NOD2 variants increase the risk for culture-positive SBP and bacterascites in cirrhosis and may affect survival.

SummarySeveral functional abnormalities in phagocytes from patients with liver cirrhosis contribute to an increased risk of infection. An increased resting respiratory burst has been observed in neutrophils from cirrhotic patients. We investigated whether an infection in cirrhosis affects the respiratory burst capacity of neutrophils and monocytes in response to Escherichia coli. This study included 45 hospitalized patients with liver cirrhosis and clinical signs of infection, 39 patients with liver cirrhosis in the absence of infection and 29 healthy subjects. Respiratory burst, lipopolysaccharide-binding protein (LBP), and immunoglobulin (Ig)G-autoantibodies against oxidized lowdensity lipoproteins (ab-oxLDL) were measured. The fraction of neutrophils spontaneously producing reactive oxygen species (ROS) was elevated in liver cirrhosis (P < 0·01). The neutrophil resting burst increased with Child-Pugh stage (P = 0·02) and correlated with augmented ROS release in response to opsonized E. coli (P < 0·05). Although LBP was increased in patients with cirrhosis (P < 0·01), higher LBP levels correlated with a lower resting burst in neutrophils (rs = -0·395; P < 0·01). In the presence of infection, the resting burst was unaltered. However, neutrophil ROS release in response to E. coli was reduced markedly (P = 0·01), and it decreased as serum C-reactive protein (CRP) concentration rose (rs = -0·437; P < 0·01), indicating the development of a sepsis-like immune paralysis. A positive correlation between ab-oxLDL and ROS release was observed (P < 0·01). In conclusion, the respiratory burst increases with severity of liver cirrhosis but is restrained by increasing LBP levels. Augmented ROS release in response to E. coli is accompanied by elevated markers of oxidative damage and becomes exhausted in the presence of infection.

BackgroundAdvanced liver disease predisposes to bacterial translocation and endotoxaemia which can contribute to elevated circulating levels of IL-10 and down-regulation of MHC class II on antigen-presenting cells. We sought to evaluate antigen-specific T-cell responses toward common viral antigens in order to investigate defects in cellular immunity in cirrhosis.MethodsPeripheral blood was obtained from 22 cirrhotic patients with systemic inflammation, 13 cirrhotic patients without systemic inflammation and 14 healthy controls. C-reactive protein was used as an indicator for systemic inflammation using a cut-off of 10 mg/l. Intracellular Th1 cytokines were quantified after T cell-stimulation with the viral peptides EBNA1 and BZLF1 or the bacterial superantigen SEB by flow cytometry. Serum levels of lipopolysaccharide-binding protein (LBP) and IL-10 were quantified by ELISA.ResultsCompared to healthy controls, patients with cirrhosis had higher circulating levels of LBP and IL-10, an expansion of peripheral blood CD14+ monocytes with low HLA-DR expression and an increased fraction of CD25-positive CD4+ and CD8+ T cells. These findings were most pronounced in cirrhotic patients with systemic inflammation but fell short of reaching statistical significance when comparing against cirrhotic patients without systemic inflammation. In the former group TNF-α production in CD4+ and CD8+ T cells was reduced after stimulation with SEB, whereas there was no significant difference between the total cohort of cirrhotic patients and controls. After stimulation with the overlapping peptide pools for viral antigens EBNA1 and BZLF1, the number of responding T cells and the amount of TNF-α or IFN-γ production did not differ between the three pre-defined groups. However, cirrhotic patients with null-responses to EBV peptides had significantly higher serum IL-10 levels than responders to EBV peptides. Furthermore, TNF-α production in responding T cells was attenuated in patients with a high frequency of CD14+ HLA-DR- monocytes.ConclusionOur data suggest that bacterial translocation, endotoxaemia, inflammation and T cell activation in cirrhosis are accompanied by an increase in circulating anti-inflammatory cytokines, reduced monocytic MHC class II expression and attenuated cytokine production in T cells. These changes are likely to contribute to altered adaptive immune responses during infection or after vaccination.

Alterations of the innate immunity contribute to the development of spontaneous bacterial peritonitis (SBP) in liver cirrhosis. Given its role in immune signaling, antimicrobial function, and macrophage differentiation, we hypothesized that genetic polymorphisms of TRAF6 modulate the risk of SBP. Thus, we determined theTRAF6 haplotype in 432 patients with cirrhosis and ascites using the haplotype-tagging single nucleotide polymorphisms rs331457 and rs5030419. In addition, peritoneal macrophages were immunomagnetically isolated and characterized. Overall, 122 (28%) patients had an episode of SBP. In the combined prospective-retrospective analysis the frequency of SBP differed between the four haplotypes (P = 0.014) and was the highest in 102 patients carrying the rs331457 but not the rs5030419 variant, when compared to other haplotypes (odds ratio 1.95 [1.22–3.12]) or to the wild-type (odds ratio 1.71 [1.04–2.82]). This association was confirmed in multivariate logistic regression (adjusted odds ratio 2.00 [1.24–3.22]) and in prospective sensitivity analysis (hazard ratio 2.09 [1.08–4.07]; P = 0.03). The risk haplotype was associated with lower concentrations of the immune activation marker soluble CD87 in ascitic fluid and with a decreased expression of IL-6 and CXCL8 in isolated peritoneal macrophages. In conclusion, genetic polymorphisms of TRAF6 are associated with decreased peritoneal immune activation and an increased risk of SBP.