title: Antigen-specific interferon-gamma responses and innate cytokine balance in TB-IRIS.
abstract: BACKGROUND
  Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains a poorly understood complication in HIV-TB patients receiving antiretroviral therapy (ART). TB-IRIS could be associated with an exaggerated immune response to TB-antigens. We compared the recovery of IFNγ responses to recall and TB-antigens and explored in vitro innate cytokine production in TB-IRIS patients.
  
  
  METHODS
  In a prospective cohort study of HIV-TB co-infected patients treated for TB before ART initiation, we compared 18 patients who developed TB-IRIS with 18 non-IRIS controls matched for age, sex and CD4 count. We analyzed IFNγ ELISpot responses to CMV, influenza, TB and LPS before ART and during TB-IRIS. CMV and LPS stimulated ELISpot supernatants were subsequently evaluated for production of IL-12p70, IL-6, TNFα and IL-10 by Luminex.
  
  
  RESULTS
  Before ART, all responses were similar between TB-IRIS patients and non-IRIS controls. During TB-IRIS, IFNγ responses to TB and influenza antigens were comparable between TB-IRIS patients and non-IRIS controls, but responses to CMV and LPS remained significantly lower in TB-IRIS patients. Production of innate cytokines was similar between TB-IRIS patients and non-IRIS controls. However, upon LPS stimulation, IL-6/IL-10 and TNFα/IL-10 ratios were increased in TB-IRIS patients compared to non-IRIS controls.
  
  
  CONCLUSIONS
  TB-IRIS patients did not display excessive IFNγ responses to TB-antigens. In contrast, the reconstitution of CMV and LPS responses was delayed in the TB-IRIS group. For LPS, this was linked with a pro-inflammatory shift in the innate cytokine balance. These data are in support of a prominent role of the innate immune system in TB-IRIS.
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Odin
authors.initials: O
authors.lastname: Goovaerts
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Jennes
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium; Centre de Recherches Médicales de Lambaréné (CERMEL), Albert Schweitzer Hospital, Lambaréné, Gabon; Institut für Tropenmedizin, Universität Tübingen, Tübingen, Baden-Württemberg, Germany.
authors.forename: Marguerite
authors.initials: M
authors.lastname: Massinga-Loembé
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Ceulemans
authors.affiliation: Makerere University College of Health Sciences, Kampala, Uganda; Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda; Infectious Diseases Network for Treatment and Research in Africa (INTERACT), Kampala, Uganda.
authors.forename: William
authors.initials: W
authors.lastname: Worodria
authors.affiliation: Makerere University College of Health Sciences, Kampala, Uganda; Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Harriet
authors.initials: H
authors.lastname: Mayanja-Kizza
authors.affiliation: Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium; Epidemiology and Social Medicine, University of Antwerp, Antwerp, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Colebunders
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Kestens
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000276:immunology / Q000627:therapeutic use; D000942:Antigens, Bacterial / Q000276:immunology*; D000995:Antitubercular Agents / Q000276:immunology / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000150:complications / Q000276:immunology; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000150:complications / Q000276:immunology*; D007251:Influenza, Human / Q000150:complications / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology; D011446:Prospective Studies; D053707:Receptors, Interleukin-12; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy / Q000276:immunology*
chemical_list: D019380:Anti-HIV Agents; D000942:Antigens, Bacterial; D000995:Antitubercular Agents; D016207:Cytokines; C508439:IL12RB2 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D053707:Receptors, Interleukin-12; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma