Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers

Claire Aguilar; Christelle Lenoir; Nathalie Lambert; Bernadette Bègue; Nicole Brousse; Danielle Canioni; Dominique Berrebi; Maryline Roy; Stéphane Gérart; Helen Chapel; Tobias Schwerd; Laurent Siproudhis; Michela Schäppi; Ali Al-Ahmari; Masaaki Mori; Akiko Yamaide; Lionel Galicier; Bénédicte Neven; John Routes; Holm H Uhlig; Sibylle Koletzko; Smita Patel; Hirokazu Kanegane; Capucine Picard; Alain Fischer; Nadine Cerf Bensussan; Frank Ruemmele; Jean-Pierre Hugot; Sylvain Latour

doi:10.1016/j.jaci.2014.04.031

Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers

J Allergy Clin Immunol. 2014 Nov;134(5):1131-41.e9. doi: 10.1016/j.jaci.2014.04.031. Epub 2014 Jun 15.

Authors

Claire Aguilar¹, Christelle Lenoir¹, Nathalie Lambert², Bernadette Bègue³, Nicole Brousse⁴, Danielle Canioni⁴, Dominique Berrebi⁵, Maryline Roy⁶, Stéphane Gérart¹, Helen Chapel⁷, Tobias Schwerd⁸, Laurent Siproudhis⁹, Michela Schäppi¹⁰, Ali Al-Ahmari¹¹, Masaaki Mori¹², Akiko Yamaide¹³, Lionel Galicier¹⁴, Bénédicte Neven¹⁵, John Routes¹⁶, Holm H Uhlig¹⁷, Sibylle Koletzko⁸, Smita Patel⁷, Hirokazu Kanegane¹⁸, Capucine Picard¹⁹, Alain Fischer²⁰, Nadine Cerf Bensussan³, Frank Ruemmele²¹, Jean-Pierre Hugot²², Sylvain Latour²³

Affiliations

¹ 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.
² Study Center for Primary Immunodeficiencies (CEDI), Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
³ 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.
⁴ Pathology Department, Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
⁵ Pathology Department, Hospital Robert Debré, APHP, Paris, France; INSERM UMR 843, Hospital Bichat, Paris, France; University Paris-Diderot, Sorbonne Paris Cité, Paris, France.
⁶ INSERM UMR 843, Hospital Bichat, Paris, France; University Paris-Diderot, Sorbonne Paris Cité, Paris, France.
⁷ Primary Immunodeficiency Unit, Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
⁸ University of Munich Medical Center, Dr von Hauner Children's Hospital, Munich, Germany.
⁹ Department of Hepato-Gastroenterology, University Hospital of Rennes, Rennes, France.
¹⁰ Pediatrics Center, Clinique des Grangettes and Medical University Center, Geneva, Switzerland.
¹¹ Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital & Research Center, Alfaisal University, Riyadh, Saudi Arabia.
¹² Department of Pediatrics, City University Medical Center, Yokohama, Japan.
¹³ Division of Allergy and Rheumatology, Chiba Children's Hospital, Chiba, Japan.
¹⁴ Department of Clinical Immunology, Hospital Saint-Louis, APHP, Paris, France.
¹⁵ Department of Immunology and Haematology, Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
¹⁶ Division of Allergy and Clinical Immunology, Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wis.
¹⁷ Translational Gastroenterology Unit and Children's Hospital, University of Oxford, Oxford, United Kingdom.
¹⁸ Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
¹⁹ 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.
²⁰ 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.
²¹ 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.
²² INSERM UMR 843, Hospital Bichat, Paris, France; University Paris-Diderot, Sorbonne Paris Cité, Paris, France; Pediatric Gastroenterology Unit, Hospital Robert Debré, APHP, Paris, France.
²³ 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.

PMID: 24942515
DOI: 10.1016/j.jaci.2014.04.031

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.

Conclusion: 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.

Keywords: Crohn disease; Inflammatory bowel disease; NOD receptors; X-linked inhibitor of apoptosis immunodeficiency; monocytes.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Age of Onset
Child
Child, Preschool
Chromosomes, Human, X* / genetics
Chromosomes, Human, X* / metabolism
Cohort Studies
Crohn Disease* / blood
Crohn Disease* / genetics
Crohn Disease* / pathology
Cytokines / blood
Cytokines / genetics
Female
Genetic Diseases, X-Linked* / blood
Genetic Diseases, X-Linked* / genetics
Genetic Diseases, X-Linked* / pathology
Hemizygote*
Heterozygote*
Humans
Infant
Lymphoproliferative Disorders* / blood
Lymphoproliferative Disorders* / genetics
Lymphoproliferative Disorders* / pathology
Male
Nod2 Signaling Adaptor Protein / genetics
Nod2 Signaling Adaptor Protein / metabolism
X-Linked Inhibitor of Apoptosis Protein / genetics*

Substances

Cytokines
NOD2 protein, human
Nod2 Signaling Adaptor Protein
X-Linked Inhibitor of Apoptosis Protein
XIAP protein, human

Supplementary concepts

Lymphoproliferative Syndrome, X-Linked, 2