title: Monokine induced by interferon gamma and IFN-gamma response to a fusion protein of Mycobacterium tuberculosis ESAT-6 and CFP-10 in Brazilian tuberculosis patients.
abstract: IFN-gamma responses to Mycobacterium tuberculosis antigens ESAT-6 and CFP-10 have been proposed as specific markers of M. tuberculosis infection. Monokine induced by gamma interferon (MIG/CXCL9) has been shown to be expressed by IFN-gamma stimulated mononuclear cells and to attract activated T-cells through the chemokine receptor CXCR3. Since MIG is induced early in the response to IFN-gamma, measuring MIG may provide an interesting marker to assess downstream IFN-gamma induced responses, in contrast to assays that mainly focus on quantifying production of IFN-gamma per se. We, therefore, investigated MIG and IFN-gamma responses to a fusion protein of ESAT-6 and CFP-10, and compared responses to the conserved mycobacterial antigen 85B (Ag85B) and purified protein derivative (PPD) of M. tuberculosis, in 29 BCG vaccine controls and 24 TB patients. IFN-gamma secreting cells were determined by ELISPOT, and MIG production was measured by ELISA and flow cytometry. Production of MIG in response to ESAT-6/CFP-10, Ag85B and PPD correlated overall with increased numbers of IFN-gamma secreting cells (r=0.55, P<0.0001). A significant increase was noted among patients compared to controls in the secretion of IFN-gamma and MIG following stimulation with ESAT-6/CFP-10 or PPD (P<0.05). Moreover, MIG intracellular expression was higher in TB patients compared to BCG vaccines (P<0.05) in response to ESAT-6/CFP-10 or PPD. We conclude that MIG production correlates significantly with enhanced T-cell IFN-gamma production induced by M. tuberculosis-specific antigens ESAT-6/CFP-10. These results point to MIG as a potential novel biomarker that may be helpful in assessing downstream responses induced by IFN-gamma in TB.
authors.affiliation: Laboratory of Immunology, Department of Parasitology, Microbiology and Immunology, Biological Sciences Institute, Federal University of Juiz de Fora, 36036-330 Juiz de Fora, Brazil.
authors.forename: Clarice
authors.initials: C
authors.lastname: Abramo
authors.forename: Krista E
authors.initials: KE
authors.lastname: Meijgaarden
authors.forename: Daniely
authors.initials: D
authors.lastname: Garcia
authors.forename: Kees L M C
authors.initials: KL
authors.lastname: Franken
authors.forename: Michèl R
authors.initials: MR
authors.lastname: Klein
authors.forename: Arend J
authors.initials: AJ
authors.lastname: Kolk
authors.forename: Sérgio C
authors.initials: SC
authors.lastname: Oliveira
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.forename: Henrique C
authors.initials: HC
authors.lastname: Teixeira
mesh_terms: D000942:Antigens, Bacterial / Q000494:pharmacology; D001938:Brazil; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D014373:Tuberculin / Q000494:pharmacology; D014376:Tuberculosis / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; C080810:CXCL9 protein, human; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C505464:ESAT-6-CFP10 fusion protein; D036341:Intercellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; D014373:Tuberculin; D007371:Interferon-gamma