title: Dedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells.
abstract: BACKGROUND
  Dedicator of cytokinesis 8 (DOCK8) deficiency is typified by recurrent infections, increased serum IgE levels, eosinophilia, and a high incidence of allergic and autoimmune manifestations.
  
  
  OBJECTIVE
  We sought to determine the role of DOCK8 in the establishment and maintenance of human B-cell tolerance.
  
  
  METHODS
  Autoantibodies were measured in the plasma of DOCK8-deficient patients. The antibody-coding genes from new emigrant/transitional and mature naive B cells were cloned and assessed for their ability to bind self-antigens. Regulatory T (Treg) cells in the blood were analyzed by means of flow cytometry, and their function was tested by examining their capacity to inhibit the proliferation of CD4(+)CD25(-) effector T cells.
  
  
  RESULTS
  DOCK8-deficient patients had increased levels of autoantibodies in their plasma. We determined that central B-cell tolerance did not require DOCK8, as evidenced by the normally low frequency of polyreactive new emigrant/transitional B cells in DOCK8-deficient patients. In contrast, autoreactive B cells were enriched in the mature naive B-cell compartment, revealing a defective peripheral B-cell tolerance checkpoint. In addition, we found that Treg cells were decreased and exhibited impaired suppressive activity in DOCK8-deficient patients.
  
  
  CONCLUSIONS
  Our data support a critical role for DOCK8 in Treg cell homeostasis and function and the enforcement of peripheral B-cell tolerance.
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Erin
authors.initials: E
authors.lastname: Janssen
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn.
authors.forename: Henner
authors.initials: H
authors.lastname: Morbach
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Mass.
authors.forename: Sumana
authors.initials: S
authors.lastname: Ullas
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Bannock
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn.
authors.forename: Christopher
authors.initials: C
authors.lastname: Massad
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn.
authors.forename: Laurence
authors.initials: L
authors.lastname: Menard
authors.affiliation: Marmara University, Istanbul, Turkey.
authors.forename: Isil
authors.initials: I
authors.lastname: Barlan
authors.affiliation: IMGT, University Montpellier, and CNRS Institute of Human Genetics, Montpellier, France.
authors.forename: Gerard
authors.initials: G
authors.lastname: Lefranc
authors.affiliation: Human Immunological Diseases Unit, National Institutes of Health, Bethesda, Md.
authors.forename: Helen
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Pediatrics and Department of Internal Medicine, Division of Genetics, Endocrinology & Metabolism, University of Kansas Medical Center, Kansas City, Kan.
authors.forename: Majed
authors.initials: M
authors.lastname: Dasouki
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Mass; Division of Pediatric Immunology and Allergy, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey.
authors.forename: Sevgi
authors.initials: S
authors.lastname: Keles
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Talal
authors.initials: T
authors.lastname: Chatila
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass. Electronic address: raif.geha@childrens.harvard.edu.
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn. Electronic address: eric.meffre@yale.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000276:immunology*; D007223:Infant; D018655:Lymphocyte Count; D008297:Male; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D001323:Autoantibodies; C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors
keywords: B-cell tolerance; Dedicator of cytokinesis 8; autoimmunity; regulatory T cells