Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation.

Humans Forkhead Transcription Factors Genetic Diseases, X-Linked Polyendocrinopathies, Autoimmune T-Lymphocytes, Regulatory Mutation Epigenesis, Genetic

CD4(+) Teff CyTOF FOXP3 T(H)2 TSDR demethylation Treg cells atypical IPEX cytokines epigenetic typical IPEX

Journal

The Journal of allergy and clinical immunology

ISSN: 1097-6825

Titre abrégé: J Allergy Clin Immunol

Pays: United States

ID NLM: 1275002

Informations de publication

Date de publication:
01 2023

Historique:

received: 28 04 2022

revised: 16 08 2022

accepted: 09 09 2022

pubmed: 25 9 2022

medline: 11 1 2023

entrez: 24 9 2022

Statut: ppublish

Résumé

Forkhead box protein 3 (FOXP3) is the master transcription factor in CD4 We sought to study the type and extent of immunologic abnormalities that remain ill-defined in IPEX, across genetic and clinical heterogeneity. We performed Treg-cell-specific epigenetic quantification and immunologic characterization of severe "typical" (n = 6) and "atypical" or asymptomatic (n = 9) patients with IPEX. Increased number of cells with Treg-cell-Specific Demethylated Region demethylation in FOXP3 is a consistent feature in patients with IPEX, with (1) highest values in those with typical IPEX, (2) increased values in subjects with pathogenic FOXP3 but still no symptoms, and (3) gradual increase over the course of disease progression. Large-scale profiling using Luminex identified plasma inflammatory signature of macrophage activation and T Elevated TSDR-demethylated cells, combined with elevation of plasmatic and cellular markers of a polarized type 2 inflammatory immune response, extends our understanding of IPEX diagnosis and heterogeneity.

Sections du résumé

BACKGROUND

Forkhead box protein 3 (FOXP3) is the master transcription factor in CD4

OBJECTIVE

We sought to study the type and extent of immunologic abnormalities that remain ill-defined in IPEX, across genetic and clinical heterogeneity.

METHODS

We performed Treg-cell-specific epigenetic quantification and immunologic characterization of severe "typical" (n = 6) and "atypical" or asymptomatic (n = 9) patients with IPEX.

RESULTS

Increased number of cells with Treg-cell-Specific Demethylated Region demethylation in FOXP3 is a consistent feature in patients with IPEX, with (1) highest values in those with typical IPEX, (2) increased values in subjects with pathogenic FOXP3 but still no symptoms, and (3) gradual increase over the course of disease progression. Large-scale profiling using Luminex identified plasma inflammatory signature of macrophage activation and T

CONCLUSIONS

Elevated TSDR-demethylated cells, combined with elevation of plasmatic and cellular markers of a polarized type 2 inflammatory immune response, extends our understanding of IPEX diagnosis and heterogeneity.

Identifiants

DOI: 10.1016/j.jaci.2022.09.013 PMID: 36152823

pubmed: 36152823

pii: S0091-6749(22)01221-0

doi: 10.1016/j.jaci.2022.09.013

pii:

doi:

Substances chimiques

Forkhead Transcription Factors 0

FOXP3 protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

233-246.e10