Abramo Clarice, Meijgaarden Krista E, Garcia Daniely, Franken Kees L M C, Klein Michèl R, Kolk Arend J, Oliveira Sérgio C, Ottenhoff Tom H M, Teixeira Henrique C
Laboratory of Immunology, Department of Parasitology, Microbiology and Immunology, Biological Sciences Institute, Federal University of Juiz de Fora, 36036-330 Juiz de Fora, Brazil.
Microbes Infect. 2006 Jan;8(1):45-51. doi: 10.1016/j.micinf.2005.05.019. Epub 2005 Jul 22.
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.
γ干扰素（IFN-γ）对结核分枝杆菌抗原ESAT-6和CFP-10的反应已被提议作为结核分枝杆菌感染的特异性标志物。γ干扰素诱导的单核因子（MIG/CXCL9）已被证明由IFN-γ刺激的单核细胞表达，并通过趋化因子受体CXCR3吸引活化的T细胞。由于MIG在对IFN-γ的反应早期被诱导，与主要侧重于量化IFN-γ本身产生的检测方法相比，检测MIG可能提供一个有趣的标志物来评估下游IFN-γ诱导的反应。因此，我们在29名卡介苗疫苗对照者和24名结核病患者中研究了MIG和IFN-γ对ESAT-6和CFP-10融合蛋白的反应，并比较了对结核分枝杆菌保守抗原85B（Ag85B）和纯化蛋白衍生物（PPD）的反应。通过ELISPOT测定分泌IFN-γ的细胞，通过ELISA和流式细胞术测量MIG的产生。对ESAT-6/CFP-10、Ag85B和PPD产生的MIG总体上与分泌IFN-γ的细胞数量增加相关（r=0.55，P<0.0001）。在用ESAT-6/CFP-10或PPD刺激后，患者与对照者相比，IFN-γ和MIG的分泌显著增加（P<0.05）。此外，在对ESAT-6/CFP-10或PPD的反应中，结核病患者的MIG细胞内表达高于卡介苗疫苗接种者（P<0.05）。我们得出结论，MIG的产生与结核分枝杆菌特异性抗原ESAT-6/CFP-10诱导的T细胞IFN-γ产生增强显著相关。这些结果表明MIG是一种潜在的新型生物标志物，可能有助于评估结核病中IFN-γ诱导的下游反应。
