The role of monocytes in the development of Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome

Immunobiology. 2014 Jan;219(1):37-44. doi: 10.1016/j.imbio.2013.07.004. Epub 2013 Jul 25.


Background: Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS) is a common complication of combined antiretroviral therapy (cART) in HIV-TB co-infected patients. However, the disease mechanism is poorly understood, prognosis of TB-IRIS is currently impossible, and diagnosis is highly challenging. We analyzed whether the gene expression of monocytes could be correlated with TB-IRIS pathogenesis and could be used to classify patients predisposed to TB-IRIS.

Methods: Monocyte gene expression was compared between patients who developed TB-IRIS and matched controls. We carried out whole-genome expression profiling using Affymetrix GeneChip(®) ST 1.1 arrays at two time-points: before cART initiation (baseline) and at week two post-cART initiation. For each time-point, we used different statistical approaches to identify molecular signatures which could be used as classifiers. We also functionally mapped the modulated cellular pathways using the software package Ingenuity Pathway Analysis.

Results: At baseline, before introduction of cART and before onset of symptoms, monocyte gene expression was already perturbed in patients who subsequently developed TB-IRIS, indicating a possible involvement of monocytes in TB-IRIS predisposition. The differences in monocyte gene expression in TB-IRIS patients became even more clear after two weeks of cART (when TB-IRIS commonly occurs), with more than 100 genes for which expression showed a fold change greater than 1.5. Both at baseline and at week two post-cART initiation, a classifier of 8 and 9 genes, respectively could be built, which allowed discrimination of TB-IRIS cases and controls. Pathway analyses revealed that the majority of the dysregulated genes in TB-IRIS - at the time of the IRIS episode, but also already at baseline - are associated with infection and inflammation. Relevant biological functions which were perturbed before/during TB-IRIS included "Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses" and "Complement System".

Conclusion: Our results indicate an involvement of monocytes in predisposition to/development of TB-IRIS, and suggest a number of functional pathways which may play a role in TB-IRIS development. This comprehensive study of gene regulation in monocytes provides baseline data for further studies into biomarkers for prognosis and diagnosis of TB-IRIS.

Keywords: Classification; Coinfection; DABG; HIV; IPA; Ingenuity Pathway Analysis; LOOCV; Microarray; Mtb; Mycobacterium tuberculosis; PBMC; PCA; PPD; R-SVM; RMA; ROC; Recursive Support Vector Machines; TB; TB-IRIS; Tuberculosis; Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome; cART; combined antiretroviral therapy; detection above background; human immunodeficiency virus; leave-one-out cross-validation; peripheral blood mononuclear cells; principal component analysis; purified protein derivative; receiver operating characteristic; robust multichip average; tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antiviral Agents / adverse effects
  • Antiviral Agents / therapeutic use
  • Cluster Analysis
  • Female
  • HIV Infections / complications
  • HIV Infections / drug therapy
  • HIV Infections / immunology*
  • Humans
  • Immune Reconstitution Inflammatory Syndrome / chemically induced
  • Immune Reconstitution Inflammatory Syndrome / genetics
  • Immune Reconstitution Inflammatory Syndrome / immunology*
  • Male
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Principal Component Analysis
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Time Factors
  • Transcriptome / drug effects
  • Transcriptome / genetics
  • Transcriptome / immunology
  • Tuberculosis / complications
  • Tuberculosis / immunology*


  • Antiviral Agents