Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: We have reported that soluble BAFF (sBAFF) robustly increases IL-6 production in vitro by peripheral monocytes of patients with primary Sjögren’s syndrome (pSS) as compared to healthy controls. In an attempt to elucidate the underlying mechanism, we have found that the expression level of BAFF receptor (BR3) is elevated in pSS monocytes and that the level is significantly and positively correlated with serum IgG level of pSS patients. These data collectively suggest that the elevated expression of BR3 on monocytes is involved in the pathogenesis of pSS which is often accompanied with hypergammaglobulinemia, and that BR3 is a possible therapeutic target to treat pSS. We have also successfully discovered two low-molecular weight compounds, pyrrolopyrimidine derivatives, BIK-12 and BIK-13, as BAFF receptor antagonists. The compounds inhibit BAFF-binding to BR3 and suppress both IL-6 production by BAFF-stimulated peripheral pSS monocytes and IgG production by peripheral pSS B cells co-cultured with BAFF-stimulated monocytes. In this study, we investigate the mechanisms of action of these compounds.
Methods: Peripheral monocytes were stimulated with sBAFF and cultured in vitro in the presence of BIK-12 or BIK-13. PBMC were stimulated with a mixture of sBAFF, recombinant human IL-21 (rhIL-21), and anti-IgM and anti-CD40 antibodies (multiple B cell activation) in the presence of BIK-12 or BIK-13. The expression levels of CD80/CD19/CD38/IgD and NF-kB/AID (Activation-induced cytidine deaminase) in the cells were analyzed by FACS and quantitative PCR, respectively. The amounts of IL-6 and IgG produced in the culture supernatants were measured by ELISA.
Results: sBAFF-induced IL-6 production by peripheral monocytes was significantly suppressed by BIK12 and BIK13 in a dose dependent manner. The elevated expression of CD80 and NF-kB, the markers of activated monocytes, in sBAFF-stimulated monocytes was also suppressed by the compounds. Interestingly, increased IgG production by activated PBMC was suppressed by BIK12 and BIK13. FACS analysis of PBMC indicated that differentiation of B cells into plasma blasts and/or plasma cells was inhibited by these compounds in a dose dependent manner. In addition, the expression level of AID was also suppressed by these compounds, suggesting that an IgG class switching was impaired.
Conclusion: Our results suggest that BAFF receptor antagonists suppress not only activation of monocytes but also IgG production by B cells possibly by impairing differentiation and an IgG class switching of B cells. Our findings strongly suggest that BIK-12 and BIK-13 are drug candidates for hyper-activated B cell-related autoimmune diseases, such as pSS.
To cite this abstract in AMA style:Yoshimoto K, Seki N, Suzuki K, Sugahara K, Takeuchi T. BAFF Receptor Antagonists Suppress Differentiation of B Cells in Vitro and Are Drug Candidates for Primary SjöGren’s Syndrome [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/baff-receptor-antagonists-suppress-differentiation-of-b-cells-in-vitro-and-are-drug-candidates-for-primary-sjogrens-syndrome/. Accessed November 28, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/baff-receptor-antagonists-suppress-differentiation-of-b-cells-in-vitro-and-are-drug-candidates-for-primary-sjogrens-syndrome/