X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production
Identifieur interne : 000492 ( France/Analysis ); précédent : 000491; suivant : 000493X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production
Auteurs : Orchidée Filipe-Santos ; Jacinta Bustamante ; Margje H. Haverkamp [Pays-Bas] ; Emilie Vinolo ; Cheng-Lung Ku ; Anne Puel ; David M. Frucht [États-Unis] ; Karin Christel ; Horst Von Bernuth ; Emmanuelle Jouanguy ; Jacqueline Feinberg ; Anne Durandy ; Brigitte Senechal [France] ; Ariane Chapgier ; Guillaume Vogt ; Ludovic De Beaucoudrey ; Claire Fieschi [France] ; Capucine Picard ; Meriem Garfa ; Jalel Chemli [Tunisie] ; Mohamed Bejaoui ; Maria N. Tsolia [Grèce] ; Necil Kutukculer [Turquie] ; Alessandro Plebani [Italie] ; Luigi Notarangelo [Italie] ; Christine Bodemer ; Frédéric Geissmann [France] ; Alain Israël ; Michel Véron ; Maike Knackstedt [Allemagne] ; Ridha Barbouche [Tunisie] ; Laurent Abel ; Klaus Magdorf [Allemagne] ; Dominique Gendrel [France] ; Fabrice Agou ; Steven M. Holland ; Jean-Laurent CasanovaSource :
- The Journal of Experimental Medicine [ 0022-1007 ] ; 2006.
Abstract
Germline mutations in five autosomal genes involved in interleukin (IL)-12–dependent, interferon (IFN)-γ–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-κB 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-γ secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-κB/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-κB activators, such as tumor necrosis factor-α, IL-1β, 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-κB/c-Rel–mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans.
Url:
DOI: 10.1084/jem.20060085
PubMed: 16818673
PubMed Central: 2118353
Affiliations:
- Allemagne, France, Grèce, Italie, Pays-Bas, Tunisie, Turquie, États-Unis
- Berlin, Gouvernorat de Tunis, Hollande-Méridionale, Maryland, Île-de-France
- Berlin, Leyde, Paris, Tunis
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last="Chemli">Jalel Chemli</name><affiliation wicri:level="1"><nlm:aff id="aff14">Department of Pediatrics, Sahloul Hospital, 4054 Sousse, Tunisia</nlm:aff><country xml:lang="fr">Tunisie</country><wicri:regionArea>Department of Pediatrics, Sahloul Hospital, 4054 Sousse</wicri:regionArea><wicri:noRegion>4054 Sousse</wicri:noRegion></affiliation></author><author><name sortKey="Bejaoui, Mohamed" sort="Bejaoui, Mohamed" uniqKey="Bejaoui M" first="Mohamed" last="Bejaoui">Mohamed Bejaoui</name><affiliation><nlm:aff wicri:cut=" and" id="N0x1cbd730N0x37e6598">National Center for Bone Marrow Transplantation</nlm:aff></affiliation></author><author><name sortKey="Tsolia, Maria N" sort="Tsolia, Maria N" uniqKey="Tsolia M" first="Maria N." last="Tsolia">Maria N. Tsolia</name><affiliation wicri:level="1"><nlm:aff id="aff17">Second Department of Pediatrics, University of Athens School of Medicine, P. and A. Kyriakou Children's Hospital, 115 27 Athens, Greece</nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea>Second Department of Pediatrics, University of Athens School of Medicine, P. and A. Kyriakou Children's Hospital, 115 27 Athens</wicri:regionArea><wicri:noRegion>115 27 Athens</wicri:noRegion></affiliation></author><author><name sortKey="Kutukculer, Necil" sort="Kutukculer, Necil" uniqKey="Kutukculer N" first="Necil" last="Kutukculer">Necil Kutukculer</name><affiliation wicri:level="1"><nlm:aff id="aff18">Department of Pediatrics, Ege University, 35100 Izmir, Turkey</nlm:aff><country xml:lang="fr">Turquie</country><wicri:regionArea>Department of Pediatrics, Ege University, 35100 Izmir</wicri:regionArea><wicri:noRegion>35100 Izmir</wicri:noRegion></affiliation></author><author><name sortKey="Plebani, Alessandro" sort="Plebani, Alessandro" uniqKey="Plebani A" first="Alessandro" last="Plebani">Alessandro Plebani</name><affiliation wicri:level="1"><nlm:aff id="aff19">Department of Pediatrics and Institute for Molecular Medicine Angello Nocivelli, University of Brescia, 25121 Brescia, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Pediatrics and Institute for Molecular Medicine Angello Nocivelli, University of Brescia, 25121 Brescia</wicri:regionArea><wicri:noRegion>25121 Brescia</wicri:noRegion></affiliation></author><author><name sortKey="Notarangelo, Luigi" sort="Notarangelo, Luigi" uniqKey="Notarangelo L" first="Luigi" last="Notarangelo">Luigi Notarangelo</name><affiliation wicri:level="1"><nlm:aff id="aff19">Department of Pediatrics and Institute for Molecular Medicine Angello Nocivelli, University of Brescia, 25121 Brescia, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Pediatrics and Institute for Molecular Medicine Angello Nocivelli, University of Brescia, 25121 Brescia</wicri:regionArea><wicri:noRegion>25121 Brescia</wicri:noRegion></affiliation></author><author><name sortKey="Bodemer, Christine" sort="Bodemer, Christine" uniqKey="Bodemer C" first="Christine" last="Bodemer">Christine Bodemer</name><affiliation><nlm:aff wicri:cut=", and" id="N0x1cbd730N0x37e6118">Dermatology Unit</nlm:aff></affiliation></author><author><name sortKey="Geissmann, Frederic" sort="Geissmann, Frederic" uniqKey="Geissmann F" first="Frédéric" last="Geissmann">Frédéric Geissmann</name><affiliation wicri:level="1"><nlm:aff id="N0x1cbd730N0x37e6118">INSERM, Laboratory of Mononuclear Phagocyte Biology, Avenir Team, Necker Enfants Malades Institute, 75015 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM, Laboratory of Mononuclear Phagocyte Biology, Avenir Team, Necker Enfants Malades Institute, 75015 Paris</wicri:regionArea><wicri:noRegion>75015 Paris</wicri:noRegion><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Israel, Alain" sort="Israel, Alain" uniqKey="Israel A" first="Alain" last="Israël">Alain Israël</name><affiliation><nlm:aff wicri:cut="; and" id="N0x1cbd730N0x37e6118">Laboratory of Molecular Signaling and Cellular Activation, URA 2582 CNRS, Pasteur Institute</nlm:aff><wicri:noCountry code="subfield">Pasteur Institute</wicri:noCountry></affiliation></author><author><name sortKey="Veron, Michel" sort="Veron, Michel" uniqKey="Veron M" first="Michel" last="Véron">Michel Véron</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Enzymatic Regulation of Cellular Activities, URA 2185 Centre National de la Recherche Scientifique (CNRS), Pasteur Institute;</nlm:aff><wicri:noCountry code="subfield">Pasteur Institute</wicri:noCountry></affiliation></author><author><name sortKey="Knackstedt, Maike" sort="Knackstedt, Maike" uniqKey="Knackstedt M" first="Maike" last="Knackstedt">Maike Knackstedt</name><affiliation wicri:level="3"><nlm:aff id="aff20">Department of Pediatric Pulmonology and Immunology, Charité, Campus Virchow Klinikum, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Pediatric Pulmonology and Immunology, Charité, Campus Virchow Klinikum, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Barbouche, Ridha" sort="Barbouche, Ridha" uniqKey="Barbouche R" first="Ridha" last="Barbouche">Ridha Barbouche</name><affiliation wicri:level="1"><nlm:aff id="N0x1cbd730N0x37e6598">Department of Immunology, Pasteur Institute, 1002 Tunis, Tunisia</nlm:aff><country xml:lang="fr">Tunisie</country><wicri:regionArea>Department of Immunology, Pasteur Institute, 1002 Tunis</wicri:regionArea><placeName><settlement type="city">Tunis</settlement><region nuts="2">Gouvernorat de Tunis</region></placeName></affiliation></author><author><name sortKey="Abel, Laurent" sort="Abel, Laurent" uniqKey="Abel L" first="Laurent" last="Abel">Laurent Abel</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation></author><author><name sortKey="Magdorf, Klaus" sort="Magdorf, Klaus" uniqKey="Magdorf K" first="Klaus" last="Magdorf">Klaus Magdorf</name><affiliation wicri:level="3"><nlm:aff id="aff20">Department of Pediatric Pulmonology and Immunology, Charité, Campus Virchow Klinikum, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Pediatric Pulmonology and Immunology, Charité, Campus Virchow Klinikum, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Gendrel, Dominique" sort="Gendrel, Dominique" uniqKey="Gendrel D" first="Dominique" last="Gendrel">Dominique Gendrel</name><affiliation wicri:level="1"><nlm:aff id="aff21">Department of Pediatrics, St. Vincent de Paul Hospital, 75014 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Department of Pediatrics, St. Vincent de Paul Hospital, 75014 Paris</wicri:regionArea><wicri:noRegion>75014 Paris</wicri:noRegion><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Agou, Fabrice" sort="Agou, Fabrice" uniqKey="Agou F" first="Fabrice" last="Agou">Fabrice Agou</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Enzymatic Regulation of Cellular Activities, URA 2185 Centre National de la Recherche Scientifique (CNRS), Pasteur Institute;</nlm:aff><wicri:noCountry code="subfield">Pasteur Institute</wicri:noCountry></affiliation></author><author><name sortKey="Holland, Steven M" sort="Holland, Steven M" uniqKey="Holland S" first="Steven M." last="Holland">Steven M. Holland</name><affiliation><nlm:aff wicri:cut=" and" id="N0x1cbd730N0x37e63e8">Laboratory of Clinical Infectious Diseases, National Institutes of Health</nlm:aff><wicri:noCountry code="subfield">National Institutes of Health</wicri:noCountry></affiliation></author><author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Pediatric Hematology-Immunology Unit, Necker Hospital;</nlm:aff><wicri:noCountry code="subfield">Necker Hospital</wicri:noCountry></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">16818673</idno><idno type="pmc">2118353</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118353</idno><idno type="RBID">PMC:2118353</idno><idno type="doi">10.1084/jem.20060085</idno><date when="2006">2006</date><idno type="wicri:Area/Pmc/Corpus">001B96</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001B96</idno><idno type="wicri:Area/Pmc/Curation">001B95</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001B95</idno><idno type="wicri:Area/Pmc/Checkpoint">003C04</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">003C04</idno><idno type="wicri:Area/Ncbi/Merge">002318</idno><idno type="wicri:Area/Ncbi/Curation">002318</idno><idno type="wicri:Area/Ncbi/Checkpoint">002318</idno><idno type="wicri:doubleKey">0022-1007:2006:Filipe Santos O:x:linked:susceptibility</idno><idno type="wicri:Area/Main/Merge">007960</idno><idno type="wicri:Area/Main/Curation">007793</idno><idno type="wicri:Area/Main/Exploration">007793</idno><idno type="wicri:Area/France/Extraction">000492</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production</title><author><name sortKey="Filipe Santos, Orchidee" sort="Filipe Santos, Orchidee" uniqKey="Filipe Santos O" first="Orchidée" last="Filipe-Santos">Orchidée Filipe-Santos</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation></author><author><name sortKey="Bustamante, Jacinta" sort="Bustamante, Jacinta" uniqKey="Bustamante J" first="Jacinta" last="Bustamante">Jacinta Bustamante</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation></author><author><name sortKey="Haverkamp, Margje H" sort="Haverkamp, Margje H" uniqKey="Haverkamp M" first="Margje H." last="Haverkamp">Margje H. Haverkamp</name><affiliation><nlm:aff wicri:cut=" and" id="N0x1cbd730N0x37e63e8">Laboratory of Clinical Infectious Diseases, National Institutes of Health</nlm:aff><wicri:noCountry code="subfield">National Institutes of Health</wicri:noCountry></affiliation><affiliation wicri:level="1"><nlm:aff id="aff12">Department of Infectious Diseases, Leiden University Medical Center, 2300 Leiden, Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Infectious Diseases, Leiden University Medical Center, 2300 Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Vinolo, Emilie" sort="Vinolo, Emilie" uniqKey="Vinolo E" first="Emilie" last="Vinolo">Emilie Vinolo</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Enzymatic Regulation of Cellular Activities, URA 2185 Centre National de la Recherche Scientifique (CNRS), Pasteur Institute;</nlm:aff><wicri:noCountry code="subfield">Pasteur Institute</wicri:noCountry></affiliation></author><author><name sortKey="Ku, Cheng Lung" sort="Ku, Cheng Lung" uniqKey="Ku C" first="Cheng-Lung" last="Ku">Cheng-Lung Ku</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation></author><author><name sortKey="Puel, Anne" sort="Puel, Anne" uniqKey="Puel A" first="Anne" last="Puel">Anne Puel</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation></author><author><name sortKey="Frucht, David M" sort="Frucht, David M" uniqKey="Frucht D" first="David M." last="Frucht">David M. Frucht</name><affiliation wicri:level="2"><nlm:aff id="N0x1cbd730N0x37e63e8">Laboratory of Cell Biology, Division of Monoclonal Antibodies, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Laboratory of Cell Biology, Division of Monoclonal Antibodies, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Christel, Karin" sort="Christel, Karin" uniqKey="Christel K" first="Karin" last="Christel">Karin Christel</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation></author><author><name sortKey="Von Bernuth, Horst" sort="Von Bernuth, Horst" uniqKey="Von Bernuth H" first="Horst" last="Von Bernuth">Horst Von Bernuth</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation></author><author><name sortKey="Jouanguy, Emmanuelle" sort="Jouanguy, Emmanuelle" uniqKey="Jouanguy E" first="Emmanuelle" last="Jouanguy">Emmanuelle Jouanguy</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation></author><author><name sortKey="Feinberg, Jacqueline" sort="Feinberg, Jacqueline" uniqKey="Feinberg J" first="Jacqueline" last="Feinberg">Jacqueline Feinberg</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation></author><author><name sortKey="Durandy, Anne" sort="Durandy, Anne" uniqKey="Durandy A" first="Anne" last="Durandy">Anne Durandy</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Normal and Pathologic Development of the Immune System, INSERM U768,</nlm:aff><wicri:noCountry code="subfield">INSERM U768</wicri:noCountry></affiliation></author><author><name sortKey="Senechal, Brigitte" sort="Senechal, Brigitte" uniqKey="Senechal B" first="Brigitte" last="Senechal">Brigitte Senechal</name><affiliation wicri:level="1"><nlm:aff id="N0x1cbd730N0x37e6118">INSERM, Laboratory of Mononuclear Phagocyte Biology, Avenir Team, Necker Enfants Malades Institute, 75015 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM, Laboratory of Mononuclear Phagocyte Biology, Avenir Team, Necker Enfants Malades Institute, 75015 Paris</wicri:regionArea><wicri:noRegion>75015 Paris</wicri:noRegion><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Chapgier, Ariane" sort="Chapgier, Ariane" uniqKey="Chapgier A" first="Ariane" last="Chapgier">Ariane Chapgier</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation></author><author><name sortKey="Vogt, Guillaume" sort="Vogt, Guillaume" uniqKey="Vogt G" first="Guillaume" last="Vogt">Guillaume Vogt</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation></author><author><name sortKey="De Beaucoudrey, Ludovic" sort="De Beaucoudrey, Ludovic" uniqKey="De Beaucoudrey L" first="Ludovic" last="De Beaucoudrey">Ludovic De Beaucoudrey</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation></author><author><name sortKey="Fieschi, Claire" sort="Fieschi, Claire" uniqKey="Fieschi C" first="Claire" last="Fieschi">Claire Fieschi</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation><affiliation wicri:level="1"><nlm:aff id="aff13">Laboratory of Immunology, Saint Louis Hospital, 75010 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Immunology, Saint Louis Hospital, 75010 Paris</wicri:regionArea><wicri:noRegion>75010 Paris</wicri:noRegion><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Picard, Capucine" sort="Picard, Capucine" uniqKey="Picard C" first="Capucine" last="Picard">Capucine Picard</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Center for the Study of Primary Immunodeficiencies,</nlm:aff></affiliation></author><author><name sortKey="Garfa, Meriem" sort="Garfa, Meriem" uniqKey="Garfa M" first="Meriem" last="Garfa">Meriem Garfa</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Confocal Microscopy,</nlm:aff></affiliation></author><author><name sortKey="Chemli, Jalel" sort="Chemli, Jalel" uniqKey="Chemli J" first="Jalel" last="Chemli">Jalel Chemli</name><affiliation wicri:level="1"><nlm:aff id="aff14">Department of Pediatrics, Sahloul Hospital, 4054 Sousse, Tunisia</nlm:aff><country xml:lang="fr">Tunisie</country><wicri:regionArea>Department of Pediatrics, Sahloul Hospital, 4054 Sousse</wicri:regionArea><wicri:noRegion>4054 Sousse</wicri:noRegion></affiliation></author><author><name sortKey="Bejaoui, Mohamed" sort="Bejaoui, Mohamed" uniqKey="Bejaoui M" first="Mohamed" last="Bejaoui">Mohamed Bejaoui</name><affiliation><nlm:aff wicri:cut=" and" id="N0x1cbd730N0x37e6598">National Center for Bone Marrow Transplantation</nlm:aff></affiliation></author><author><name sortKey="Tsolia, Maria N" sort="Tsolia, Maria N" uniqKey="Tsolia M" first="Maria N." last="Tsolia">Maria N. Tsolia</name><affiliation wicri:level="1"><nlm:aff id="aff17">Second Department of Pediatrics, University of Athens School of Medicine, P. and A. Kyriakou Children's Hospital, 115 27 Athens, Greece</nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea>Second Department of Pediatrics, University of Athens School of Medicine, P. and A. Kyriakou Children's Hospital, 115 27 Athens</wicri:regionArea><wicri:noRegion>115 27 Athens</wicri:noRegion></affiliation></author><author><name sortKey="Kutukculer, Necil" sort="Kutukculer, Necil" uniqKey="Kutukculer N" first="Necil" last="Kutukculer">Necil Kutukculer</name><affiliation wicri:level="1"><nlm:aff id="aff18">Department of Pediatrics, Ege University, 35100 Izmir, Turkey</nlm:aff><country xml:lang="fr">Turquie</country><wicri:regionArea>Department of Pediatrics, Ege University, 35100 Izmir</wicri:regionArea><wicri:noRegion>35100 Izmir</wicri:noRegion></affiliation></author><author><name sortKey="Plebani, Alessandro" sort="Plebani, Alessandro" uniqKey="Plebani A" first="Alessandro" last="Plebani">Alessandro Plebani</name><affiliation wicri:level="1"><nlm:aff id="aff19">Department of Pediatrics and Institute for Molecular Medicine Angello Nocivelli, University of Brescia, 25121 Brescia, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Pediatrics and Institute for Molecular Medicine Angello Nocivelli, University of Brescia, 25121 Brescia</wicri:regionArea><wicri:noRegion>25121 Brescia</wicri:noRegion></affiliation></author><author><name sortKey="Notarangelo, Luigi" sort="Notarangelo, Luigi" uniqKey="Notarangelo L" first="Luigi" last="Notarangelo">Luigi Notarangelo</name><affiliation wicri:level="1"><nlm:aff id="aff19">Department of Pediatrics and Institute for Molecular Medicine Angello Nocivelli, University of Brescia, 25121 Brescia, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Pediatrics and Institute for Molecular Medicine Angello Nocivelli, University of Brescia, 25121 Brescia</wicri:regionArea><wicri:noRegion>25121 Brescia</wicri:noRegion></affiliation></author><author><name sortKey="Bodemer, Christine" sort="Bodemer, Christine" uniqKey="Bodemer C" first="Christine" last="Bodemer">Christine Bodemer</name><affiliation><nlm:aff wicri:cut=", and" id="N0x1cbd730N0x37e6118">Dermatology Unit</nlm:aff></affiliation></author><author><name sortKey="Geissmann, Frederic" sort="Geissmann, Frederic" uniqKey="Geissmann F" first="Frédéric" last="Geissmann">Frédéric Geissmann</name><affiliation wicri:level="1"><nlm:aff id="N0x1cbd730N0x37e6118">INSERM, Laboratory of Mononuclear Phagocyte Biology, Avenir Team, Necker Enfants Malades Institute, 75015 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM, Laboratory of Mononuclear Phagocyte Biology, Avenir Team, Necker Enfants Malades Institute, 75015 Paris</wicri:regionArea><wicri:noRegion>75015 Paris</wicri:noRegion><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Israel, Alain" sort="Israel, Alain" uniqKey="Israel A" first="Alain" last="Israël">Alain Israël</name><affiliation><nlm:aff wicri:cut="; and" id="N0x1cbd730N0x37e6118">Laboratory of Molecular Signaling and Cellular Activation, URA 2582 CNRS, Pasteur Institute</nlm:aff><wicri:noCountry code="subfield">Pasteur Institute</wicri:noCountry></affiliation></author><author><name sortKey="Veron, Michel" sort="Veron, Michel" uniqKey="Veron M" first="Michel" last="Véron">Michel Véron</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Enzymatic Regulation of Cellular Activities, URA 2185 Centre National de la Recherche Scientifique (CNRS), Pasteur Institute;</nlm:aff><wicri:noCountry code="subfield">Pasteur Institute</wicri:noCountry></affiliation></author><author><name sortKey="Knackstedt, Maike" sort="Knackstedt, Maike" uniqKey="Knackstedt M" first="Maike" last="Knackstedt">Maike Knackstedt</name><affiliation wicri:level="3"><nlm:aff id="aff20">Department of Pediatric Pulmonology and Immunology, Charité, Campus Virchow Klinikum, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Pediatric Pulmonology and Immunology, Charité, Campus Virchow Klinikum, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Barbouche, Ridha" sort="Barbouche, Ridha" uniqKey="Barbouche R" first="Ridha" last="Barbouche">Ridha Barbouche</name><affiliation wicri:level="1"><nlm:aff id="N0x1cbd730N0x37e6598">Department of Immunology, Pasteur Institute, 1002 Tunis, Tunisia</nlm:aff><country xml:lang="fr">Tunisie</country><wicri:regionArea>Department of Immunology, Pasteur Institute, 1002 Tunis</wicri:regionArea><placeName><settlement type="city">Tunis</settlement><region nuts="2">Gouvernorat de Tunis</region></placeName></affiliation></author><author><name sortKey="Abel, Laurent" sort="Abel, Laurent" uniqKey="Abel L" first="Laurent" last="Abel">Laurent Abel</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation></author><author><name sortKey="Magdorf, Klaus" sort="Magdorf, Klaus" uniqKey="Magdorf K" first="Klaus" last="Magdorf">Klaus Magdorf</name><affiliation wicri:level="3"><nlm:aff id="aff20">Department of Pediatric Pulmonology and Immunology, Charité, Campus Virchow Klinikum, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Pediatric Pulmonology and Immunology, Charité, Campus Virchow Klinikum, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Gendrel, Dominique" sort="Gendrel, Dominique" uniqKey="Gendrel D" first="Dominique" last="Gendrel">Dominique Gendrel</name><affiliation wicri:level="1"><nlm:aff id="aff21">Department of Pediatrics, St. Vincent de Paul Hospital, 75014 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Department of Pediatrics, St. Vincent de Paul Hospital, 75014 Paris</wicri:regionArea><wicri:noRegion>75014 Paris</wicri:noRegion><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Agou, Fabrice" sort="Agou, Fabrice" uniqKey="Agou F" first="Fabrice" last="Agou">Fabrice Agou</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Enzymatic Regulation of Cellular Activities, URA 2185 Centre National de la Recherche Scientifique (CNRS), Pasteur Institute;</nlm:aff><wicri:noCountry code="subfield">Pasteur Institute</wicri:noCountry></affiliation></author><author><name sortKey="Holland, Steven M" sort="Holland, Steven M" uniqKey="Holland S" first="Steven M." last="Holland">Steven M. Holland</name><affiliation><nlm:aff wicri:cut=" and" id="N0x1cbd730N0x37e63e8">Laboratory of Clinical Infectious Diseases, National Institutes of Health</nlm:aff><wicri:noCountry code="subfield">National Institutes of Health</wicri:noCountry></affiliation></author><author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School;</nlm:aff><wicri:noCountry code="subfield">Necker Medical School</wicri:noCountry></affiliation><affiliation><nlm:aff id="N0x1cbd730N0x37e6118">Pediatric Hematology-Immunology Unit, Necker Hospital;</nlm:aff><wicri:noCountry code="subfield">Necker Hospital</wicri:noCountry></affiliation></author></analytic><series><title level="j">The Journal of Experimental Medicine</title><idno type="ISSN">0022-1007</idno><idno type="eISSN">1540-9538</idno><imprint><date when="2006">2006</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Germline mutations in five autosomal genes involved in interleukin (IL)-12–dependent, interferon (IFN)-γ–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-κB 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-γ secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-κB/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-κB activators, such as tumor necrosis factor-α, IL-1β, 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-κB/c-Rel–mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Allemagne</li><li>France</li><li>Grèce</li><li>Italie</li><li>Pays-Bas</li><li>Tunisie</li><li>Turquie</li><li>États-Unis</li></country><region><li>Berlin</li><li>Gouvernorat de Tunis</li><li>Hollande-Méridionale</li><li>Maryland</li><li>Île-de-France</li></region><settlement><li>Berlin</li><li>Leyde</li><li>Paris</li><li>Tunis</li></settlement></list><tree><noCountry><name sortKey="Abel, Laurent" sort="Abel, Laurent" uniqKey="Abel L" first="Laurent" last="Abel">Laurent Abel</name><name sortKey="Agou, Fabrice" sort="Agou, Fabrice" uniqKey="Agou F" first="Fabrice" last="Agou">Fabrice Agou</name><name sortKey="Bejaoui, Mohamed" sort="Bejaoui, Mohamed" uniqKey="Bejaoui M" first="Mohamed" last="Bejaoui">Mohamed Bejaoui</name><name sortKey="Bodemer, Christine" sort="Bodemer, Christine" uniqKey="Bodemer C" first="Christine" last="Bodemer">Christine Bodemer</name><name sortKey="Bustamante, Jacinta" sort="Bustamante, Jacinta" uniqKey="Bustamante J" first="Jacinta" last="Bustamante">Jacinta Bustamante</name><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name><name sortKey="Chapgier, Ariane" sort="Chapgier, Ariane" uniqKey="Chapgier A" first="Ariane" last="Chapgier">Ariane Chapgier</name><name sortKey="Christel, Karin" sort="Christel, Karin" uniqKey="Christel K" first="Karin" last="Christel">Karin Christel</name><name sortKey="De Beaucoudrey, Ludovic" sort="De Beaucoudrey, Ludovic" uniqKey="De Beaucoudrey L" first="Ludovic" last="De Beaucoudrey">Ludovic De Beaucoudrey</name><name sortKey="Durandy, Anne" sort="Durandy, Anne" uniqKey="Durandy A" first="Anne" last="Durandy">Anne Durandy</name><name sortKey="Feinberg, Jacqueline" sort="Feinberg, Jacqueline" uniqKey="Feinberg J" first="Jacqueline" last="Feinberg">Jacqueline Feinberg</name><name sortKey="Filipe Santos, Orchidee" sort="Filipe Santos, Orchidee" uniqKey="Filipe Santos O" first="Orchidée" last="Filipe-Santos">Orchidée Filipe-Santos</name><name sortKey="Garfa, Meriem" sort="Garfa, Meriem" uniqKey="Garfa M" first="Meriem" last="Garfa">Meriem Garfa</name><name sortKey="Holland, Steven M" sort="Holland, Steven M" uniqKey="Holland S" first="Steven M." last="Holland">Steven M. Holland</name><name sortKey="Israel, Alain" sort="Israel, Alain" uniqKey="Israel A" first="Alain" last="Israël">Alain Israël</name><name sortKey="Jouanguy, Emmanuelle" sort="Jouanguy, Emmanuelle" uniqKey="Jouanguy E" first="Emmanuelle" last="Jouanguy">Emmanuelle Jouanguy</name><name sortKey="Ku, Cheng Lung" sort="Ku, Cheng Lung" uniqKey="Ku C" first="Cheng-Lung" last="Ku">Cheng-Lung Ku</name><name sortKey="Picard, Capucine" sort="Picard, Capucine" uniqKey="Picard C" first="Capucine" last="Picard">Capucine Picard</name><name sortKey="Puel, Anne" sort="Puel, Anne" uniqKey="Puel A" first="Anne" last="Puel">Anne Puel</name><name sortKey="Veron, Michel" sort="Veron, Michel" uniqKey="Veron M" first="Michel" last="Véron">Michel Véron</name><name sortKey="Vinolo, Emilie" sort="Vinolo, Emilie" uniqKey="Vinolo E" first="Emilie" last="Vinolo">Emilie Vinolo</name><name sortKey="Vogt, Guillaume" sort="Vogt, Guillaume" uniqKey="Vogt G" first="Guillaume" last="Vogt">Guillaume Vogt</name><name sortKey="Von Bernuth, Horst" sort="Von Bernuth, Horst" uniqKey="Von Bernuth H" first="Horst" last="Von Bernuth">Horst Von Bernuth</name></noCountry><country name="Pays-Bas"><region name="Hollande-Méridionale"><name sortKey="Haverkamp, Margje H" sort="Haverkamp, Margje H" uniqKey="Haverkamp M" first="Margje H." last="Haverkamp">Margje H. Haverkamp</name></region></country><country name="États-Unis"><region name="Maryland"><name sortKey="Frucht, David M" sort="Frucht, David M" uniqKey="Frucht D" first="David M." last="Frucht">David M. Frucht</name></region></country><country name="France"><region name="Île-de-France"><name sortKey="Senechal, Brigitte" sort="Senechal, Brigitte" uniqKey="Senechal B" first="Brigitte" last="Senechal">Brigitte Senechal</name></region><name sortKey="Fieschi, Claire" sort="Fieschi, Claire" uniqKey="Fieschi C" first="Claire" last="Fieschi">Claire Fieschi</name><name sortKey="Geissmann, Frederic" sort="Geissmann, Frederic" uniqKey="Geissmann F" first="Frédéric" last="Geissmann">Frédéric Geissmann</name><name sortKey="Gendrel, Dominique" sort="Gendrel, Dominique" uniqKey="Gendrel D" first="Dominique" last="Gendrel">Dominique Gendrel</name></country><country name="Tunisie"><noRegion><name sortKey="Chemli, Jalel" sort="Chemli, Jalel" uniqKey="Chemli J" first="Jalel" last="Chemli">Jalel Chemli</name></noRegion><name sortKey="Barbouche, Ridha" sort="Barbouche, Ridha" uniqKey="Barbouche R" first="Ridha" last="Barbouche">Ridha Barbouche</name></country><country name="Grèce"><noRegion><name sortKey="Tsolia, Maria N" sort="Tsolia, Maria N" uniqKey="Tsolia M" first="Maria N." last="Tsolia">Maria N. Tsolia</name></noRegion></country><country name="Turquie"><noRegion><name sortKey="Kutukculer, Necil" sort="Kutukculer, Necil" uniqKey="Kutukculer N" first="Necil" last="Kutukculer">Necil Kutukculer</name></noRegion></country><country name="Italie"><noRegion><name sortKey="Plebani, Alessandro" sort="Plebani, Alessandro" uniqKey="Plebani A" first="Alessandro" last="Plebani">Alessandro Plebani</name></noRegion><name sortKey="Notarangelo, Luigi" sort="Notarangelo, Luigi" uniqKey="Notarangelo L" first="Luigi" last="Notarangelo">Luigi Notarangelo</name></country><country name="Allemagne"><region name="Berlin"><name sortKey="Knackstedt, Maike" sort="Knackstedt, Maike" uniqKey="Knackstedt M" first="Maike" last="Knackstedt">Maike Knackstedt</name></region><name sortKey="Magdorf, Klaus" sort="Magdorf, Klaus" uniqKey="Magdorf K" first="Klaus" last="Magdorf">Klaus Magdorf</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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