Universität zu Köln

Hoelscher, Christoph, Heitmann, Lisa, Owusu-Dabo, Ellis, Horstmann, Rolf D., Meyer, Christian G., Ehlers, Stefan and Thye, Thorsten (2016). A Mutation in IL4RA Is Associated with the Degree of Pathology in Human TB Patients. Mediat. Inflamm., 2016. LONDON: HINDAWI LTD. ISSN 1466-1861

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Abstract

The contribution of interleukin- (IL-) 4 receptor-alpha-(R alpha-) 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-4R alpha 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-4R alpha subunit, we analyzed IL-13 transgenic mice with a genetic ablation of the IL-4R alpha. 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-4R alpha-dependent mechanisms are involved in mediating tissue pathology of human TB.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hoelscher, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Heitmann, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Owusu-Dabo, Ellis UNSPECIFIED UNSPECIFIED UNSPECIFIED Horstmann, Rolf D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Meyer, Christian G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ehlers, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Thye, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-291214
DOI:	10.1155/2016/4245028
Journal or Publication Title:	Mediat. Inflamm.
Volume:	2016
Date:	2016
Publisher:	HINDAWI LTD
Place of Publication:	LONDON
ISSN:	1466-1861
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; IN-VITRO; INTERLEUKIN-4; INTERFERON; ACTIVATION; CYTOKINE; RECEPTOR; ASTHMA; GAMMA Multiple languages Cell Biology; Immunology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/29121