TY - JOUR
T1 - Antigen-specific interferon-gamma responses and innate cytokine balance in TB-IRIS
AU - Goovaerts, Odin
AU - Jennes, Wim
AU - Massinga-Loembé, Marguerite
AU - Ceulemans, Ann
AU - Worodria, William
AU - Mayanja-Kizza, Harriet
AU - Colebunders, Robert
AU - Kestens, Luc
AU - TB-IRIS Study Group
N1 - FTX
PY - 2014
Y1 - 2014
N2 - 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.CONCLUSION: 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.
AB - 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.CONCLUSION: 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.
KW - Adult
KW - Anti-HIV Agents
KW - Antigens, Bacterial
KW - Antitubercular Agents
KW - CD4 Lymphocyte Count
KW - Cytokines
KW - Cytomegalovirus Infections
KW - Enzyme-Linked Immunospot Assay
KW - Female
KW - HIV Infections
KW - Humans
KW - Immune Reconstitution Inflammatory Syndrome
KW - Influenza, Human
KW - Interferon-gamma
KW - Interleukin-10
KW - Interleukin-12
KW - Interleukin-6
KW - Lipopolysaccharides
KW - Male
KW - Mycobacterium tuberculosis
KW - Prospective Studies
KW - Receptors, Interleukin-12
KW - Tuberculosis
U2 - 10.1371/journal.pone.0113101
DO - 10.1371/journal.pone.0113101
M3 - A1: Web of Science-article
C2 - 25415590
SN - 1932-6203
VL - 9
SP - e113101
JO - PLoS ONE
JF - PLoS ONE
IS - 11
ER -