Antigen-specific interferon-gamma responses and innate cytokine balance in TB-IRIS

PLoS One. 2014 Nov 21;9(11):e113101. doi: 10.1371/journal.pone.0113101. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-HIV Agents / immunology
  • Anti-HIV Agents / therapeutic use
  • Antigens, Bacterial / immunology*
  • Antitubercular Agents / immunology
  • Antitubercular Agents / therapeutic use
  • CD4 Lymphocyte Count
  • Cytokines / immunology*
  • Cytokines / metabolism
  • Cytomegalovirus Infections / complications
  • Cytomegalovirus Infections / immunology
  • Enzyme-Linked Immunospot Assay
  • Female
  • HIV Infections / complications
  • HIV Infections / drug therapy
  • HIV Infections / immunology
  • Humans
  • Immune Reconstitution Inflammatory Syndrome / complications
  • Immune Reconstitution Inflammatory Syndrome / immunology*
  • Influenza, Human / complications
  • Influenza, Human / immunology
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / immunology
  • Male
  • Mycobacterium tuberculosis / immunology
  • Prospective Studies
  • Receptors, Interleukin-12
  • Tuberculosis / complications
  • Tuberculosis / drug therapy
  • Tuberculosis / immunology*

Substances

  • Anti-HIV Agents
  • Antigens, Bacterial
  • Antitubercular Agents
  • Cytokines
  • IL12RB2 protein, human
  • Interleukin-6
  • Lipopolysaccharides
  • Receptors, Interleukin-12
  • Interleukin-10
  • Interleukin-12
  • Interferon-gamma

Grants and funding

The TB-IRIS project was funded by an EC FP6 Specific Targeted Research Project (STREP) grant LSHP-CT-2007-037659-TBIRIS. This work was done in association with the Infectious Diseases Network for Treatment and Research in Africa (INTERACT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.