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.
Highlights
Liver cirrhosis predisposes patients to terminal bacterial infections[1,2] previously attributed predominantly to defects of innate immunity[3,4]
We found that while CD27+ memory B-cells from cirrhotic patients displayed increased expression of the death receptor CD95 (Fas), these cells paradoxically were resistant to Fas-mediated apoptosis ex vivo
TNF-related apoptosis-inducing ligand (TRAIL)-R1 expression was minimal on both healthy donors (HD) and CIR B-cells (Fig. 1B) while TRAIL-R2 was more frequently present on memory B-cells at similar frequencies in both CIR and HD (Fig. 1C) and similar geometric mean fluorescence intensity
Summary
Liver cirrhosis predisposes patients to terminal bacterial infections[1,2] previously attributed predominantly to defects of innate immunity[3,4]. We observed that peripheral CD27+ memory B-cell frequency amongst CD19+ B-cells is approximately 10% in individuals with cirrhosis (either due to chronic hepatitis C (HCV) or metabolic/alcoholic liver disease) compared with 30% in healthy individuals or those with non-cirrhotic HCV infection. Cirrhotic plasma induced apoptosis in healthy donor memory B-cells as well as increased their sensitivity to Fas-mediated apoptosis, phenomena partially mediated by sFasL and lipopolysaccharide (LPS). These studies strongly implicate Fas-mediated apoptosis as a key mechanism of memory B-cell loss in cirrhosis and may contribute to the impairment of innate and adaptive immunity characteristic of end-stage liver disease. Subjects and controls were recruited from the Gastroenterology Clinic at the Corporal Michael
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