title: BCG-specific IgG-secreting peripheral plasmablasts as a potential biomarker of active tuberculosis in HIV negative and HIV positive patients.
abstract: BACKGROUND
  Diagnosis of active tuberculosis (TB) among sputum-negative cases, patients with HIV infection and extra-pulmonary TB is difficult. In this study, assessment of BCG-specific IgG-secreting peripheral plasmablasts, was used to identify active TB in these high-risk groups.
  
  
  METHODS
  Peripheral blood mononuclear cells were isolated from patients with TB and controls and cultured in vitro using an assay called Antibodies in Lymphocyte Supernatant, which measures spontaneous IgG antibody release from migratory plasmablasts. A BCG-specific ELISA and flow cytometry were used to quantify in vivo activated plasmablasts in blood samples from Ethiopian subjects who were HIV negative or HIV positive. Patients diagnosed with different clinical forms of sputum-negative active TB or other diseases (n=96) were compared with asymptomatic individuals including latent TB and non-TB controls (n=85). Immunodiagnosis of TB also included the tuberculin skin test and the interferon (IFN)-γ release assay, QuantiFERON.
  
  
  RESULTS
  This study demonstrated that circulating IgG+ plasmablasts and spontaneous secretion of BCG-specific IgG antibodies were significantly higher in patients with active TB compared with latent TB cases and non-TB controls. BCG-specific IgG titres were particularly high among patients coinfected with TB and HIV with CD4 T-cell counts <200 cells/ml who produced low levels of Mycobacterium tuberculosis-specific IFNγ in vitro.
  
  
  CONCLUSIONS
  These results suggest that BCG-specific IgG-secreting peripheral plasmablasts could be successfully used as a host-specific biomarker to improve diagnosis of active TB, particularly in people who are HIV positive, and facilitate administration of effective treatment to patients. Elevated IgG responses were associated with impaired peripheral T-cell responses, including reduced T-cell numbers and low M tuberculosis-specific IFNγ production.
authors.affiliation: Department of Medicine, Center for Infectious Medicine (CIM), Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Senait
authors.initials: S
authors.lastname: Ashenafi
authors.forename: Getachew
authors.initials: G
authors.lastname: Aderaye
authors.forename: Martha
authors.initials: M
authors.lastname: Zewdie
authors.forename: Rubhana
authors.initials: R
authors.lastname: Raqib
authors.forename: Amsalu
authors.initials: A
authors.lastname: Bekele
authors.forename: Isabelle
authors.initials: I
authors.lastname: Magalhaes
authors.forename: Beede
authors.initials: B
authors.lastname: Lema
authors.forename: Meseret
authors.initials: M
authors.lastname: Habtamu
authors.forename: Rokeya Sultana
authors.initials: RS
authors.lastname: Rekha
authors.forename: Getachew
authors.initials: G
authors.lastname: Aseffa
authors.forename: Markus
authors.initials: M
authors.lastname: Maeurer
authors.forename: Abraham
authors.initials: A
authors.lastname: Aseffa
authors.forename: Mattias
authors.initials: M
authors.lastname: Svensson
authors.forename: Jan
authors.initials: J
authors.lastname: Andersson
authors.forename: Susanna
authors.initials: S
authors.lastname: Brighenti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D018791:CD4 Lymphocyte Count; D005260:Female; D018023:HIV Seronegativity / Q000276:immunology; D006679:HIV Seropositivity / Q000150:complications / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D007371:Interferon-gamma / Q000097:blood; D055985:Latent Tuberculosis / Q000175:diagnosis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009163:Mycobacterium bovis / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism*; D013183:Sputum / Q000382:microbiology; D018709:Statistics, Nonparametric; D014397:Tuberculosis, Pulmonary / Q000150:complications / Q000175:diagnosis* / Q000276:immunology*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007074:Immunoglobulin G; D007371:Interferon-gamma