title: Transplantation from a symptomatic carrier sister restores host defenses but does not prevent colitis in NEMO deficiency.
abstract: NF-κB essential modulator (NEMO) deficiency causes ectodermal dysplasia with immunodeficiency in males, while manifesting as incontinentia pigmenti in heterozygous females. We report a family with NEMO deficiency, in which a female carrier displayed skewed X-inactivation favoring the mutant NEMO allele associated with symptoms of Behçet's disease. Hematopoietic stem cell transplantation of an affected boy from this donor reconstituted an immune system with retained skewed X-inactivation. After transplantation no more severe infections occurred, indicating that an active wild-type NEMO allele in only 10% of immune cells restores host defense. Yet he developed inflammatory bowel disease (IBD). While gut infiltrating immune cells stained strongly for nuclear p65 indicating restored NEMO function, this was not the case in intestinal epithelial cells - in contrast to cells from conventional IBD patients. These results extend murine observations that epithelial NEMO-deficiency suffices to cause IBD. High anti-TNF doses controlled the intestinal inflammation and symptoms of Behçet's disease.
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Klemann
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Ulm, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pannicke
authors.affiliation: Department of Clinical Genetics and Genomics, Royal Brompton and Harefield NHS Foundation Trust, Imperial College London, UK.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Morris-Rosendahl
authors.affiliation: CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Katerina
authors.initials: K
authors.lastname: Vlantis
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center Freiburg, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Rizzi
authors.affiliation: Department of Pediatrics, and Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Holm
authors.initials: H
authors.lastname: Uhlig
authors.affiliation: Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vraetz
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Speckmann
authors.affiliation: Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Strahm
authors.affiliation: CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center Freiburg, Germany; Institute for Transfusion Medicine, University of Ulm, Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Ulm, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Germany. Electronic address: jan.rohr@uniklinik-freiburg.de.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Rohr
mesh_terms: D000483:Alleles; D001528:Behcet Syndrome / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D008297:Male; D035781:Siblings
chemical_list: C491731:IKBKG protein, human; D051550:I-kappa B Kinase
keywords: Anti-TNF treatment; Behçet's disease; HSCT; IBD; IKBKG; NEMO deficiency; Skewed X-inactivation
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