title: Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers.
abstract: BACKGROUND
  Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients.
  
  
  OBJECTIVE
  We characterize the IBD affecting a large cohort of patients with mutations in XIAP and examine the possible pathophysiologic mechanisms.
  
  
  METHODS
  We performed a phenotypical and histologic analysis of the IBD affecting 17 patients with hemizygous mutations in XIAP, including 3 patients identified by screening 83 patients with pediatric-onset IBD. The X chromosome inactivation was analyzed in female carriers of heterozygous XIAP mutations, including 2 adults with IBD. The functional consequences of XIAP deficiency were analyzed.
  
  
  RESULTS
  Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease. The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat. In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis. Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte chemoattractant protein 1 (MCP-1) production, as well as IL-10, in response to NOD2 and Toll-like receptor 2/4 costimulation. Nucleotide binding and oligomerization domain containing 1 (NOD1)-mediated IL-6 and IL-8 production was defective in fibroblasts from XIAP-deficient patients. The 2 heterozygous female carriers of XIAP mutations with IBD displayed abnormal expression of the XIAP mutated allele, resulting in impaired activation of the NOD2 pathway.
  
  
  CONCLUSIONS
  IBD in patients with XIAP deficiency is similar to Crohn disease and is associated with defective NOD2 function in monocytes. Importantly, we report that it is not restricted to male patients because we identified 2 symptomatic female heterozygous carriers of XIAP mutations.
authors.affiliation: Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Aguilar
authors.affiliation: Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Lenoir
authors.affiliation: Study Center for Primary Immunodeficiencies (CEDI), Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lambert
authors.affiliation: University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Laboratory of Interactions of the Intestinal Epithelium and the Immune System, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Bègue
authors.affiliation: Pathology Department, Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Brousse
authors.affiliation: Pathology Department, Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
authors.forename: Danielle
authors.initials: D
authors.lastname: Canioni
authors.affiliation: Pathology Department, Hospital Robert Debré, APHP, Paris, France; INSERM UMR 843, Hospital Bichat, Paris, France; University Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Berrebi
authors.affiliation: INSERM UMR 843, Hospital Bichat, Paris, France; University Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Roy
authors.affiliation: Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gérart
authors.affiliation: Primary Immunodeficiency Unit, Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Chapel
authors.affiliation: University of Munich Medical Center, Dr von Hauner Children's Hospital, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schwerd
authors.affiliation: Department of Hepato-Gastroenterology, University Hospital of Rennes, Rennes, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Siproudhis
authors.affiliation: Pediatrics Center, Clinique des Grangettes and Medical University Center, Geneva, Switzerland.
authors.forename: Michela
authors.initials: M
authors.lastname: Schäppi
authors.affiliation: Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital & Research Center, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Ali
authors.initials: A
authors.lastname: Al-Ahmari
authors.affiliation: Department of Pediatrics, City University Medical Center, Yokohama, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Division of Allergy and Rheumatology, Chiba Children's Hospital, Chiba, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamaide
authors.affiliation: Department of Clinical Immunology, Hospital Saint-Louis, APHP, Paris, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Galicier
authors.affiliation: Department of Immunology and Haematology, Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Neven
authors.affiliation: Division of Allergy and Clinical Immunology, Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wis.
authors.forename: John
authors.initials: J
authors.lastname: Routes
authors.affiliation: Translational Gastroenterology Unit and Children's Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Holm H
authors.initials: HH
authors.lastname: Uhlig
authors.affiliation: University of Munich Medical Center, Dr von Hauner Children's Hospital, Munich, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Koletzko
authors.affiliation: Primary Immunodeficiency Unit, Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Smita
authors.initials: S
authors.lastname: Patel
authors.affiliation: Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kanegane
authors.affiliation: Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Study Center for Primary Immunodeficiencies (CEDI), Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France; Laboratory of Human Genetics of Infectious Diseases, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Department of Immunology and Haematology, Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Laboratory of Interactions of the Intestinal Epithelium and the Immune System, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France.
authors.forename: Nadine Cerf
authors.initials: NC
authors.lastname: Bensussan
authors.affiliation: University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Laboratory of Interactions of the Intestinal Epithelium and the Immune System, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France; Pediatric Gastroenterology Unit, Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Ruemmele
authors.affiliation: INSERM UMR 843, Hospital Bichat, Paris, France; University Paris-Diderot, Sorbonne Paris Cité, Paris, France; Pediatric Gastroenterology Unit, Hospital Robert Debré, APHP, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hugot
authors.affiliation: Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France. Electronic address: sylvain.latour@inserm.fr.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D003424:Crohn Disease / Q000097:blood / Q000235:genetics / Q000473:pathology; D016207:Cytokines / Q000097:blood / Q000235:genetics; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000097:blood / Q000235:genetics / Q000473:pathology; D057898:Hemizygote; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008232:Lymphoproliferative Disorders / Q000097:blood / Q000235:genetics / Q000473:pathology; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics*
chemical_list: D016207:Cytokines; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human
keywords: Crohn disease; Inflammatory bowel disease; NOD receptors; X-linked inhibitor of apoptosis immunodeficiency; monocytes