Toll-like receptor 9 activation enhances B cell activating factor and interleukin-21 induced anti-proteinase 3 autoantibody production in vitro

Nikola Lepse, Judith Land, Abraham Rutgers, Cees G. M. Kallenberg, Coen A. Stegeman, Wayel H. Abdulahad, Peter Heeringa*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

18 Citations (Scopus)

Abstract

Objectives. Granulomatosis with polyangiitis (GPA) is a relapsing small-vessel vasculitis characterized by circulating ANCA against PR3. The mechanisms that trigger PR3-ANCA production are unknown. The aim of this study was to determine whether endogenous factors [B cell activating factor (BAFF) and IL-21] and exogenous factors [oligodeoxynucleotides containing CpG motifs (CpG-ODN)] synergize in stimulating PR3-ANCA production in GPA patients.

Methods. Peripheral blood mononuclear cells from GPA patients and healthy controls (HCs) were cultured in the presence of BAFF and IL-21, with or without CpG-ODN, for 12 days. PR3-ANCA production in culture supernatants was quantified by Phadia EliA. Phenotypic characterization and the influence of CpG-ODN treatment on IL-21 receptor (IL-21R), transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) and BAFF receptor (BAFF-R) expression on B cells was analysed by flow cytometry.

Results. Stimulation with BAFF and IL-21 significantly increased ANCA production in patient samples, which could be augmented further by addition of CpG-ODN. Stimulation with CpG-ODN increased the percentage of IL-21R(+) and TACI(+) B cells but did not affect BAFF-R expression. GPA patients had an increased percentage of circulating IL-21R(+) and a decreased percentage of TACI(+) circulating memory B cells when compared with HCs. Additionally, patients had decreased expression of BAFF-R on B cells, which was inversely correlated with BAFF concentrations in plasma.

Conclusion. Our data demonstrate that endogenous and exogenous factors can synergize to promote PR3-ANCA production. Mechanistically, CpG-ODN up-regulated IL-21R and TACI expression on B cells, possibly sensitizing these cells for IL-21-and BAFF-mediated signals. Agents inhibiting Toll-like receptor 9, BAFF and IL-21 signalling pathways may serve as potential therapeutics for intervention in GPA patients.

Original languageEnglish
Pages (from-to)162-172
Number of pages11
JournalRheumatology
Volume55
Issue number1
DOIs
Publication statusPublished - Jan-2016

Keywords

  • GPA
  • vasculitis
  • ANCA
  • B cells
  • IL-21
  • BAFF
  • TLR9
  • IL-21R
  • BAFF-R
  • TACI
  • ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY
  • SYSTEMIC-LUPUS-ERYTHEMATOSUS
  • ANCA-ASSOCIATED VASCULITIS
  • PRIMARY SJOGRENS-SYNDROME
  • WEGENERS-GRANULOMATOSIS
  • DISEASE-ACTIVITY
  • STAPHYLOCOCCUS-AUREUS
  • CONSENSUS CONFERENCE
  • SERUM-LEVELS
  • T-CELLS

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