title: Deficiency of innate and acquired immunity caused by an IKBKB mutation.
abstract: BACKGROUND
  Severe combined immunodeficiency (SCID) comprises a heterogeneous group of heritable deficiencies of humoral and cell-mediated immunity. Many patients with SCID have lymphocyte-activation defects that remain uncharacterized.
  
  
  METHODS
  We performed genetic studies in four patients, from four families of Northern Cree ancestry, who had clinical characteristics of SCID, including early onset of severe viral, bacterial, and fungal infections despite normal B-cell and T-cell counts. Genomewide homozygosity mapping was used to identify a candidate region, which was found on chromosome 8; all genes within this interval were sequenced. Immune-cell populations, signal transduction on activation, and effector functions were studied.
  
  
  RESULTS
  The patients had hypogammaglobulinemia or agammaglobulinemia, and their peripheral-blood B cells and T cells were almost exclusively of naive phenotype. Regulatory T cells and γδ T cells were absent. All patients carried a homozygous duplication--c.1292dupG in exon 13 of IKBKB, which encodes IκB kinase 2 (IKK2, also known as IKKβ)--leading to loss of expression of IKK2, a component of the IKK-nuclear factor κB (NF-κB) pathway. Immune cells from the patients had impaired responses to stimulation through T-cell receptors, B-cell receptors, toll-like receptors, inflammatory cytokine receptors, and mitogens.
  
  
  CONCLUSIONS
  A form of human SCID is characterized by normal lymphocyte development despite a loss of IKK2 function. IKK2 deficiency results in an impaired response to activation stimuli in a variety of immune cells, leading to clinically relevant impairment of adaptive and innate immunity. Although Ikk2 deficiency is lethal in mouse embryos, our observations suggest a more restricted, unique role of IKK2-NF-κB signaling in humans. (Funded by the German Federal Ministry of Education and Research and others.).
authors.affiliation: From the Institute for Transfusion Medicine, University Hospital Ulm (U.P., C.L., H.S., K.S.), the Institute of Physiological Chemistry (B.B., T.W.), the Center for Biomedical Research, Genomics Core Facility (K. Holzmann), University of Ulm, and the Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg-Hessen (E.-M.R., H.S., K.S.), Ulm; the Center of Chronic Immunodeficiency, University Medical Center Freiburg (S.F., P.H., A.R.-E., K. Hese, M.R., A.J., M.S., S.E.), the Faculty of Biology, University of Freiburg (S.F.), the Center for Pediatrics and Adolescent Medicine (P.H., S.E.), and the Department of Rheumatology and Clinical Immunology (M.S.), University Hospital Freiburg, Freiburg; and the Translational Center for Regenerative Medicine, University of Leipzig, Leipzig (S.B.) - all in Germany; the Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm (S.B.); and the Department of Pediatrics, University of Saskatchewan, Saskatoon (A.R.), and the Departments of Biochemistry and Medical Genetics (T.Z.) and Pediatrics and Child Health (T.Z., M.L.S.), University of Manitoba, Winnipeg - both in Canada.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pannicke
authors.forename: Bernd
authors.initials: B
authors.lastname: Baumann
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fuchs
authors.forename: Philipp
authors.initials: P
authors.lastname: Henneke
authors.forename: Anne
authors.initials: A
authors.lastname: Rensing-Ehl
authors.forename: Marta
authors.initials: M
authors.lastname: Rizzi
authors.forename: Ales
authors.initials: A
authors.lastname: Janda
authors.forename: Katrin
authors.initials: K
authors.lastname: Hese
authors.forename: Michael
authors.initials: M
authors.lastname: Schlesier
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Holzmann
authors.forename: Stephan
authors.initials: S
authors.lastname: Borte
authors.forename: Constanze
authors.initials: C
authors.lastname: Laux
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Rump
authors.forename: Alan
authors.initials: A
authors.lastname: Rosenberg
authors.forename: Teresa
authors.initials: T
authors.lastname: Zelinski
authors.forename: Hubert
authors.initials: H
authors.lastname: Schrezenmeier
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
authors.forename: Marlis L
authors.initials: ML
authors.lastname: Schroeder
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000361:Agammaglobulinemia / Q000235:genetics*; D001402:B-Lymphocytes / Q000502:physiology; D017809:Fatal Outcome; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics*; D007113:Immunity, Innate / Q000235:genetics; D007198:Indians, North American; D007223:Infant; D007231:Infant, Newborn; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA; D016511:Severe Combined Immunodeficiency / Q000235:genetics*; D013601:T-Lymphocytes / Q000502:physiology
chemical_list: D051550:I-kappa B Kinase