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The human immune response to tuberculosis and its treatment: a view from the blood.

Cliff JM, Kaufmann SH, McShane H, van Helden P, O'Garra A - Immunol. Rev. (2015)

Bottom Line: Using modular and pathway analyses of the complex data has shown, now in multiple studies, that the signature of active tuberculosis is dominated by overexpression of interferon-inducible genes (consisting of both type I and type II interferon signaling), myeloid genes, and inflammatory genes.There is also downregulation of genes encoding B and T-cell function.The signature suggested a previously under-appreciated role for type I interferons in development of active tuberculosis disease, and numerous mechanisms have now been uncovered to explain how type I interferon impedes the protective response to M. tuberculosis infection.

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Affiliation: TB Centre and Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, UK.

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Modular and pathway analysis reveal a dominant IFN-inducible signature in tuberculosis. Modular analysis reveals overabundance of IFN-inducible genes (M3.1) and myeloid genes (M1.5 and M2.6) and under abundance of B (M1.3) and T cell (M2.8) related genes (A) (4); (B) (From Cliff et al., Distinct phases of blood gene expression pattern through tuberculosis treatment reflect modulation of the humoral immune response. J Infect Dis 2013; 207(1): pp. 18–29, by permission of Oxford University Press). (12). (C) The canonical pathway for IFN signaling from Ingenuity Pathways Analysis; with transcripts over-represented in test set patients with active tuberculosis (1, 4) shaded red. GAS, Gamma-activated site; ISRE, IFN-sensitive element. Modified from (1, 4). Transcript abundance in whole blood and (c) separated blood leucocyte populations of representative IFN-inducible genes (from top to bottom: OAS1, IFI6, IFI44, IFI44L, OAS3, IRF7,IFIH1, IFI16, IFIT3, IFIT2, OAS2, IFITM3, IFITM1, GBP1, GBP5, STAT1, GBP2, TAP1, STAT1, STAT2, IFI35, TAP2, CD274, SOCS1, CXCL10, IFIT5) in active tuberculosis. Transcript abundance/expression is normalized to the median of the healthy controls. Modified from (A and C modified from Berry et al., Nature 2010) (1, 3, 4).
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fig06: Modular and pathway analysis reveal a dominant IFN-inducible signature in tuberculosis. Modular analysis reveals overabundance of IFN-inducible genes (M3.1) and myeloid genes (M1.5 and M2.6) and under abundance of B (M1.3) and T cell (M2.8) related genes (A) (4); (B) (From Cliff et al., Distinct phases of blood gene expression pattern through tuberculosis treatment reflect modulation of the humoral immune response. J Infect Dis 2013; 207(1): pp. 18–29, by permission of Oxford University Press). (12). (C) The canonical pathway for IFN signaling from Ingenuity Pathways Analysis; with transcripts over-represented in test set patients with active tuberculosis (1, 4) shaded red. GAS, Gamma-activated site; ISRE, IFN-sensitive element. Modified from (1, 4). Transcript abundance in whole blood and (c) separated blood leucocyte populations of representative IFN-inducible genes (from top to bottom: OAS1, IFI6, IFI44, IFI44L, OAS3, IRF7,IFIH1, IFI16, IFIT3, IFIT2, OAS2, IFITM3, IFITM1, GBP1, GBP5, STAT1, GBP2, TAP1, STAT1, STAT2, IFI35, TAP2, CD274, SOCS1, CXCL10, IFIT5) in active tuberculosis. Transcript abundance/expression is normalized to the median of the healthy controls. Modified from (A and C modified from Berry et al., Nature 2010) (1, 3, 4).

Mentions: Transcriptomic analyses of blood from patients with tuberculosis has revealed a dominant signature of IFN-inducible genes, including those down-stream of type I and type II (IFN-γ) signaling (4, 8, 10, 12), upregulation of complement related genes (12) and those associated with myeloid function and inflammation (4, 7, 8, 11, 12, 21, 62) (Fig.6). In addition, the signature reflects downregulation of genes encoding B and T-cell functions (4, 12, 21) (Fig.6), the latter accounted for by decreased numbers of T cells in the blood of active tuberculosis patients (4). This perhaps reflects apoptosis of such cells in the blood or their migration to the infected tissue (4).


The human immune response to tuberculosis and its treatment: a view from the blood.

Cliff JM, Kaufmann SH, McShane H, van Helden P, O'Garra A - Immunol. Rev. (2015)

Modular and pathway analysis reveal a dominant IFN-inducible signature in tuberculosis. Modular analysis reveals overabundance of IFN-inducible genes (M3.1) and myeloid genes (M1.5 and M2.6) and under abundance of B (M1.3) and T cell (M2.8) related genes (A) (4); (B) (From Cliff et al., Distinct phases of blood gene expression pattern through tuberculosis treatment reflect modulation of the humoral immune response. J Infect Dis 2013; 207(1): pp. 18–29, by permission of Oxford University Press). (12). (C) The canonical pathway for IFN signaling from Ingenuity Pathways Analysis; with transcripts over-represented in test set patients with active tuberculosis (1, 4) shaded red. GAS, Gamma-activated site; ISRE, IFN-sensitive element. Modified from (1, 4). Transcript abundance in whole blood and (c) separated blood leucocyte populations of representative IFN-inducible genes (from top to bottom: OAS1, IFI6, IFI44, IFI44L, OAS3, IRF7,IFIH1, IFI16, IFIT3, IFIT2, OAS2, IFITM3, IFITM1, GBP1, GBP5, STAT1, GBP2, TAP1, STAT1, STAT2, IFI35, TAP2, CD274, SOCS1, CXCL10, IFIT5) in active tuberculosis. Transcript abundance/expression is normalized to the median of the healthy controls. Modified from (A and C modified from Berry et al., Nature 2010) (1, 3, 4).
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fig06: Modular and pathway analysis reveal a dominant IFN-inducible signature in tuberculosis. Modular analysis reveals overabundance of IFN-inducible genes (M3.1) and myeloid genes (M1.5 and M2.6) and under abundance of B (M1.3) and T cell (M2.8) related genes (A) (4); (B) (From Cliff et al., Distinct phases of blood gene expression pattern through tuberculosis treatment reflect modulation of the humoral immune response. J Infect Dis 2013; 207(1): pp. 18–29, by permission of Oxford University Press). (12). (C) The canonical pathway for IFN signaling from Ingenuity Pathways Analysis; with transcripts over-represented in test set patients with active tuberculosis (1, 4) shaded red. GAS, Gamma-activated site; ISRE, IFN-sensitive element. Modified from (1, 4). Transcript abundance in whole blood and (c) separated blood leucocyte populations of representative IFN-inducible genes (from top to bottom: OAS1, IFI6, IFI44, IFI44L, OAS3, IRF7,IFIH1, IFI16, IFIT3, IFIT2, OAS2, IFITM3, IFITM1, GBP1, GBP5, STAT1, GBP2, TAP1, STAT1, STAT2, IFI35, TAP2, CD274, SOCS1, CXCL10, IFIT5) in active tuberculosis. Transcript abundance/expression is normalized to the median of the healthy controls. Modified from (A and C modified from Berry et al., Nature 2010) (1, 3, 4).
Mentions: Transcriptomic analyses of blood from patients with tuberculosis has revealed a dominant signature of IFN-inducible genes, including those down-stream of type I and type II (IFN-γ) signaling (4, 8, 10, 12), upregulation of complement related genes (12) and those associated with myeloid function and inflammation (4, 7, 8, 11, 12, 21, 62) (Fig.6). In addition, the signature reflects downregulation of genes encoding B and T-cell functions (4, 12, 21) (Fig.6), the latter accounted for by decreased numbers of T cells in the blood of active tuberculosis patients (4). This perhaps reflects apoptosis of such cells in the blood or their migration to the infected tissue (4).

Bottom Line: Using modular and pathway analyses of the complex data has shown, now in multiple studies, that the signature of active tuberculosis is dominated by overexpression of interferon-inducible genes (consisting of both type I and type II interferon signaling), myeloid genes, and inflammatory genes.There is also downregulation of genes encoding B and T-cell function.The signature suggested a previously under-appreciated role for type I interferons in development of active tuberculosis disease, and numerous mechanisms have now been uncovered to explain how type I interferon impedes the protective response to M. tuberculosis infection.

View Article: PubMed Central - PubMed

Affiliation: TB Centre and Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, UK.

Show MeSH
Related in: MedlinePlus