title: Liver and blood cytokine microenvironment in HCV patients is associated to liver fibrosis score: a proinflammatory cytokine ensemble orchestrated by TNF and tuned by IL-10.
abstract: BACKGROUND
  In this study, we have evaluated the immunological status of hepatitis C virus (HCV)-infected patients aiming at identifying putative biomarkers associated with distinct degrees of liver fibrosis. Peripheral blood and tissue T-cells as well as cytokine levels were quantified by flow cytometry.
  
  
  RESULTS
  Data analysis demonstrated higher frequency of circulating CD8(+) T-cells and Tregs along with a mixed proinflammatory/IL-10-modulated cytokine pattern in HCV patients. Patients with severe liver fibrosis presented lower frequency of circulating CD8(+) T-cells, higher levels of proinflammatory cytokines, but lower levels of IL-10, in addition to the higher viral load. Despite the lower frequency of intrahepatic T-cells and scarce frequency of Tregs, patients with severe liver fibrosis showed higher levels of proinflammatory cytokines (TNF and IFN-γ). The tissue proinflammatory cytokine pattern supported further studies of serum cytokines as relevant biomarkers associated with different liver fibrosis scores. Serum cytokine signature showed that mild liver fibrosis is associated with higher IL-10 serum levels as compared to severe liver disease. There was a clear positive connection of IL-10 with the TNF node in patients with mild liver fibrosis, whereas there is an evident inverse correlation between IL-10 with all other cytokine nodes.
  
  
  CONCLUSIONS
  These results suggest the absence of modulatory events in patients with severe liver damage as opposed to mild fibrosis. Machine-learning data mining pointed out TNF and IL-10 as major attributes to differentiate HCV patients from non-infected individuals with highest performance. In conclusion, our findings demonstrated that HCV infection triggers a local and systemic cytokine ensemble orchestrated by TNF and tuned by IL-10 in such a manner that mirrors the liver fibrosis score, which highly suggests the relevance of these set of biomarkers for clinical investigations.
authors.affiliation: Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas - UFAM, Manaus, AM, Brazil. soriane.cruz@hotmail.com.|Departamento de Ensino e Pesquisa, Fundação de Hematologia e Hemoterapia do Amazonas - Hemoam, Manaus, AM, Brazil. soriane.cruz@hotmail.com.
authors.forename: Soriane
authors.initials: S
authors.lastname: de Souza-Cruz
authors.affiliation: Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas - UEA, Manaus, AM, Brazil. v.marilu@terra.com.br.|Fundação de Medicina Tropical Doutor Heitor Vieira Dourado - FMT-HVD, Manaus, AM, Brazil. v.marilu@terra.com.br.
authors.forename: Marilú Barbieri
authors.initials: MB
authors.lastname: Victória
authors.affiliation: Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas - UFAM, Manaus, AM, Brazil. andrea_s_monteiro@hotmail.com.|Departamento de Ensino e Pesquisa, Fundação de Hematologia e Hemoterapia do Amazonas - Hemoam, Manaus, AM, Brazil. andrea_s_monteiro@hotmail.com.
authors.forename: Andréa Monteiro
authors.initials: AM
authors.lastname: Tarragô
authors.affiliation: Departamento de Ensino e Pesquisa, Fundação de Hematologia e Hemoterapia do Amazonas - Hemoam, Manaus, AM, Brazil. allyson.gui.costa@gmail.com.|Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas - UEA, Manaus, AM, Brazil. allyson.gui.costa@gmail.com.|Fundação de Medicina Tropical Doutor Heitor Vieira Dourado - FMT-HVD, Manaus, AM, Brazil. allyson.gui.costa@gmail.com.
authors.forename: Allyson Guimarães
authors.initials: AG
authors.lastname: da Costa
authors.affiliation: Departamento de Ensino e Pesquisa, Fundação de Hematologia e Hemoterapia do Amazonas - Hemoam, Manaus, AM, Brazil. jppimentel@gmail.com.
authors.forename: João Paulo Diniz
authors.initials: JP
authors.lastname: Pimentel
authors.affiliation: Departamento de Ensino e Pesquisa, Fundação de Hematologia e Hemoterapia do Amazonas - Hemoam, Manaus, AM, Brazil. erickaflorencio@hotmail.com.
authors.forename: Ericka Florêncio
authors.initials: EF
authors.lastname: Pires
authors.affiliation: Departamento de Ensino e Pesquisa, Fundação de Hematologia e Hemoterapia do Amazonas - Hemoam, Manaus, AM, Brazil. lorenearaujo_@hotmail.com.
authors.forename: Lorene de Paula
authors.initials: Lde P
authors.lastname: Araújo
authors.affiliation: Grupo Integrado de Pesquisas em Biomarcadores, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil. jordana.reis@cpqrr.fiocruz.br.|Laboratory of Biomarkers for Diagnosis and Monitoring, René Rachou Research Center - FIOCRUZ/MG, Av. Augusto de Lima 1715, Barro Preto, Belo Horizonte, CEP 30190-002, Minas Gerais, Brazil. jordana.reis@cpqrr.fiocruz.br.
authors.forename: Jordana Grazziela
authors.initials: JG
authors.lastname: Coelho-dos-Reis
authors.affiliation: Laboratory of Bioinformatics and Molecular Analysis - INGEB / FACOM, Federal University of Uberlandia, Campus Patos de Minas, Major Jerônimo, 566, Lab 602, Patos de Minas, CEP 38700-002, MG, Brazil. matheus@ingeb.ufu.br.
authors.forename: Matheus de Souza
authors.initials: Mde S
authors.lastname: Gomes
authors.affiliation: Laboratory of Bioinformatics and Molecular Analysis - INGEB / FACOM, Federal University of Uberlandia, Campus Patos de Minas, Major Jerônimo, 566, Lab 602, Patos de Minas, CEP 38700-002, MG, Brazil. laurence.amaral@gmail.com.
authors.forename: Laurence Rodrigues
authors.initials: LR
authors.lastname: Amaral
authors.affiliation: Grupo Integrado de Pesquisas em Biomarcadores, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil. atcteixeira@gmail.com.|Laboratory of Biomarkers for Diagnosis and Monitoring, René Rachou Research Center - FIOCRUZ/MG, Av. Augusto de Lima 1715, Barro Preto, Belo Horizonte, CEP 30190-002, Minas Gerais, Brazil. atcteixeira@gmail.com.
authors.forename: Andréa
authors.initials: A
authors.lastname: Teixeira-Carvalho
authors.affiliation: Grupo Integrado de Pesquisas em Biomarcadores, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil. oamfilho@cpqrr.fiocruz.br.|Laboratory of Biomarkers for Diagnosis and Monitoring, René Rachou Research Center - FIOCRUZ/MG, Av. Augusto de Lima 1715, Barro Preto, Belo Horizonte, CEP 30190-002, Minas Gerais, Brazil. oamfilho@cpqrr.fiocruz.br.
authors.forename: Olindo Assis
authors.initials: OA
authors.lastname: Martins-Filho
authors.affiliation: Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas - UEA, Manaus, AM, Brazil. v.flamir@terra.com.br.|Fundação de Medicina Tropical Doutor Heitor Vieira Dourado - FMT-HVD, Manaus, AM, Brazil. v.flamir@terra.com.br.
authors.forename: Flamir da Silva
authors.initials: Fda S
authors.lastname: Victória
authors.affiliation: Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas - UFAM, Manaus, AM, Brazil. malheiroadriana@yahoo.com.br.|Departamento de Ensino e Pesquisa, Fundação de Hematologia e Hemoterapia do Amazonas - Hemoam, Manaus, AM, Brazil. malheiroadriana@yahoo.com.br.
authors.forename: Adriana
authors.initials: A
authors.lastname: Malheiro
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000097:blood* / Q000276:immunology / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000097:blood*; D016753:Interleukin-10 / Q000097:blood*; D008099:Liver / Q000276:immunology / Q000821:virology; D008103:Liver Cirrhosis / Q000097:blood* / Q000276:immunology / Q000821:virology; D008297:Male; D008875:Middle Aged
chemical_list: D016753:Interleukin-10; D007371:Interferon-gamma