BAFF promotes regulatory T-cell apoptosis and blocks cytokine production by activating B cells in primary biliary cirrhosis

Abstract

Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology. A number of questions regarding its etiology are unclear. CD4+CD25+ regulatory T cells (Tregs) play a critical role in self-tolerance and, for unknown reasons, their relative number is reduced in PBC patients. B-cell-activating factor (BAFF) is a key survival factor during B-cell maturation and its concentration is increased in peripheral blood of PBC patients. It has been reported that activated B cells inhibit Treg cell proliferation and there are no BAFF receptors on Tregs. Therefore, we speculated that excessive BAFF may result in Treg reduction via B cells. To prove our hypothesis, we isolated Tregs and B cells from PBC and healthy donors. BAFF and IgM concentrations were then analyzed by ELISA and CD40, CD80, CD86, IL-10, and TGF-β expression in B cells and Tregs were measured by flow cytometry. BAFF up-regulated CD40, CD80, CD86, and IgM expression in B cells. However, BAFF had no direct effect on Treg cell apoptosis and cytokine secretion. Nonetheless, we observed that BAFF-activated B cells could induce Treg cell apoptosis and reduce IL-10 and TGF-β expression. We also showed that BAFF-activated CD4+ T cells had no effect on Treg apoptosis. Furthermore, we verified that bezafibrate, a hypolipidemic drug, can inhibit BAFF-induced Treg cell apoptosis. In conclusion, BAFF promotes Treg cell apoptosis and inhibits cytokine production by activating B cells in PBC patients. The results of this study suggest that inhibition of BAFF activation is a strategy for PBC treatment.

Expression of BAFF and BR3 in patients with systemic lupus erythematosus

“…BAFF functions as a potent stimulator to promote maturation and differentiation of B cells, as well as to support survival of B cells and plasmablasts ( 10 , 11 ). Many studies of potential biomarkers have failed to yield evidence of useful correlations with composite measures of disease activity ( 12 ).…”

The Contribution of B Cells in Autoimmune Liver Diseases

“…Interestingly, the degree of peripheral BAFF elevation may correlate with serum liver enzymes in these patients. 60 Furthermore, BAFF has been evaluated in the context of B and T cell interactions in PBC and shown to directly promote B cell-induced apoptosis of regulatory T cells, which would allow autoreactive B cells to promote further biliary damage. In addition, BAFF was found to reduce the production of IL-10 and TGF-β by regulatory B cells.…”

Deviations in Peripheral Blood Cell Populations are Associated with the Stage of Primary Biliary Cholangitis and Presence of Itching

“…What is more, mice with T-cell-restricted expression of a dominant negative form of the transforming growth factor (TGF)-β receptor type II were observed to develop spontaneously autoimmune cholangitis resembling human PBC, with the presence of AMA together with portal lymphocytic infiltration (CD4 + , CD8 + ). By means of this fact, the deprivation of TGF-β signaling restricted to T cells might be the reason of pathological appearance of PBC (Bernuzzi et al 2010 ; Fenoglio et al 2012 ; Huang et al 2014 ; Wang et al 2015 ; Zhang et al 2013 ; Yang et al 2008 ). Lan et al ( 2009 ) detected elevated number of interleukin (IL)-17 producing cells in liver tissues of PBC patients in comparison to healthy controls.…”