Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations.
Autoimmune lymphoproliferative syndrome
Fas
Fas ligand
apoptosis
inborn error of immunity
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:
05 2023
05 2023
Historique:
received:
11
08
2022
revised:
01
11
2022
accepted:
28
11
2022
medline:
8
5
2023
pubmed:
10
1
2023
entrez:
9
1
2023
Statut:
ppublish
Résumé
Fas ligand (FasL) is expressed by activated T cells and induces death in target cells upon binding to Fas. Loss-of-function FAS or FASLG mutations cause autoimmune-lymphoproliferative syndrome (ALPS) characterized by expanded double-negative T cells (DNT) and elevated serum biomarkers. While most ALPS patients carry heterozygous FAS mutations, FASLG mutations are rare and usually biallelic. Only 2 heterozygous variants were reported, associated with an atypical clinical phenotype. We revisited the significance of heterozygous FASLG mutations as a cause of ALPS. Clinical features and biomarkers were analyzed in 24 individuals with homozygous or heterozygous FASLG variants predicted to be deleterious. Cytotoxicity assays were performed with patient T cells and biochemical assays with recombinant FasL. Homozygous FASLG variants abrogated cytotoxicity and resulted in early-onset severe ALPS with elevated DNT, raised vitamin B Heterozygous loss-of-function mutations are better tolerated for FASLG than for FAS, which may explain the low frequency of ALPS-FASLG.
Sections du résumé
BACKGROUND
Fas ligand (FasL) is expressed by activated T cells and induces death in target cells upon binding to Fas. Loss-of-function FAS or FASLG mutations cause autoimmune-lymphoproliferative syndrome (ALPS) characterized by expanded double-negative T cells (DNT) and elevated serum biomarkers. While most ALPS patients carry heterozygous FAS mutations, FASLG mutations are rare and usually biallelic. Only 2 heterozygous variants were reported, associated with an atypical clinical phenotype.
OBJECTIVE
We revisited the significance of heterozygous FASLG mutations as a cause of ALPS.
METHODS
Clinical features and biomarkers were analyzed in 24 individuals with homozygous or heterozygous FASLG variants predicted to be deleterious. Cytotoxicity assays were performed with patient T cells and biochemical assays with recombinant FasL.
RESULTS
Homozygous FASLG variants abrogated cytotoxicity and resulted in early-onset severe ALPS with elevated DNT, raised vitamin B
CONCLUSION
Heterozygous loss-of-function mutations are better tolerated for FASLG than for FAS, which may explain the low frequency of ALPS-FASLG.
Identifiants
pubmed: 36621650
pii: S0091-6749(23)00001-5
doi: 10.1016/j.jaci.2022.11.028
pii:
doi:
Substances chimiques
Fas Ligand Protein
0
Biomarkers
0
Vitamins
0
fas Receptor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1391-1401.e7Informations de copyright
Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.