title: Race- and gender-related variation in natural killer p46 expression associated with differential anti-hepatitis C virus immunity.
abstract: Major racial and gender differences have been documented in the natural history and treatment responses of chronic hepatitis C virus (HCV) infection; however, distinct mechanisms have remained enigmatic. We hypothesized that racial- and gender-related differences in natural killer (NK) cell populations may explain altered natural history and treatment responses. Our study cohort consisted of 29 African-American (AA; 55% male) and 29 Caucasian-American (CA; 48% male) healthy uninfected control subjects. Multiparameter flow cytometric analysis was used to characterize levels, phenotype with respect to 14 NK receptors, and lymphokine-activated killing (LAK) function. Gene expression was assessed by real-time reverse-transcriptase polymerase chain reaction after 6-hour in vitro stimulation with Toll-like receptor (TLR) ligands. The ability to control HCV infection was assessed in the Huh-7.5/JFH-1 coculture system. NK expression of natural cytotoxicity receptor NKp46 was strongly associated with CA race and female gender and correlated positively with LAK activity (P = 0.0054). NKp46(high) NKs were more efficient at controlling HCV than their NKp46(low) counterparts (P < 0.001). Similarly, ligation of NKp46 on isolated NK cells resulted in a significant reduction in the HCV copy number detected in Huh-7.5/JFH-1 coculture (multiplicity of infection: 0.01) at an effector:target ratio of 5:1 (P < 0.005). After TLR stimulation, genes involved in cytotoxicity, but not cytokine genes, were significantly up-regulated in NKp46(high) NKs. Cytokine stimulation (interleukin [IL]-12 and IL-15) demonstrated that NKp46(high) NK cells have significantly higher interferon-gamma production than NKp46(low) cells. TLR stimulation significantly induced degranulation as well as tumor necrosis factor alpha (TNF-α)-related apoptosis-inducing ligand, Fas, and TNF-α protein expression in NKp46(high) NKs. NKp46 ligand was induced on HCV-infected hepatocytes.
  
  
  CONCLUSIONS
  NKp46 expression may contribute to differential HCV responses. NKp46 expression correlates with anti-HCV activity in vitro and thus may prove to be a useful therapeutic target.
authors.affiliation: Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Golden-Mason
authors.forename: Amy E L
authors.initials: AE
authors.lastname: Stone
authors.forename: Kiran M
authors.initials: KM
authors.lastname: Bambha
authors.forename: Linling
authors.initials: L
authors.lastname: Cheng
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Rosen
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D016022:Case-Control Studies; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D018450:Disease Progression; D005260:Female; D015967:Gene Expression Regulation, Viral; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000208:ethnology / Q000235:genetics* / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics* / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D012016:Reference Values; D012680:Sensitivity and Specificity; D012737:Sex Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: D055627:Natural Cytotoxicity Triggering Receptor 1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma