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Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction
Mutations of the transcription factor FoxP3 in patients with “IPEX” (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) disrupt regulatory T cells (Treg), causing an array of multiorgan autoimmunity. To understand the functional impact of mutations across FoxP3 domains, withou...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10565790/ https://www.ncbi.nlm.nih.gov/pubmed/37605532 http://dx.doi.org/10.1016/j.celrep.2023.113018 |
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author | Leon, Juliette Chowdhary, Kaitavjeet Zhang, Wenxiang Ramirez, Ricardo N. André, Isabelle Hur, Sun Mathis, Diane Benoist, Christophe |
author_facet | Leon, Juliette Chowdhary, Kaitavjeet Zhang, Wenxiang Ramirez, Ricardo N. André, Isabelle Hur, Sun Mathis, Diane Benoist, Christophe |
author_sort | Leon, Juliette |
collection | PubMed |
description | Mutations of the transcription factor FoxP3 in patients with “IPEX” (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) disrupt regulatory T cells (Treg), causing an array of multiorgan autoimmunity. To understand the functional impact of mutations across FoxP3 domains, without genetic and environmental confounders, six human FOXP3 missense mutations are engineered into mice. Two classes of mutations emerge from combined immunologic and genomic analyses. A mutation in the DNA-binding domain shows the same lymphoproliferation and multiorgan infiltration as complete FoxP3 knockouts but delayed by months. Tregs expressing this mutant FoxP3 are destabilized by normal Tregs in heterozygous females compared with hemizygous males. Mutations in other domains affect chromatin opening differently, involving different cofactors and provoking more specific autoimmune pathology (dermatitis, colitis, diabetes), unmasked by immunological challenges or incrossing NOD autoimmune-susceptibility alleles. This work establishes that IPEX disease heterogeneity results from the actual mutations, combined with genetic and environmental perturbations, explaining then the intra-familial variation in IPEX. |
format | Online Article Text |
id | pubmed-10565790 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
record_format | MEDLINE/PubMed |
spelling | pubmed-105657902023-10-11 Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction Leon, Juliette Chowdhary, Kaitavjeet Zhang, Wenxiang Ramirez, Ricardo N. André, Isabelle Hur, Sun Mathis, Diane Benoist, Christophe Cell Rep Article Mutations of the transcription factor FoxP3 in patients with “IPEX” (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) disrupt regulatory T cells (Treg), causing an array of multiorgan autoimmunity. To understand the functional impact of mutations across FoxP3 domains, without genetic and environmental confounders, six human FOXP3 missense mutations are engineered into mice. Two classes of mutations emerge from combined immunologic and genomic analyses. A mutation in the DNA-binding domain shows the same lymphoproliferation and multiorgan infiltration as complete FoxP3 knockouts but delayed by months. Tregs expressing this mutant FoxP3 are destabilized by normal Tregs in heterozygous females compared with hemizygous males. Mutations in other domains affect chromatin opening differently, involving different cofactors and provoking more specific autoimmune pathology (dermatitis, colitis, diabetes), unmasked by immunological challenges or incrossing NOD autoimmune-susceptibility alleles. This work establishes that IPEX disease heterogeneity results from the actual mutations, combined with genetic and environmental perturbations, explaining then the intra-familial variation in IPEX. 2023-08-29 2023-08-21 /pmc/articles/PMC10565790/ /pubmed/37605532 http://dx.doi.org/10.1016/j.celrep.2023.113018 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Leon, Juliette Chowdhary, Kaitavjeet Zhang, Wenxiang Ramirez, Ricardo N. André, Isabelle Hur, Sun Mathis, Diane Benoist, Christophe Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction |
title | Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction |
title_full | Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction |
title_fullStr | Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction |
title_full_unstemmed | Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction |
title_short | Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction |
title_sort | mutations from patients with ipex ported to mice reveal different patterns of foxp3 and treg dysfunction |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10565790/ https://www.ncbi.nlm.nih.gov/pubmed/37605532 http://dx.doi.org/10.1016/j.celrep.2023.113018 |
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