title: The role of monocytes in the development of Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome.
abstract: 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".
  
  
  CONCLUSIONS
  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.
authors: Cellular and Molecular Immunology Unit, Vrije Universiteit Brussel, Brussels, Belgium; Myeloid Cell Immunology Laboratory, VIB, Brussels, Belgium.
authors: Huyen Thi Thanh
authors: HT
authors: Tran
authors: Rafael
authors: R
authors: Van den Bergh
authors: Trung Nghia
authors: TN
authors: Vu
authors: Kris
authors: K
authors: Laukens
authors: William
authors: W
authors: Worodria
authors: Marguerite Massinga
authors: MM
authors: Loembé
authors: Robert
authors: R
authors: Colebunders
authors: Luc
authors: L
authors: Kestens
authors: Patrick
authors: P
authors: De Baetselier
authors: Geert
authors: G
authors: Raes
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use; D016000:Cluster Analysis; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D008297:Male; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013997:Time Factors; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D014376:Tuberculosis / Q000150:complications / Q000276:immunology*
chemical_list: D000998:Antiviral Agents
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