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Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis

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Abstract

Heightened morbidity and mortality in pulmonary tuberculosis (TB) are consequences of complex disease processes triggered by the causative agent, Mycobacterium tuberculosis (Mtb). Mtb modulates inflammation at distinct stages of its intracellular life. Recognition and phagocytosis, replication in phagosomes and cytosol escape induce tightly regulated release of cytokines [including interleukin (IL)-1, tumor necrosis factor (TNF), IL-10], chemokines, lipid mediators, and type I interferons (IFN-I). Mtb occupies various lung lesions at sites of pathology. Bacteria are barely detectable at foci of lipid pneumonia or in perivascular/bronchiolar cuffs. However, abundant organisms are evident in caseating granulomas and at the cavity wall. Such lesions follow polar trajectories towards fibrosis, encapsulation and mineralization or liquefaction, extensive matrix destruction, and tissue injury. The outcome is determined by immune factors acting in concert. Gradients of cytokines and chemokines (CCR2, CXCR2, CXCR3/CXCR5 agonists; TNF/IL-10, IL-1/IFN-I), expression of activation/death markers on immune cells (TNF receptor 1, PD-1, IL-27 receptor) or abundance of enzymes [arginase-1, matrix metalloprotease (MMP)-1, MMP-8, MMP-9] drive genesis and progression of lesions. Distinct lesions coexist such that inflammation in TB encompasses a spectrum of tissue changes. A better understanding of the multidimensionality of immunopathology in TB will inform novel therapies against this pulmonary disease.

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Abbreviations

Ahr:

Aryl hydrocarbon receptor

AMPK:

5' AMP-activated protein kinase

cGAS:

Cyclic GMP-AMP synthase

CR:

Complement receptor

CT:

Computer tomography

DC-SIGN:

Dendritic cell-specific ICAM-grabbing nonintegrin

DTH:

Delayed-type hypersensitivity

FDG:

18-fluoro-deoxy-glucose

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

HIF:

Hypoxia-inducible factor

IDO-1:

Indoleamine 2,3-dioxygenase-1

IFN:

Interferon

IFNAR1:

IFN-alpha receptor 1

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

LTBI:

Latent Mtb infection

ManLAM:

Mannose-capped lipoarabinomannan

MARCO:

Macrophage receptor with collagenous structure

MCL:

Macrophage C-type lectin

MDSC:

Myeloid-derived suppressor cell

MINCLE:

Macrophage-inducible Ca2+-dependent (C-type) lectin

MMP:

Matrix metalloprotease

Mtb :

Mycobacterium tuberculosis

NEC:

Necrosis-associated extracellular cluster

NF-κB:

Nuclear factor “kappa-light-chain-enhancer” of activated B cells

NHP:

Nonhuman primate

NK:

Natural killer

NLRP2:

NOD-like receptor protein 3

NOD2:

Nucleotide-binding and oligomerization domain-2

PDIM:

Phthiocerol dimycocerosate

PET:

Positron emission tomography

PGL:

Phenolic glycolipid

RD:

Region of difference

TB:

Tuberculosis

TDM:

Trehalose dimycolate

Th:

T helper cell

TIMP:

Tissue inhibitor of matrix protease

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

VEGF:

Vascular endothelial growth factor

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Acknowledgments

We thank Mary Louise Grossman for excellent help preparing the manuscript and Diane Schad for graphical assistance. Work in the lab of S.H.E.K. was supported by European Union’s Seventh Framework Program project “ADITEC” (HEALTH-F4-2011-280873); the European Union’s Horizon 2020 project “TBVAC2020” (grant no. 643381); and the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) Infect ERA project “Anti-Bacterial Immune Regulation” (ABIR) (grant no. 031A404).

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Correspondence to Anca Dorhoi or Stefan H.E. Kaufmann.

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This article is a contribution to the Special Issue on Immunopathology of Mycobacterial Diseases - Guest Editor: Stefan H.E. Kaufmann

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Dorhoi, A., Kaufmann, S.H. Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis. Semin Immunopathol 38, 153–166 (2016). https://doi.org/10.1007/s00281-015-0531-3

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