title: Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA.
abstract: BACKGROUND
  A number of heritable immune dysregulatory diseases result from defects affecting regulatory T (Treg) cell development, function, or both. They include immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, which is caused by mutations in forkhead box P3 (FOXP3), and IPEX-like disorders caused by mutations in IL-2 receptor α (IL2RA), signal transducer and activator of transcription 5b (STAT5b), and signal transducer and activator of transcription 1 (STAT1). However, the genetic defects underlying many cases of IPEX-like disorders remain unknown.
  
  
  OBJECTIVE
  We sought to identify the genetic abnormalities in patients with idiopathic IPEX-like disorders.
  
  
  METHODS
  We performed whole-exome and targeted gene sequencing and phenotypic and functional analyses of Treg cells.
  
  
  RESULTS
  A child who presented with an IPEX-like syndrome and severe Treg cell deficiency was found to harbor a nonsense mutation in the gene encoding LPS-responsive beige-like anchor (LRBA), which was previously implicated as a cause of common variable immunodeficiency with autoimmunity. Analysis of subjects with LRBA deficiency revealed marked Treg cell depletion; profoundly decreased expression of canonical Treg cell markers, including FOXP3, CD25, Helios, and cytotoxic T lymphocyte-associated antigen 4; and impaired Treg cell-mediated suppression. There was skewing in favor of memory T cells and intense autoantibody production, with marked expansion of T follicular helper and contraction of T follicular regulatory cells. Whereas the frequency of recent thymic emigrants and the differentiation of induced Treg cells were normal, LRBA-deficient T cells exhibited increased apoptosis and reduced activities of the metabolic sensors mammalian target of rapamycin complexes 1 and 2.
  
  
  CONCLUSIONS
  LRBA deficiency is a novel cause of IPEX-like syndrome and Treg cell deficiency associated with metabolic dysfunction and increased apoptosis of Treg cells.
authors.affiliation: Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Louis-Marie
authors.initials: LM
authors.lastname: Charbonnier
authors.affiliation: Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Erin
authors.initials: E
authors.lastname: Janssen
authors.affiliation: Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Janet
authors.initials: J
authors.lastname: Chou
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, Mass.
authors.forename: Toshiro K
authors.initials: TK
authors.lastname: Ohsumi
authors.affiliation: Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Sevgi
authors.initials: S
authors.lastname: Keles
authors.affiliation: Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Joyce T
authors.initials: JT
authors.lastname: Hsu
authors.affiliation: Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Massaad
authors.affiliation: Division of Immunology, Department of Pediatrics, University of California at Los Angeles, Los Angeles, Calif.
authors.forename: Maria
authors.initials: M
authors.lastname: Garcia-Lloret
authors.affiliation: Division of Pediatric Infectious Diseases, American University of Beirut, Beirut, Lebanon.
authors.forename: Rima
authors.initials: R
authors.lastname: Hanna-Wakim
authors.affiliation: Division of Pediatric Infectious Diseases, American University of Beirut, Beirut, Lebanon.
authors.forename: Ghassan
authors.initials: G
authors.lastname: Dbaibo
authors.affiliation: Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Abdullah A
authors.initials: AA
authors.lastname: Alangari
authors.affiliation: Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Alsultan
authors.affiliation: Immunology and Allergy, Pediatric Department, King Abdulaziz Medical City-WR, Jeddah, Saudi Arabia.
authors.forename: Daifulah
authors.initials: D
authors.lastname: Al-Zahrani
authors.affiliation: Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
authors.affiliation: Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass. Electronic address: talal.chatila@childrens.harvard.edu.
authors.forename: Talal A
authors.initials: TA
authors.lastname: Chatila
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics*; D000293:Adolescent; D001323:Autoantibodies / Q000276:immunology; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000151:congenital; D003967:Diarrhea; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology; D006801:Humans; D007154:Immune System Diseases / Q000151:congenital; D016753:Interleukin-10 / Q000276:immunology; D008297:Male; D009154:Mutation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001323:Autoantibodies; D016753:Interleukin-10; C428703:LRBA protein, human
keywords: Autoantibodies; LPS-responsive beige-like anchor; T follicular helper cells; T follicular regulatory cells; X-linked syndrome; autoimmunity; enteropathy; forkhead box P3; immune dysregulation; mammalian target of rapamycin complex; polyendocrinopathy; regulatory T cells