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

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-C and I-C 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 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-C and I-C 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. 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, CSR and IgG/IgA production in IgD+ B cells. Overall, we highlight a novel and fundamental role for the TLR3/B cell survival factor axis in sustaining B cell activation in the RA synovium.

Synthetic Double-Stranded RNA Poly(I:C) Aggravates IgA Nephropathy by Triggering IgA Class Switching Recombination through the TLR3-BAFF Axis

“…In our previous studies, we revealed that high levels of BAFF can promote IgA CSR and the secretion of aberrantly glycosylated IgA1 [20,26,44] . TLR3-BAFF axis, first mentioned in the field rheumatoid arthritis, has supported in vivo that TLR3-BAFF can induce AID expression and Ig class-switching in B cells [45,46] . In fact, plenty of findings show that TACI, as the receptor of BAFF, plays a key role in the enhancement of mucosal dendritic cells-mediated IgA CSR [47][48][49] .…”

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…In rheumatoid arthritis, synovial fibroblasts contribute to ELF formation through the secretion of homeostatic chemokines such as CXCL13, CCL21 and CXCL12 5, 23, 42, 43, 44. Interestingly, synovial fibroblasts can also contribute to other aspect of ELF activity, where they can produce B‐cell‐activating factor and a proliferation‐inducing ligand (known as APRIL) 45. These factors support activation‐induced cytidine deaminase (AID) expression, which drives somatic hypermutation and antibody class‐switching in B cells 45.…”

“…Interestingly, synovial fibroblasts can also contribute to other aspect of ELF activity, where they can produce B‐cell‐activating factor and a proliferation‐inducing ligand (known as APRIL) 45. These factors support activation‐induced cytidine deaminase (AID) expression, which drives somatic hypermutation and antibody class‐switching in B cells 45. Here, it is important to understand the relationship between the stromal tissue compartment and the nature of the inflammatory infiltrate because ELFs are not a universal feature of synovitis in inflammatory arthritis and only occur in a certain cohort of patients.…”

Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity

“…In vitro, increased TLR activation and BAFF levels have been shown to trigger activation-induced cytidine deaminase expression, which also induces somatic hypermutation and class switching in naive B cells (72). Another study showed that neutrophilderived cytokines including BAFF can induce somatic hypermutation and class switching in marginal zone B cells (73).…”