Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations

Nat Med. 2014 Dec;20(12):1410-1416. doi: 10.1038/nm.3746. Epub 2014 Oct 20.

Abstract

The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Agammaglobulinemia / genetics*
  • Agammaglobulinemia / immunology
  • Anemia, Hemolytic, Autoimmune / genetics
  • Anemia, Hemolytic, Autoimmune / immunology
  • Animals
  • Autoimmune Diseases / genetics*
  • Autoimmune Diseases / immunology
  • B-Lymphocytes / immunology
  • B7-1 Antigen / metabolism
  • CTLA-4 Antigen / genetics*
  • CTLA-4 Antigen / immunology
  • Child
  • Codon, Nonsense
  • Endocytosis / genetics
  • Endocytosis / immunology
  • Exons
  • Female
  • Granuloma / genetics
  • Granuloma / immunology
  • Heterozygote
  • Humans
  • Immune System Diseases / genetics
  • Lung Diseases, Interstitial / genetics
  • Lung Diseases, Interstitial / immunology
  • Male
  • Mice
  • Middle Aged
  • Mutation, Missense
  • Pedigree
  • Polyendocrinopathies, Autoimmune / genetics
  • Polyendocrinopathies, Autoimmune / immunology
  • Purpura, Thrombocytopenic, Idiopathic / genetics
  • Purpura, Thrombocytopenic, Idiopathic / immunology
  • Recurrence
  • Respiratory Tract Infections / genetics
  • Respiratory Tract Infections / immunology
  • Syndrome
  • T-Lymphocytes, Regulatory / immunology*
  • Young Adult

Substances

  • B7-1 Antigen
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Codon, Nonsense

Supplementary concepts

  • Autoimmune enteropathy