A Mutation in IL4RA Is Associated with the Degree of Pathology in Human TB Patients
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 h...
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| Format: | Article |
| Language: | English |
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Wiley
2016-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2016/4245028 |
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| author | Christoph Hölscher Lisa Heitmann Ellis Owusu-Dabo Rolf D. Horstmann Christian G. Meyer Stefan Ehlers Thorsten Thye |
| author_facet | Christoph Hölscher Lisa Heitmann Ellis Owusu-Dabo Rolf D. Horstmann Christian G. Meyer Stefan Ehlers Thorsten Thye |
| author_sort | Christoph Hölscher |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8ccdadb541dc444da2779ef152125e58 |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-8ccdadb541dc444da2779ef152125e582025-02-03T06:12:09ZengWileyMediators of Inflammation0962-93511466-18612016-01-01201610.1155/2016/42450284245028A Mutation in IL4RA Is Associated with the Degree of Pathology in Human TB PatientsChristoph Hölscher0Lisa Heitmann1Ellis Owusu-Dabo2Rolf D. Horstmann3Christian G. Meyer4Stefan Ehlers5Thorsten Thye6Infection Immunology, Research Center Borstel, Parkallee 22, 23845 Borstel, GermanyInfection Immunology, Research Center Borstel, Parkallee 22, 23845 Borstel, GermanyDepartment of Community Health, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, GhanaGerman Center for Infection Research, GermanyGerman Center for Infection Research, GermanyGerman Center for Infection Research, GermanyGerman Center for Infection Research, GermanyThe 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.http://dx.doi.org/10.1155/2016/4245028 |
| spellingShingle | Christoph Hölscher Lisa Heitmann Ellis Owusu-Dabo Rolf D. Horstmann Christian G. Meyer Stefan Ehlers Thorsten Thye A Mutation in IL4RA Is Associated with the Degree of Pathology in Human TB Patients Mediators of Inflammation |
| title | A Mutation in IL4RA Is Associated with the Degree of Pathology in Human TB Patients |
| title_full | A Mutation in IL4RA Is Associated with the Degree of Pathology in Human TB Patients |
| title_fullStr | A Mutation in IL4RA Is Associated with the Degree of Pathology in Human TB Patients |
| title_full_unstemmed | A Mutation in IL4RA Is Associated with the Degree of Pathology in Human TB Patients |
| title_short | A Mutation in IL4RA Is Associated with the Degree of Pathology in Human TB Patients |
| title_sort | mutation in il4ra is associated with the degree of pathology in human tb patients |
| url | http://dx.doi.org/10.1155/2016/4245028 |
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