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Haploinsufficiency in PTPN2 leads to early-onset systemic autoimmunity from Evans syndrome to lupus.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2024 Sep 02; Vol. 221 (9). Date of Electronic Publication: 2024 Jul 19. - Publication Year :
- 2024
-
Abstract
- An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients' T cells. Furthermore, patients exhibited high serum levels of inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in STAT factors. Flow cytometry analysis of patients' blood cells revealed typical alterations associated with autoimmunity and all patients presented with autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.<br /> (© 2024 Jeanpierre et al.)
- Subjects :
- Humans
Female
Male
Child
Adolescent
Mutation
Thrombocytosis genetics
Thrombocytosis immunology
Suppressor of Cytokine Signaling 1 Protein genetics
Autoantibodies immunology
Cytokines metabolism
Child, Preschool
T-Lymphocytes immunology
Thrombocytopenia
Haploinsufficiency genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 2 genetics
Anemia, Hemolytic, Autoimmune genetics
Anemia, Hemolytic, Autoimmune immunology
Lupus Erythematosus, Systemic genetics
Lupus Erythematosus, Systemic immunology
Autoimmunity genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 221
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 39028869
- Full Text :
- https://doi.org/10.1084/jem.20232337