Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation.
JCI Insight
; 7(24)2022 12 22.
Article
in En
| MEDLINE
| ID: mdl-36546480
ABSTRACT
Primary atopic disorders are a group of inborn errors of immunity that skew the immune system toward severe allergic disease. Defining the biology underlying these extreme monogenic phenotypes reveals shared mechanisms underlying common polygenic allergic disease and identifies potential drug targets. Germline gain-of-function (GOF) variants in JAK1 are a cause of severe atopy and eosinophilia. Modeling the JAK1GOF (p.A634D) variant in both zebrafish and human induced pluripotent stem cells (iPSCs) revealed enhanced myelopoiesis. RNA-Seq of JAK1GOF human whole blood, iPSCs, and transgenic zebrafish revealed a shared core set of dysregulated genes involved in IL-4, IL-13, and IFN signaling. Immunophenotypic and transcriptomic analysis of patients carrying a JAK1GOF variant revealed marked Th cell skewing. Moreover, long-term ruxolitinib treatment of 2 children carrying the JAK1GOF (p.A634D) variant remarkably improved their growth, eosinophilia, and clinical features of allergic inflammation. This work highlights the role of JAK1 signaling in atopic immune dysregulation and the clinical impact of JAK1/2 inhibition in treating eosinophilic and allergic disease.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Eosinophilia
/
Induced Pluripotent Stem Cells
/
Hypersensitivity
/
Hypersensitivity, Immediate
Type of study:
Etiology_studies
Limits:
Animals
/
Child
/
Humans
Language:
En
Journal:
JCI Insight
Year:
2022
Document type:
Article
Affiliation country:
Canadá