title: TLR4/CD14 Variants-Related Serologic and Immunologic Dys-Regulations Predict Severe Sepsis in Febrile De-Compensated Cirrhotic Patients.
abstract: 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.
authors.affiliation: Division of Infection, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Fan
authors.affiliation: Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Liu
authors.affiliation: Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Shuo-Ming
authors.initials: SM
authors.lastname: Ou
authors.affiliation: Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Clinical Medicine, Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Chia-Chang
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Clinical Medicine, Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Li
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Kuei-Chuan
authors.initials: KC
authors.lastname: Lee
authors.affiliation: Division of Infection, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Shiang-Fen
authors.initials: SF
authors.lastname: Huang
authors.affiliation: Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Clinical Medicine, Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Yang
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Yun-Cheng
authors.initials: YC
authors.lastname: Hsieh
authors.affiliation: Institute of Clinical Medicine, Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Shie-Liang
authors.initials: SL
authors.lastname: Hsieh
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Hou
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015415:Biomarkers; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005334:Fever; D015870:Gene Expression; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000235:genetics*; D008103:Liver Cirrhosis / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D018805:Sepsis / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D018950:Lipopolysaccharide Receptors; D051197:Toll-Like Receptor 4