title: β2-Microglobulin deficiency causes a complex immunodeficiency of the innate and adaptive immune system.
abstract: BACKGROUND
  Most patients with MHC class I (MHC-I) deficiency carry genetic defects in transporter associated with antigen processing 1 (TAP1) or TAP2. The clinical presentation can vary, and about half of the patients have severe skin disease. Previously, one report described β2-microglobulin (β2m) deficiency as another monogenetic cause of MHC-I deficiency, but no further immunologic evaluation was performed.
  
  
  OBJECTIVE
  We sought to describe the molecular and immunologic features of β2m deficiency in 2 Turkish siblings with new diagnoses.
  
  
  METHODS
  Based on clinical and serologic findings, the genetic defect was detected by means of candidate gene analysis. The immunologic characterization comprises flow cytometry, ELISA, functional assays, and immunohistochemistry.
  
  
  RESULTS
  Here we provide the first extensive clinical and immunologic description of β2m deficiency in 2 siblings. The sister had recurrent respiratory tract infections and severe skin disease, whereas the brother was fairly asymptomatic but had bronchiectasis. Not only polymorphic MHC-I but also the related CD1a, CD1b, CD1c, and neonatal Fc receptor molecules were absent from the surfaces of β2m-deficient cells. Absent neonatal Fc receptor surface expression led to low serum IgG and albumin levels in both siblings, whereas the heterozygous parents had normal results for all tested parameters except β2m mRNA (B2M) expression. Similar to TAP deficiency in the absence of a regular CD8 T-cell compartment, CD8(+) γδ T cells were strongly expanded. Natural killer cells were normal in number but not "licensed to kill."
  
  
  CONCLUSIONS
  The clinical presentation of patients with β2m deficiency resembles that of patients with other forms of MHC-I deficiency, but because of the missing stabilizing effect of β2m on other members of the MHC-I family, the immunologic defect is more extensive than in patients with TAP deficiency.
authors.affiliation: Internal Medicine Division of Allergy and Clinical Immunology, Ege University Medical Faculty, İzmir, Turkey. Electronic address: tanmehomu@yahoo.com.
authors.forename: Ömür
authors.initials: Ö
authors.lastname: Ardeniz
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Unger
authors.affiliation: Department of Medical Genetics, Ege University Medical Faculty, İzmir, Turkey.
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Onay
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ammann
authors.affiliation: Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Keck
authors.affiliation: Grigore T. Popa University of Medicine and Pharmacy, Department of Immunology, Iasi, Romania.
authors.forename: Corina
authors.initials: C
authors.lastname: Cianga
authors.affiliation: Department of Dermatology, Ege University Medical Faculty, İzmir, Turkey.
authors.forename: Bengü
authors.initials: B
authors.lastname: Gerçeker
authors.affiliation: Department of Internal Medicine II, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Martin
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Fuchs
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Salzer
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey.
authors.forename: Aydan
authors.initials: A
authors.lastname: İkincioğulları
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey.
authors.forename: Deniz
authors.initials: D
authors.lastname: Güloğlu
authors.affiliation: Department of Dermatology, Ege University Medical Faculty, İzmir, Turkey.
authors.forename: Tuğrul
authors.initials: T
authors.lastname: Dereli
authors.affiliation: Department of Internal Medicine II, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, and the Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Baden-Württemberg-Hessen, Ulm, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.affiliation: Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Schmitt-Graeff
authors.affiliation: Grigore T. Popa University of Medicine and Pharmacy, Department of Immunology, Iasi, Romania.
authors.forename: Petru
authors.initials: P
authors.lastname: Cianga
authors.affiliation: Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Fisch
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
mesh_terms: D056704:Adaptive Immunity; D000293:Adolescent; D000328:Adult; D018949:Antigens, CD1 / Q000235:genetics / Q000276:immunology; D001987:Bronchiectasis / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D003241:Consanguinity; D005260:Female; D017353:Gene Deletion; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000097:blood / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008297:Male; D010375:Pedigree; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D011961:Receptors, Fc / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D012008:Recurrence; D012141:Respiratory Tract Infections / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D035781:Siblings; D012883:Skin Ulcer / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D018949:Antigens, CD1; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D020033:Protein Isoforms; D011961:Receptors, Fc; D001613:beta 2-Microglobulin
keywords: CD1; CD8 T cells; MHC class I; human; hypogammaglobulinemia; neonatal Fc receptor; β(2)-Microglobulin deficiency; γδ T cells