X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production

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dc.contributor.authorFilipe-Santos, Orchidee
dc.contributor.authorBustamante, Jacinta
dc.contributor.authorHaverkamp, Margje H.
dc.contributor.authorVinolo, Emilie
dc.contributor.authorKu, Cheng-Lung
dc.contributor.authorPuel, Anne
dc.contributor.authorFrucht, David M.
dc.contributor.authorChristel, Karin
dc.contributor.authorvon Bernuth, Horst
dc.contributor.authorJouanguy, Emmanuelle
dc.contributor.authorFeinberg, Jacqueline
dc.contributor.authorDurandy, Anne
dc.contributor.authorSenechal, Brigitte
dc.contributor.authorChapgier, Ariane
dc.contributor.authorVogt, Guillaume
dc.contributor.authorde Beaucoudrey, Ludovic
dc.contributor.authorFieschi, Claire
dc.contributor.authorPicard, Capucine
dc.contributor.authorGarfa, Meriem
dc.contributor.authorChemli, Jalel
dc.contributor.authorBejaoui, Mohamed
dc.contributor.authorTsolia, Maria N.
dc.contributor.authorKutukculer, Necil
dc.contributor.authorPlebani, Alessandro
dc.contributor.authorNotarangelo, Luigi
dc.contributor.authorBodemer, Christine
dc.contributor.authorGeissmann, Frederic
dc.contributor.authorIsrael, Alain
dc.contributor.authorVeron, Michel
dc.contributor.authorKnackstedt, Maike
dc.contributor.authorBarbouche, Ridha
dc.contributor.authorAbel, Laurent
dc.contributor.authorMagdorf, Klaus
dc.contributor.authorGendrel, Dominique
dc.contributor.authorAgou, Fabrice
dc.contributor.authorHolland, Steven M.
dc.contributor.authorCasanova, Jean-Laurent
dc.date.accessioned2019-10-27T19:17:47Z
dc.date.available2019-10-27T19:17:47Z
dc.date.issued2006
dc.departmentEge Üniversitesien_US
dc.description.abstractGermline mutations in five autosomal genes involved in interleukin (IL)-12-dependent, interferon (IFN)-gamma-mediated immunity cause Mendelian susceptibility to mycobacterial diseases (MSMD). The molecular basis of X-linked recessive (XR)-MSMD remains unknown. We report here mutations in the leucine zipper (LZ) domain of the NF-kappa B essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD. The mutant proteins were produced in normal amounts in blood and fibroblastic cells. However, the patients' monocytes presented an intrinsic defect in T cell-dependent IL-12 production, resulting in defective IFN-gamma secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-kappa B/c-Rel-mediated CD40 signaling after the stimulation of monocytes and dendritic cells by CD40L-expressing T cells and fibroblasts, respectively. However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immunoglobulin class switch of B cells were normal. Moreover, the patients' blood and fibroblastic cells responded to other NF-kappa B activators, such as tumor necrosis factor-alpha, IL-beta, and lipopolysaccharide. These two mutations in the NEMO LZ domain provide the first genetic etiology of XR-MSMD. They also demonstrate the importance of the T cell- and CD40L-triggered, CD40-, and NEMO/NF-kappa B/c-Rel-mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans.en_US
dc.description.sponsorshipIntramural NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA; Medical Research CouncilMedical Research Council UK (MRC) [G0900867]en_US
dc.identifier.doi10.1084/jem.20050085en_US
dc.identifier.endpage1759en_US
dc.identifier.issn0022-1007
dc.identifier.issn1540-9538
dc.identifier.issue7en_US
dc.identifier.pmid16818673en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage1745en_US
dc.identifier.urihttps://doi.org/10.1084/jem.20050085
dc.identifier.urihttps://hdl.handle.net/11454/38474
dc.identifier.volume203en_US
dc.identifier.wosWOS:000238940500017en_US
dc.identifier.wosqualityN/Aen_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherRockefeller Univ Pressen_US
dc.relation.ispartofJournal of Experimental Medicineen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.titleX-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 productionen_US
dc.typeArticleen_US

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