleukin-21 Receptor alpha Subunit / blood
  • Interleukins / blood*
  • Interleukins / genetics
  • Lupus Erythematosus, Systemic / blood
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology*
  • Lymphocyte Culture Test, Mixed
  • Male
  • Middle Aged
  • Oligodeoxyribonucleotides / pharmacology
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Toll-Like Receptor 9 / agonists
  • Toll-Like Receptor 9 / blood
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / blood
  • Up-Regulation

Substances

  • Adjuvants, Immunologic
  • Antigens, CD19
  • Biomarkers
  • CpG ODN 2006
  • IL21R protein, human
  • Interleukin-21 Receptor alpha Subunit
  • Interleukins
  • Oligodeoxyribonucleotides
  • TLR9 protein, human
  • Toll-Like Receptor 9
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • interleukin-21