HIF-1? Promote B Cell Producing IL-6 To Induce Tfh Cell Differentiation In The Pathogenesis Of Rheumatic Arthritis

Objective: Rheumatoid arthritis(RA)is an systemic autoimmune disease with inflammatory arthritis,in which the abnormal proliferation of synovial tissue with a hypoxia status is a typical pathological status.Hypoxia inducible factor(HIF)can help lymphocytes adapt to hypoxia microenvironment.However,the function of HIF-1? on B cells is not comprehensive.In this study,we assessed the T and B cell phenotypes and function in RA,and study the effects of HIF-1? to the abnormal activation of adaptive immune system.Methods: Firstly,we recruited a cohort of RA patients,and use multi-color flow cytometer tech to detect T cell and B cell subsets and the phosphorylation level of signal transduction and activator of transcription 3(STAT3).The STAT3 stimulating cytokines were detected by ELISA.Then,we tried to identify the main source of IL-6 in the peripheral blood of RA.Next,we analyzed the transcriptome of na?ve B cells as well as plasmablasts,compared the differently expressed genes,made enrichment analysis,and searched the hub genes which were highly expressed in na?ve B cells.In addition,we breed mice that were conditionally knocked out Hif1? in B cells to explore the mechanism of HIF-1? to IL-6 production.Finally,we co-cultured the Hif1?-deficient B cells with na?ve T cells to evaluate the contribution of B cells to T cell differentiation.Results: The levels of p STAT3 in various subsets of T cells is correlated with disease activity and the plasma IL-6.We also found that B cells,especially naive B cells,can secrete large amount of IL-6.HIF-1? in B cells is an important transcription factor that regulates IL-6 production,and Hif1?-deficient B cells will attenuat T cell differentiation in vitro.Conclusion: HIF-1? in B cells can regulate the transcription and expression of IL-6,which is critical in promoting the activation and differentiation of T cells.