Genetic variants and dysfunctional monocyte had been reported to be associated with
infection susceptibility in advanced cirrhotic patients. This study aims to explore genetic predictive markers and relevant immune dysfunction that contributed to
severe sepsis in febrile acute de-compensated cirrhotic patents. Polymorphism analysis of candidate genes was undergone in 108 febrile acute de-compensated cirrhotic patients and 121 healthy volunteers. Various plasma inflammatory/regulatory
cytokines, proportion of classical (CD 16-, phagocytic) and non-classical (CD16+, inflammatory) monocytes,
lipopolysaccharide (LPS)-stimulated
toll-like receptor 4 (TLR4) and intracellular/extracellular
cytokines on cultured non-classical monocytes, mCD14/
HLA-DR expression and phagocytosis of classical monocytes were measured. For TLR4+896A/G variant allele carriers with
severe sepsis, high plasma
endotoxin/IL-10 inhibits
HLA-DR expression and impaired phagocytosis were noted in their classical monocyte. In the same group, increased non-classical monocyte subset, enhanced LPS-stimulated TLR4 expression and TNFα/
nitrite production, and systemic
inflammation [high plasma
soluble CD14 (
sCD14) and total
nitric oxide (NOx) levels] were noted. For CD14-159C/T variant allele carriers with
severe sepsis, persist
endotoxemia inhibited mCD14/
HLA-DR expression and impaired phagocytosis of their classical monocyte. In the same group, increased non-classical monocyte subset up-regulated TLR4-NFκB-iNOS and p38MAPK pathway, stimulated TNFα/
nitrite production and elicited systemic
inflammation. In febrile acute de-compensated cirrhotic patients, TLR4+896A/G and CD14-159C/T polymorphisms-related non-classical and classical monocytes dysfunction resulted in increased
severe sepsis risk.
Malnutrition, high plasma
endotoxin and
sCD14 levels, single TLR4+896A/G or CD14-159C/T variant allele carriers and double variant allele carriers are significant predictive factors for the development of
severe sepsis among them.