title: A Mutation in IL4RA Is Associated with the Degree of Pathology in Human TB Patients.
abstract: The contribution of interleukin- (IL-) 4 receptor-alpha- (Rα-) dependent events in the pathogenesis of tuberculosis (TB) is controversial. We have recently shown IL-13 overexpression in mice to cause recrudescent Mtb replication and centrally necrotizing granulomas strongly resembling pathology of human TB. A deletion of IL-4Rα completely abrogates TB tissue pathology in these mice. To validate our results in human TB patients, we here determined the association of distinct variants of the IL4, IL13, IL4RA, IL13RA1, and IL13RA2 genes with cavity formation in a large Ghanaian cohort of HIV-negative individuals with newly diagnosed pulmonary TB. In fact, the structural variant of the IL4RA I50V, previously shown to result in enhanced signal transduction, was significantly associated with greater cavity size, and a variant of IL13RA2 was associated with disease in females. To evaluate whether the human-like TB pathology in IL-13-overexpressing mice is specifically mediated through the IL-4Rα subunit, we analyzed IL-13 transgenic mice with a genetic ablation of the IL-4Rα. In these mice, the IL-13-mediated increased susceptibility, human-like pathology of collagen deposition around centrally necrotizing granulomas, and alternative macrophage activation were abolished. Together, our genetic association study in human TB patients further supports the assumption that IL-13/IL-4Rα-dependent mechanisms are involved in mediating tissue pathology of human TB.
authors.affiliation: Infection Immunology, Research Center Borstel, Parkallee 22, 23845 Borstel, Germany; German Center for Infection Research, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hölscher
authors.affiliation: Infection Immunology, Research Center Borstel, Parkallee 22, 23845 Borstel, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Heitmann
authors.affiliation: Department of Community Health, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
authors.forename: Ellis
authors.initials: E
authors.lastname: Owusu-Dabo
authors.affiliation: German Center for Infection Research, Germany; Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Strasse 74, 20359 Hamburg, Germany.
authors.forename: Rolf D
authors.initials: RD
authors.lastname: Horstmann
authors.affiliation: German Center for Infection Research, Germany; Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Strasse 74, 20359 Hamburg, Germany.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Meyer
authors.affiliation: German Center for Infection Research, Germany; Microbial Inflammation Research, Research Center Borstel, Parkallee 22, 23845 Borstel, Germany; Molecular Inflammation Medicine, Christian Albrechts University, Christian-Albrechts-Platz 4, 24098 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehlers
authors.affiliation: German Center for Infection Research, Germany; Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Strasse 74, 20359 Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Thye
mesh_terms: D000818:Animals; D005260:Female; D005869:Ghana; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014397:Tuberculosis, Pulmonary / Q000235:genetics*
chemical_list: D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D053662:Interleukin-4 Receptor alpha Subunit; D015847:Interleukin-4