title: CD11c+CD123Low dendritic cell subset and the triad TNF-α/IL-17A/IFN-γ integrate mucosal and peripheral cellular responses in HIV patients with high-grade anal intraepithelial neoplasia: a systems biology approach.
abstract: BACKGROUND
  The incidence of anal cancer has increased over the past 25 years, and HIV/HPV coinfection is the most important risk factor for anal squamous cell carcinoma. In this study, we demonstrated that the evaluation of systemic and compartmentalized anal mucosa immune response is relevant to differentiating HIV(+) patients at risk of anal intraepithelial neoplasia (AIN).
  
  
  METHODS
  A systems biology approach was used to integrate different immunological parameters from anal mucosal tissue and peripheral blood assessed by phenotypic and intracytoplasmic analysis of lymphocytes and dendritic cell subsets.
  
  
  RESULTS
  Our data demonstrated that anal mucosal mononuclear cells from AIN(+)HIV(+) patients showed a robust capacity in producing proinflammatory/regulatory cytokines, mainly mTNF-α > IL-4 > IL-10 > IL-6 = IL-17A. Mucosal TNF-α/IFN-γ/IL-17A are selective high-grade squamous intraepithelial lesion (HSIL)-related biomarkers. Higher levels of circulating CD11cCD123cells and CD1a cells along with elevated levels of IFN-γCD4 T cells are major features associated with HSIL in AIN(+)HIV(+) patients. Regardless of the presence of AIN, HIV(+) patients presented a complex biomarker network, rich in negative connections. Among those patients, however, HSIL+ patients displayed stronger positive links between peripheral blood and anal mucosa environments, exemplified by the subnet of IL-17A/TNF-α/CD4IFN-γ/CD11cCD123 cells.
  
  
  CONCLUSIONS
  The significant association between HSIL and the levels of TNF-α/IL-17A/IFN-γ along with the different subsets of DCs present in the anal mucosa milieu should be studied in more detail as a way to identify and categorize HIV(+) patients vis à vis the high risk of anal cancer outcome.
authors.affiliation: *Department of Surgery, Medicine School, Federal University of Amazonas, Manaus, Brazil; †Graduate Program in Tropical Medicine, State University of Amazonas, Manaus, Brazil; ‡Tropical Medicine Foundation of Amazonas, Manaus, Brazil; §Hematology and Hemotherapic Foundation of Amazonas, Manaus, Brazil; ‖Graduate Program in Basic and Applied Immunology, Federal University of Amazonas, Manaus, Brazil; ¶Laboratory of Biomarkers for Diagnosis and Monitoring, René Rachou Research Center, FIOCRUZ, Belo Horizonte, Brazil; and #Department of Anatomic Pathology, Medicine School, Federal University of Minas Gerais, Brazil.
authors.forename: Adriana G D P
authors.initials: AG
authors.lastname: Guimarães
authors.forename: Allysson G
authors.initials: AG
authors.lastname: da Costa
authors.forename: Olindo A
authors.initials: OA
authors.lastname: Martins-Filho
authors.forename: João P D
authors.initials: JP
authors.lastname: Pimentel
authors.forename: Danielle A G
authors.initials: DA
authors.lastname: Zauli
authors.forename: Vanessa
authors.initials: V
authors.lastname: Peruhype-Magalhães
authors.forename: Andréa
authors.initials: A
authors.lastname: Teixeira-Carvalho
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Béla
authors.forename: Marcelo A P
authors.initials: MA
authors.lastname: Xavier
authors.forename: Jordana G
authors.initials: JG
authors.lastname: Coelho-Dos-Reis
authors.forename: Josilene S
authors.initials: JS
authors.lastname: Abranches
authors.forename: José J P
authors.initials: JJ
authors.lastname: Guimarães
authors.forename: Adriana
authors.initials: A
authors.lastname: Malheiro
authors.forename: Luiz C L
authors.initials: LC
authors.lastname: Ferreira
mesh_terms: D001005:Anus Neoplasms / Q000150:complications / Q000276:immunology*; D015415:Biomarkers / Q000032:analysis*; D039521:CD11c Antigen / Q000032:analysis; D002278:Carcinoma in Situ / Q000150:complications / Q000276:immunology*; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology*; D015658:HIV Infections / Q000150:complications / Q000276:immunology*; D006801:Humans; D018928:Immunity, Mucosal; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D053650:Interleukin-3 Receptor alpha Subunit / Q000032:analysis; D007413:Intestinal Mucosa / Q000276:immunology; D008214:Lymphocytes / Q000737:chemistry / Q000276:immunology*; D018570:Risk Assessment; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D015415:Biomarkers; D039521:CD11c Antigen; C508717:IL17A protein, human; C115022:IL3RA protein, human; D020381:Interleukin-17; D053650:Interleukin-3 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma