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ANCA-stimulated neutrophils release BLyS and promote B cell survival: a clinically relevant cellular process
  1. N J Holden1,
  2. J M Williams2,
  3. M D Morgan1,
  4. A Challa1,
  5. J Gordon1,
  6. R J Pepper3,
  7. A D Salama3,
  8. L Harper1,
  9. C O S Savage1
  1. 1School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
  2. 2Wellcome Trust Clinical Research Facility, University Hospital Birmingham Foundation Trust, Birmingham, UK
  3. 3Centre for Nephrology, University College London, Royal Free Hospital, London, UK
  1. Correspondence to Professor C O S Savage, Renal Immunobiology Group, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; c.o.s.savage{at}bham.ac.uk

Abstract

Objectives To determine a role for antineutrophil cytoplasmic antibody (ANCA)-activated neutrophils in promoting B cell survival through the release of B lymphocyte stimulator (BLyS).

Methods Neutrophil BLyS expression was measured by flow cytometry. Concentrations of BLyS in cell supernatants and donor serum samples were measured by ELISA. Cell survival assays were carried out using an L3055 cell line and viability measured by flow cytometry.

Results Tumour necrosis factor α and formyl-Met-Leu-Phe (fMLP) treatment of non-primed neutrophils and treatment of primed neutrophils with anti-PR3 ANCA IgG resulted in a significant increase in surface expression of BLyS within 30 min which returned to basal levels by 2 h. Supernatants from ANCA-stimulated neutrophils were shown to contain increased levels of BLyS and to promote the survival of the centroblast cell line L3055. Serum BLyS concentrations are increased in patients with active ANCA-associated systemic vasculitis and these levels are increased further following 1–3 months of treatment with rituximab.

Conclusions ANCA specifically causes the release of BLyS from activated neutrophils which can support B cell survival in vitro. The presence of serum BLyS in active disease and its increase following B cell depletion suggest it is an important factor in disease pathogenesis and may facilitate disease relapse.

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Footnotes

  • Funding This work was funded by a Stuart Strange Vasculitis Trust postdoctoral fellowship.

  • Competing interests COSS is currently employed by Glaxo Smith Kline.

  • Ethics approval This study was conducted with the approval of the South Birmingham ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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