title: Defective lymphoid organogenesis underlies the immune deficiency caused by a heterozygous S32I mutation in IκBα.
abstract: Patients with ectodermal dysplasia with immunodeficiency (ED-ID) caused by mutations in the inhibitor of NF-κB α (IκBα) are susceptible to severe recurrent infections, despite normal T and B cell numbers and intact in vitro lymphocyte function. Moreover, the outcome of hematopoietic stem cell transplantation (HSCT) in these patients is poor despite good engraftment. Mice heterozygous for the IκBα S32I mutation found in patients exhibited typical features of ED-ID. Strikingly, the mice lacked lymph nodes, Peyer's patches, splenic marginal zones, and follicular dendritic cells and failed to develop contact hypersensitivity (CHS) or form germinal centers (GCs), all features not previously recognized in patients and typical of defective noncanonical NF-κB signaling. Lymphotoxin β receptor (LTβR)-driven induction of chemokines and adhesion molecules mediated by both canonical and noncanonical NF-κB pathways was impaired, and levels of p100 were markedly diminished in the mutant. IκBα mutant → Rag2(-/-), but not WT→IκBα mutant, bone marrow chimeras formed proper lymphoid organs and developed CHS and GCs. Defective architectural cell function explains the immunodeficiency and poor outcome of HSCT in patients with IκBα deficiency and suggests that correction of this niche is critical for reconstituting their immune function.
authors.affiliation: Division of Allergy and Immunology and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115 Department of Pediatrics, Division of Transfusion Medicine, and Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Jana L
authors.initials: JL
authors.lastname: Mooster
authors.affiliation: Division of Allergy and Immunology and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115 Department of Pediatrics, Division of Transfusion Medicine, and Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Severine
authors.initials: S
authors.lastname: Le Bras
authors.affiliation: Division of Allergy and Immunology and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115 Department of Pediatrics, Division of Transfusion Medicine, and Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Massaad
authors.affiliation: Division of Allergy and Immunology and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115 Department of Pediatrics, Division of Transfusion Medicine, and Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Haifa
authors.initials: H
authors.lastname: Jabara
authors.affiliation: Division of Allergy and Immunology and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115 Department of Pediatrics, Division of Transfusion Medicine, and Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Juhan
authors.initials: J
authors.lastname: Yoon
authors.affiliation: Division of Allergy and Immunology and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115 Department of Pediatrics, Division of Transfusion Medicine, and Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Claire
authors.initials: C
authors.lastname: Galand
authors.affiliation: Division of Allergy and Immunology and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115 Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
authors.forename: Balthasar A
authors.initials: BA
authors.lastname: Heesters
authors.affiliation: Division of Allergy and Immunology and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115 Department of Pediatrics, Division of Transfusion Medicine, and Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Burton
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Hamid
authors.initials: H
authors.lastname: Mattoo
authors.affiliation: Department of Pediatrics, Division of Transfusion Medicine, and Department of Pathology, Harvard Medical School, Boston, MA 02115 Department of Pediatrics, Division of Transfusion Medicine, and Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: John
authors.initials: J
authors.lastname: Manis
authors.affiliation: Division of Allergy and Immunology and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115 Department of Pediatrics, Division of Transfusion Medicine, and Department of Pathology, Harvard Medical School, Boston, MA 02115 Raif.Geha@childrens.harvard.edu.
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003062:Codon; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006579:Heterozygote; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics* / Q000378:metabolism; D007153:Immunologic Deficiency Syndromes / Q000209:etiology; D008221:Lymphoid Tissue / Q000196:embryology* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D038081:Organogenesis / Q000235:genetics* / Q000276:immunology*; D010766:Phosphorylation; D059748:Proteolysis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D003062:Codon; D020672:I-kappa B Proteins; C000606205:Nfkbia protein, mouse; D051193:Toll-Like Receptors; D048069:Tumor Necrosis Factors; D000072000:NF-KappaB Inhibitor alpha