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.

T-bet-expressing B cells during HIV and HCV infections

“…Some of these clones include rheumatoid factor-producing V H 1-69 and V K 3-20-rearranged IgM-secreting B-cells [35,36] that clinically may present with type II cryoglobulinemia. Traditional memory B cell expansion does not occur in HCV-infected individuals [60–62], and typically the CD27 + memory B cell pool has been found to be similar [60] or slightly reduced in frequency [61] due to defects in proliferation [61,62], enhanced differentiation into IgG-secreting plasmablasts [61,62], compartmentalization to the liver [63], and/or enhanced memory B cell apoptosis [61,64], the latter of which is more likely related to advanced liver disease than HCV infection itself [64–66]. Instead, as in HIV, tissue-like memory B cells are expanded in HCV-infected individuals; this is discussed further below [67–69].…”

Hyperactive Follicular Helper T Cells Contribute to Dysregulated Humoral Immunity in Patients With Liver Cirrhosis

“…Peripheral non-classical CD14 + CD16 + monocytes are increased in LC patients and display abnormal functions (6). LC profoundly depletes the circulating CD27 + memory B cells (7, 8). Accompanying this, hyper-globulinemia and elevated IgG and IgA levels were observed in advancing cirrhosis, irrespective of the underlying etiology (9).…”

Enhanced B‐cell differentiation driven by advanced cirrhosis resulting in hyperglobulinemia

“…3 Similar to aberrant B-cell memory phenotypes observed in other immunocompromised states such as human immunodeficiency virus infection, 4 cirrhotic patients have decreased and dysfunctional peripheral CD27 + memory B cells. 3 The decreased frequency of peripheral CD27 + memory B cells may partially be explained by enhanced apoptosis induced by serum endotoxin and Fas ligand, 5 factors associated with gut microbial translocation, and monocyte activation in cirrhosis. The impact of abnormalities in the B-cell memory compartment observed ex vivo on immune function in vivo remains speculative.…”