title: Endotoxemia contributes to CD27+ memory B-cell apoptosis via enhanced sensitivity to Fas ligation in patients with Cirrhosis.
abstract: Peripheral CD27+memory B-cells become quantitatively reduced and dysfunctional in patients with cirrhosis through poorly characterized mechanisms. We hypothesized that the disappearance of CD27+memory B-cells results from enhanced sensitivity to apoptosis caused by exposure to gut microbial translocation products. Using isolated naïve and memory B-cells from patients with cirrhosis and age-matched controls, ex vivo and activation-induced sensitivity to Fas-mediated apoptosis was assessed under relevant experimental conditions. We observed differential expression of CD95(Fas) in CD27+B-cells from cirrhotic patients that was inversely correlated with peripheral CD27+B-cell frequency. While memory B-cells from cirrhotic patients were resistant to Fas-mediated apoptosis ex vivo, Toll-like receptor 4(TLR4)-ligation restored Fas-sensitivity. Sensitivity to Fas-mediated apoptosis could be transferred to healthy donor memory B-cells by co-culturing these cells with plasma from cirrhotic patients, a sensitivity partially mediated by Fas and TLR4 signaling, and partially rescued via B-cell receptor crosslinking. We conclude that peripheral CD27+memory B-cells in cirrhosis exhibit increased sensitivity to Fas-induced apoptosis in an activation-dependent manner to which endotoxin contributes, associated with reduced frequency of circulating memory B-cells. Destruction of this critical cell subset may contribute to the cirrhotic immunodeficiency state and heightened risk of systemic infections in advanced liver disease.
authors.affiliation: Medicine and Research Services, Corporal Michael J. Crescenz VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA.|Division of Gastroenterology, Department of Medicine, University of Pennsylvania, 9th floor BRB, 421 Curie Blvd, Philadelphia, PA 19104, USA.
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Chang
authors.affiliation: Medicine and Research Services, Corporal Michael J. Crescenz VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA.|Division of Gastroenterology, Department of Medicine, University of Pennsylvania, 9th floor BRB, 421 Curie Blvd, Philadelphia, PA 19104, USA.
authors.forename: Yonghai
authors.initials: Y
authors.lastname: Li
authors.affiliation: Medicine and Research Services, Corporal Michael J. Crescenz VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA.|Division of Gastroenterology, Department of Medicine, University of Pennsylvania, 9th floor BRB, 421 Curie Blvd, Philadelphia, PA 19104, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Kaplan
mesh_terms: D000368:Aged; D017209:Apoptosis; D001402:B-Lymphocytes / Q000737:chemistry / Q000473:pathology*; D019446:Endotoxemia / Q000473:pathology*; D005260:Female; D005355:Fibrosis / Q000150:complications*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis*; D019014:fas Receptor / Q000032:analysis*
chemical_list: C491901:FAS protein, human; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D019014:fas Receptor