SP0084 POST-ACTIVATED B CELLS IN AUTOIMMUNITY

Abstract

Background: B cells are key players in autoimmune diseases such as systemic lupus erythematosus (SLE), primary Sjogren”s syndrome (pSS) and rheumatoid arthritis (RA). In the past, it was believed that B cells from these patients were hyperresponsive to B cell receptor (BCR) and Toll-like receptor (TLR) signaling. New insights suggest that B cells from these patients present a post-activated functiotype. Objectives: We aim at characterizing B cells and B cell responses of SLE, pSS and RA patients to understand which venues can be taken towards new therapies for these diseases. Methods: B cells and B cell subsets from peripheral blood samples from SLE, pSS and RA patients and healthy donors (HD), as well as few autoimmune tissues, were analyzed for: phosphotyrosine kinase (PTK) phosphorylation kinetics, protein phosphatase activity, expression of phosphatases or of checkpoint molecules, such as e.g.PD-1, before and after BCR engagement, alone or together with TLR9 and CD40 stimulation, differentiation and proliferation. Expression of transcription factors, such as e.g.STAT1, and the effect of interferons in their expression in B cells from patients were also evaluated. Results: B cell responses upon BCR engagement in SLE, pSS, RA patients were abnormal with diminished BCR downstream PTK phosphorylation. TLR9, but not CD40 responses were also abnormal. Part of the abnormality related to diffuse up-regulation of phosphatases that apparently counteracted PTK signaling. The abnormality was partially mimicked by repeated signaling through the BCR of HD B cells and could be overcome by CD40 engagement. Check-point molecules, such as e.g.PD-1, was differentially expressed in SLE naive and memory B cells. SLE naive and memory B cells expressed higher amounts of STAT1 compared to those of pSS, RA and HD. Conclusion: Post-activated B cells are characterized by a phenotype of dysregulated expression of certain check-point molecules, such as PD-1, some transcription factors, like STAT1 and certain phosphatases (figure 1). Our data suggest that CD40 activation is involved in modulating BCR responses in post-activated B cells. This has implications for innovative therapies since blocking BCR signaling pathways and CD40 activation as well as targeting certain phosphatases may have synergistic value for treating systemic autoimmunity. Disclosure of Interests: None declared