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. 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.
Highlights
Together with the HIV pandemic there has been a global increase in the number of tuberculosis (TB) infections [1]
In a prospective cohort study of HIV-TB co-infected patients treated for TB before antiretroviral therapy (ART) initiation, we compared 18 patients who developed tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) with 18 non-IRIS controls matched for age, sex and CD4 count
The reconstitution of CMV and LPS responses was delayed in the TB-IRIS group
Summary
Together with the HIV pandemic there has been a global increase in the number of tuberculosis (TB) infections [1]. Despite recent WHO recommendations for early antiretroviral therapy (ART) [3], treatment is started at late stages of HIV infection in many developing countries [4]. This puts patients at increased risk of developing tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) during ART [5]. Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains a poorly understood complication in HIV-TB patients receiving antiretroviral therapy (ART). During TB-IRIS, IFNc 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. Upon LPS stimulation, IL-6/IL-10 and TNFa/IL-10 ratios were increased in TB-IRIS patients compared to non-IRIS controls
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