Our findings indicate that TLR ligands associated with bacterial translocation circulating in cirrhotic

patients directly activate B cells in vitro, an effect that can be attenuated with TLR4 PLX4032 and/or TLR9 blockade. TLR9 is constitutively expressed on B cells,31 and it has been suggested that TLR9 agonists might affect the nature of B-cell Ig responses in cirrhosis.18 Human B cells express minimal basal levels of TLR4, but up-regulate TLR4 expression on exposure to various stimuli.32 LPS-LBP bound to sCD14 can directly bind MD-2 on mCD14-negative cells.26 Consistent with earlier studies, we found that sCD14 levels were elevated in cirrhotic plasma,33 and that sCD14 levels correlated with in vitro B-cell activation. Elevated sCD14 levels have previously been found in systemic lupus erythematosus34 and HIV infection,35 both of which are also associated with CD27+ B-cell reductions. In particular, HIV, which infects gastrointestinal lymphoid tissue early in infection and compromises intestinal integrity, leads to increased bacterial translocation, nonspecific immune activation,36 and, ultimately, is associated with memory B-cell loss.37–39 Our data

suggest a similar pathogenesis of memory B-cell loss in cirrhosis, albeit within the limitations of what can be demonstrated in ex vivo human B cells. In vivo animal studies will be critical 5-Fluoracil price to determine the complex

interaction of portal hypertension, bacterial translocation, hypersplenism, and hepatic microenvironmental factors on B-cell memory generation and maintenance. The fate Metalloexopeptidase of “lost” CD27+ B-cells in cirrhosis remains incompletely defined. One potential fate is the evolution of an “exhausted” phenotype similar to that described in HIV disease, in which an increased frequency of hypoproliferative CD27−CD21− B cells with elevated expression of an inhibitory molecule, such as FcRL4 and other inhibitory molecules, disproportionately consisting of HIV-specific B cells has been identified.39 Though we did identify an increase in CD27−CD21− B-cells in cirrhotic patients with HCC, we did not identify an increase of FcRL4-expressing cells in any group of patients or cell subset (data not shown). An alternative explanation for the reduction of CD27+ B cells in chronic HCV patients is an increased conversion of activated CD27+ B-cells to short-lived plasmablasts.6, 7 Our data, showing an increase in CD27+CD38hi in cirrhotics, provide modest support for this hypothesis for the cirrhotic patient subset. HCV E2-CD81 interactions40 also have been postulated to drive activation-induced apoptosis in chronic HCV. In vitro studies support an activating role of CD81 ligation in B cells from chronic HCV patients.