CTLA-4 Defizienz

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How does CTLA-4 function in healthy individuals?

Cytotoxic T lymphocytic antigen-4 (CTLA-4) is a dominant suppressor of T cell response in the immune system. The protein is constitutively expressed on regulatory T cells (Tregs), which mediate peripheral tolerance and prevent autoimmune diseases by suppressing the function of conventional T cells. CTLA-4 is also expressed on activated conventional T cells, where it is stored in intracellular vesicles and transported onto the cell surface upon T cell activation. CTLA-4 binds CD80 and CD86, which in return also bind to the co-stimulatory T cell activator CD28. Both CD80 and CD86 are expressed on the surface of antigen-presenting cells (APC). CTLA-4 has a higher affinity and avidity for the two ligands CD80 and CD86 compared to CD28. CTLA-4 binds its ligands, captures them from the surface of APC and internalizes them via a process that is called transendocytosis, leading to a reduction of APC-mediated T cell activation. Mice with homozygous knock-out mutations in Ctla4, leading to a complete lack of CTLA-4, spontaneously develop a fatal lymphoproliferative disease with multiorgan lymphocytic infiltration and tissue destruction after birth and die after 3-4 weeks. Heterozygous mutations in Ctla4 mice are reported to be healthy. In contrast CTLA4 mutations in humans, leading to an immunodeficient phenotype are heterozygous and lead to haploinsufficiency.

Identification of heterozygous mutations in CTLA4 and the effect on the immune systeme

Whole-exome sequencing and genetic linkage analysis was performed on 14 members of a large family with 39 individuals. Five family members presented with clinical symptoms including recurrent respiratory infections, hypogammaglobulinemia, autoimmune enteropathy, granulomatous lymphocytic interstitial lung disease (GLILD), autoimmune cytopenia and lymphocytic organ infiltration and were primarily diagnosed with CVID (Common Variable Immunodeficiency). After an affected-only analysis allowing for reduced a nonsense mutation at position c.105 (C35*) in the first exon of CTLA4 segregating with the disease was identified in 5 affected family members. However the same mutation was found in additional six family members that are considered healthy. Screening of 71 unrelated patients with CVID and enteropathy or autoimmunity revealed five additional index patients with different novel heterozygous CTLA4 mutations. Working up the family history revealed four more symptomatic and two asymptomatic CTLA4 mutation carriers, leading to a total of six families, 14 symptomatic and 8 asymptomatic mutation carriers. Functional tests were conducted and revealed that CTLA-4 protein levels and transendocytosis in the mutation carriers were reduced and Tregs of individuals with heterozygous CTLA4 mutations were unable to suppress CD4⁺ T cell proliferation as compared to healthy CTLA4^+/+ controls (Schubert et al, Nature Medicine, 2014). Previously Kuehn et al., Science, 2014 described a similar phenotype in 9 patients. The extended phenotype of the gut has been reported by Zeissig et al, GUT, 2014. Several questions remain to be answered. The syndromic phenotype resulting from mutations in CTLA4 has to be further characterized and personalized treatment options for symptomatic patients have to be established. The reduced penetrance implicating a modifier that could be environmental, genetic, or epigenetic has to be further investigated. References: 1. Schubert et al., Nature Medicine, 2014 Oct 20; Vol. 20 no.12 pp. 1410-1416 PMID: 25329329 2. Kuehn et al., Science, 2014 Sep 26; Vol. 345 no. 6204 pp. 1623-1627  PMID: 25213377 3. Zeissig et al., GUT, 2014 Nov 03; 0:1-9 PMID: 25367873