Session Title: Rheumatoid Arthritis: Human Etiology and Pathogenesis II
Session Type: Abstract Submissions (ACR)
Background/Purpose: Rheumatoid arthritis (RA) is characterized by the formation of synovial niches of autoreactive B cells which are favored by the autocrine production of B cell survival factor BAFF by RA synovial fibroblasts (RASF). Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor which also acts as a potent immune-regulator. Here we investigated whether i) SLPI is expressed by RASF and is modulated by Toll-like receptors (TLR) ligands; ii) it can regulates BAFF expression by RASF and downstream B cell activation; iii) exerts immunoregulatory effects in vivo in the collagen induced arthritis (CIA) and the chimeric RA synovium/SCID models of arthritis.
Methods: mRNA and protein expression of SLPI in RASF and RADF (dermal) stimulated with TLR2/TLR3/TLR4 ligands was assessed by QT-PCR and ELISA. RASF were treated with/without recombinant SLPI to study: i) BAFF mRNA/protein expression; ii) AID expression and Ig class-switching in IgD+ B cells stimulated with BAFF/IL-4 or in co-culture with RASF. Furthermore, severity of arthritis, production of anti-CII antibodies, and joint histopathology were studied in CIA mice treated with rSLPI after arthritis onset. Finally, BAFF expression and antibody production were examined in rSLPI-treated RA/SCID mice.
Results: RASF expressed significantly higher baseline SLPI mRNA compared to RADF. 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 mRNA/protein in TLR3-treated RASF. Furthermore, SLPI down-modulated AID expression and IgA, IgG and IgM production in IgD+ B cells stimulated with BAFF/IL-4 or in co-culture with RASF. SLPI reduced BAFF expression and IgG/IgM production in RA/SCID mice while severity of arthritis, cartilage damage and anti-CII-IgG2a were significantly reduced in CIA mice by rSLPI administered after arthritis onset.
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 and damage in animal models of arthritis, highlighting a novel endogenous anti-inflammatory pathway which could be exploited for therapeutic purposes in RA.
Y. N. Kam,
C. D. Buckley,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/secretory-leukocyte-protease-inhibitor-released-by-rheumatoid-synovial-fibroblasts-exerts-a-negative-control-of-baff-dependent-b-cell-activation-in-vitro-and-in-vivo-in-the-collagen-induced-and-chimer/