Cross talk between stromal cells and immune cells in rheumatoid arthritis: the role of Toll-like receptor activated synovial fibroblasts in B cell autoreactivity.

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the synovial joints leading to cartilage destruction and bone erosion. One of the hallmarks of RA is the presence of circulating autoantibodies and the expansion of autoreactive B cells. Within RA joints, ectopic B cell follicles remain functional and support Immunoglobulin (Ig) somatic hypermutation, class-switching and in situ autoantibody production even in the absence of recirculating cells, as evidenced by the RA-SCID model, suggesting that autocrine mechanisms support ongoing B cell activation within the RA joints. In this PhD thesis, I investigate the mechanisms regulating RA synovial fibroblasts (SFs) production of B cell survival/proliferation factors BAFF/APRIL, with particular focus on toll-like receptors (TLR) signaling and how these factors in turn regulate B cell activation. First, I demonstrate that TLR3 stimulation on RASFs led to strong induction of BAFF/APRIL mRNA expression. Resting and TLR3-stimulated RASFs released higher protein levels of BAFF/APRIL as compared to RA dermal fibroblasts (RADF) controls. TLR3 stimulation of RASFs, but not RADF in co-culture with IgD+ B cells strongly enhanced activation induced cytidine deaminase (AID) expression, Iγ-Cμ and Iα-Cμ circular transcripts (CTs) as well as class-switching to IgG/IgA. Notably, TLR3-induced effects were completely abrogated by the combined blockade of BAFFR/BCMA. Following this, I report a negative feedback mechanism centered on secretory leukocyte protease inhibitor (SLPI) which, is induced in RASFs in response to TLR3 stimulation and modulates RASFs-dependent B cell responses, in part, via inhibition of BAFF production in RASFs but also by direct down-regulation of B cell activation, expression of AID and class-switching to IgG/IgA. Overall, I highlight a novel and fundamental role for the TLR3-B cell survival factor axis in regulating B cell activation in the RA synovium, which may have profound relevance in response/resistance to biological therapies targeting B cells in RA.