A BAFF/APRIL-dependent TLR3-stimulated pathway enhances the capacity of rheumatoid synovial fibroblasts to induce AID expression and Ig class-switching in B cells

Bombardieri, M., Kam, N.-W., Brentano, F., Choi, K., Filer, A., Kyburz, D., McInnes, I.B. , Gay, S., Buckley, C. and Pitzalis, C. (2011) A BAFF/APRIL-dependent TLR3-stimulated pathway enhances the capacity of rheumatoid synovial fibroblasts to induce AID expression and Ig class-switching in B cells. Annals of the Rheumatic Diseases, 70(10), pp. 1857-1865. (doi: 10.1136/ard.2011.150219) (PMID:21798884)

Abstract

Objectives To dissect the role of toll-like receptor (TLR) signalling and B cell survival/proliferating factors in the crosstalk between rheumatoid arthritis synovial fibroblasts (RASF) and B cells. Methods RASF, rheumatoid arthritis dermal fibroblasts (RADF) and osteoarthritis synovial fibroblasts (OASF) were analysed for the expression of B cell survival/proliferating factors BAFF and APRIL in resting conditions and upon stimulation with TLR2/TLR3/TLR4 ligands. Unswitched IgD+B cells were co-cultured with RASF/OASF/RADF in the presence/absence of TLR ligands and with/without BAFF/APRIL blocking antibodies. Activation-induced cytidine deaminase (AID) mRNA expression, I gamma-C mu and I alpha-C mu circular transcripts (CTs; markers of ongoing class-switching to IgG and IgA) and IgM/A/G production were measured to assess functional activation of B cells. Results TLR3 and to a lesser extent TLR4, but not TLR2 stimulation, induced up to similar to 1000-fold BAFF mRNA and increased soluble BAFF release. APRIL was less significantly regulated by TLR3. Resting and TLR3-stimulated RASF released higher levels of BAFF/APRIL compared with RADF. TLR3 stimulation of RASF but not RADF in co-culture with B cells strongly enhanced AID expression, I gamma-C mu and I alpha-C mu CTs and class-switching to IgG/IgA. Blockade of BAFF/APRIL signalling completely inhibited TLR3-induced, RASF-dependent expression of AID, CTs and the secretion of IgG/IgA. Conclusions RASF produce high levels of BAFF and APRIL constitutively and in response to TLR3 stimulation. These factors are critical in directly modulating AID expression, class-switch recombination and IgG/IgA production in IgD+ B cells. Overall, this work highlights a novel and fundamental role for the TLR3/B cell survival factor axis in sustaining B cell activation in the rheumatoid arthritis synovium

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McInnes, Professor Iain
• Authors: Bombardieri, M., Kam, N.-W., Brentano, F., Choi, K., Filer, A., Kyburz, D., McInnes, I.B., Gay, S., Buckley, C., and Pitzalis, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Annals of the Rheumatic Diseases
• ISSN: 0003-4967