title: Dysregulation of Apoptosis Is a Risk Factor for Tuberculosis Disease Progression.
abstract: BACKGROUND
  A major barrier to effective tuberculosis control is our limited understanding of risk factors for tuberculosis disease progression. This study examined the role of apoptosis in immunity to tuberculosis.
  
  
  METHODS
  Cell subsets from tuberculosis cases and tuberculin skin test-positive (TST(+)) and TST-negative (TST(-)) household contacts (HHCs) were analyzed for expression of annexin-V and propidium iodide by flow cytometry. RNA microarrays were used to determine differences in apoptotic gene expression levels and multiplex ligation-dependent probe amplification was used to analyze gene expression in HHCs who progressed to active tuberculosis.
  
  
  RESULTS
  T cells from TST(+)HHC exhibited higher levels of apoptosis than tuberculosis cases; however, tuberculosis cases had a higher proportion of late apoptotic cells within the CD3(+)PD-1(+) subset. Tuberculosis cases had reduced levels of antiapoptotic genes compared to HHCs with a significant reduction in BCL2 associated with disease progression at least 1 year prior to progression.
  
  
  CONCLUSIONS
  While T cells are clearly able to mount a robust immune response to Mycobacterium tuberculosis, there are increased levels of apoptosis seen in effector T cells from tuberculosis patients. Dysregulation of several apoptotic genes suggest that apoptosis is a major functional pathway that could be targeted for future host-directed therapeutics.
authors.affiliation: Vaccines & Immunity, Medical Research Council Unit, Fajara, The Gambia University of Manchester, United Kingdom.
authors.forename: Thomas O J P
authors.initials: TO
authors.lastname: Elliott
authors.affiliation: Vaccines & Immunity, Medical Research Council Unit, Fajara, The Gambia.
authors.forename: Olumuyiwa
authors.initials: O
authors.lastname: Owolabi
authors.affiliation: Vaccines & Immunity, Medical Research Council Unit, Fajara, The Gambia.
authors.forename: Simon
authors.initials: S
authors.lastname: Donkor
authors.affiliation: Vaccines & Immunity, Medical Research Council Unit, Fajara, The Gambia.
authors.forename: Beate
authors.initials: B
authors.lastname: Kampmann
authors.affiliation: Vaccines & Immunity, Medical Research Council Unit, Fajara, The Gambia Centre for International Health, Department of Preventive and Social Medicine, Faculty of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Hill
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, The Netherlands.
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, The Netherlands.
authors.forename: Marielle C
authors.initials: MC
authors.lastname: Haks
authors.affiliation: Department of Immunology, Max Planck Institute of Infection Biology, Berlin, Germany.
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
authors.affiliation: Department of Immunology, Max Planck Institute of Infection Biology, Berlin, Germany.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Maertzdorf
authors.affiliation: Vaccines & Immunity, Medical Research Council Unit, Fajara, The Gambia.
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Sutherland
mesh_terms: D000328:Adult; D017304:Annexin A5 / Q000235:genetics / Q000378:metabolism; D000942:Antigens, Bacterial / Q000276:immunology; D017209:Apoptosis; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D055985:Latent Tuberculosis / Q000276:immunology* / Q000473:pathology; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009169:Mycobacterium tuberculosis; D011419:Propidium; D012307:Risk Factors; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014374:Tuberculin Test; D055815:Young Adult
chemical_list: D017304:Annexin A5; D000942:Antigens, Bacterial; D011419:Propidium
keywords: Bcl2; RT-MLPA; active tuberculosis disease; apoptosis; flow cytometry; latent tuberculosis infection; microarray; tuberculosis; tuberculosis progressors