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A1.12 Endogenous SLPI released by rheumatoid synovial fibroblasts control BAFF-dependent-B cell activation in vitro and in the CIA and RA/SCID-arthritis models
  1. N W Kam1,
  2. F Brentano2,
  3. D Kyburz2,
  4. S Gay2,
  5. A Filer3,
  6. C Buckley3,
  7. C Pitzalis1,
  8. M Bombardieri1
  1. 1William Harvey Research Institute, Queen Mary University of London, London, UK
  2. 2Department of Rheumatology, University Hospital Zürich, Zürich, Switzerland
  3. 3Division of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, UK

Abstract

Background and Aims Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor with potent anti-microbicidal/immunoregulatory activities. Rheumatoid arthritis (RA) is characterised by synovial niches of autoreactive B cells. Autocrine production of B cell survival factor BAFF by RA synovial fibroblasts (RASF) supports ongoing B cell activation within the RA synovium. We investigated whether SLPI: (1)is produced by Toll-like receptors (TLRs)-treated RASF and regulates B cell activation; (2)exerts immunoregulatory effects in the RA synovium/SCID chimeric model and in collagen induced arthritis (CIA).

Methods mRNA and protein expression of SLPI in RASF/RADF (dermal) stimulated with/without TLR2/TLR3/TLR4 ligands was assessed by QT-PCR and ELISA. RASF were treated with/without recombinant SLPI (rSLPI) to study: (1) BAFF expression; (2) AID expression and class-switching in co-culture with IgD+B cells. BAFF expression and antibody production were examined in rSLPI-treated RA/SCID mice. Severity of arthritis, anti-CII antibodies, and joint histopathology were studied in rSLPI-treated CIA mice.

Results Stimulation of RASF with TLR3-ligands led to a 15-fold induction of SLPI mRNA. SLPI protein was time-dependently released from TLR3-stimulated RASF, but not RADF. SLPI restrained the production of BAFF, AID and IgA/G/M in TLR3-treated RASF and co-cultures, respectively. SLPI reduced BAFF expression and IgG/IgM production in RA/SCID mice while severity of arthritis, cartilage damage and anti-CII-IgG2a were reduced in SLPI-treated CIA.

Conclusion RASF release high levels of SLPI constitutively and upon TLR3 stimulation. SLPI directly modulates BAFF and B cell activation in vitro/in vivo and reduces joint inflammation in CIA, highlighting a novel endogenous anti-inflammatory pathway with therapeutic potential in RA.

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