Background/Purpose: B cells may have a negative regulatory role, mainly mediated by interleukin 10 (IL-10). We recently showed that regulatory B-cell functions are impaired in patients with rheumatoid arthritis (RA) and that mice transgenic for a proliferation-inducing ligand (APRIL) are protected against collagen-induced arthritis. We aimed to explore the effect of APRIL on human B-cell production of IL-10.

Methods: CpG induced IL-10 B-cell production was compared in presence or absence of APRIL and B lymphocyte stimulating factor (BLys). The expression of the BLyS and APRIL receptor transmembrane activator and CAML interactor (TACI) and of BLyS specific receptor (BAFF-R) was compared between IL-10 producing and non-producing B cells. The effect of APRIL stimulated B cells on T cell cytokine production was analyzed after 3 days of co-culture. Signaling pathways of B cells activated by CpG and APRIL were analyzed by western blot. Similar experiments were performed on cells of RA patients.

Results: IL-10 production by B cells was greater with APRIL than BLyS treatment or control medium (9.5 [6.8-13.2]% vs 6.2 [3.9-7.0]%, p=0.007, and 4.2 [3.3-8.0]%, p=0.002, respectively, n= 11 controls). This increase was abrogated by co-culture with APRIL inhibitors (8.4 [3.7-13.8]% vs 3.5 [1.9-8.8]%, p<0.01, n=8 controls). APRIL did not stimulate IL-10 production of monocytes and T cells. TACI expression was greater in IL-10 producing than non-IL-10–producing B cells (1.9 [1.3-4.4]% vs 0.4 [0-2.3]%; p=0.031, n= 7 controls) whereas BAFF-R expression was lower (2.3 [2.0-2.5] vs 2.7 [2.3-2.8] of mean fluorescence intensity; p=0.021, n= 7 controls). When compared with non-stimulated B cells, APRIL-stimulated B cells decreased the secretion of TNF-α (-36±13%, p=0.02) and IFN-γ (-14±3%; p=0.02) by T cells but not IL-17 (-14±14%; p=0.31, n= 8 controls). APRIL further stimulated CpG-activated STAT3 and STAT3 inhibition specifically decreased IL-10 production by B cells (-28±3%, p<0.05, n= 7 controls). APRIL also promoted IL-10 production by B cells in 11 RA patients (7.0 [4.1-11.8]% vs 6.1 [3.1-9.8]%, p= 0.024 and 3.6 [2.2-7.3]%, p= 0.009 for APRIL, BLyS and control medium respectively). Similar pattern of APRIL and BLyS receptors on IL-10 producing B cells were observed between the controls and 7 RA patients.

Conclusion: APRIL but not BLyS promotes IL-10 production by B cells and enhances the regulatory role of B cells on T cells by decreasing T-cell secretion of TNF-α and. IFN-γ. IL-10 producing B cells in RA patients are responsive to APRIL, which suggests a possible therapeutic application of APRIL for expanding IL-10 producing B cells in these patients. This could also explain the difference of clinical efficacy observed between belimumab and atacicept in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-proliferative-inducing-ligand-april-promotes-il-10-production-of-human-b-cells/