The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.
Polyendocrinopathies, Autoimmune
/ genetics
Interferon-gamma
/ metabolism
Humans
Animals
Nitriles
/ therapeutic use
Mice
Pyrazoles
/ therapeutic use
Pyrimidines
/ therapeutic use
Transcription Factors
/ genetics
AIRE Protein
Female
Male
Mice, Knockout
Adult
Chemokine CXCL9
/ genetics
Autoantibodies
/ blood
T-Lymphocytes
/ immunology
Janus Kinase Inhibitors
/ therapeutic use
Journal
The New England journal of medicine
ISSN: 1533-4406
Titre abrégé: N Engl J Med
Pays: United States
ID NLM: 0255562
Informations de publication
Date de publication:
30 May 2024
30 May 2024
Historique:
medline:
29
5
2024
pubmed:
29
5
2024
entrez:
29
5
2024
Statut:
ppublish
Résumé
Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
Sections du résumé
BACKGROUND
BACKGROUND
Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood.
METHODS
METHODS
We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using
RESULTS
RESULTS
Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues.
CONCLUSIONS
CONCLUSIONS
Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
Identifiants
pubmed: 38810185
doi: 10.1056/NEJMoa2312665
doi:
Substances chimiques
Interferon-gamma
82115-62-6
Nitriles
0
ruxolitinib
82S8X8XX8H
Pyrazoles
0
Pyrimidines
0
Transcription Factors
0
AIRE Protein
0
Chemokine CXCL9
0
Autoantibodies
0
Janus Kinase Inhibitors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1873-1884Subventions
Organisme : NHLBI NIH HHS
ID : ZIA AI001175
Pays : United States
Informations de copyright
Copyright © 2024 Massachusetts Medical Society.