Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations

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 investigated a large autosomal-dominant family with five individuals presenting with a complex immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune 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 novel splice site and missense mutations in CTLA4. While clinical penetrance was incomplete (eight adults of a total of 19 CTLA4 mutation carriers were considered unaffected), CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in patients and carriers with CTLA4 mutations. Whilst Treg cells were generally present at elevated numbers, 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 and antibody levels. Taken together, mutations in CTLA-4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding results in a complex syndrome with features of both autoimmunity and immunodeficiency.

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“…The recently described autosomal dominant syndrome of cytotoxic T lymphocyte-associated protein 4 (CTLA4) deficiency shares a clinical picture of hypogammaglobulinaemia, lymphoproliferation, progressive loss of B cells, recurrent infections and prominent autoimmune features [33,34] with APDS, although patients with CTLA4 deficiency tend to have a later onset of disease [33].…”

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“…In mice, Treg-specific deletion of CTLA-4 elicits systemic hyper-proliferation of Tconv cells and fatal autoimmune diseases affecting multiple organs, including severe myocarditis [20]. Recently, heterozygous CTLA-4 mutations in humans were identified in patients with multiple autoimmune symptoms accompanied by impaired suppressive function of Treg cells [21,22]. As CTLA-4 has much higher affinity than CD28 for their common ligands CD80 and CD86, CTLA-4 expressed by Treg cells may physically outcompete CD28 on Tconv [23,24].…”

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“…However, disease because of partial loss of CTLA-4 was recently described. 4,5 "CTLA-4 haploinsufficiency with autoimmune infiltration" (CHAI) patients have heterozygous loss-of-function mutations in CTLA-4 and develop lymphocytic infiltration of multiple nonlymphoid organs similar to Ctla4 knockout mice. Additionally, prior reports have described patients clinically resembling CHAI disease, but with recessive inheritance.…”