PUBLICATION
Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation
- Authors
- Biggs, C.M., Cordeiro-Santanach, A., Prykhozhij, S.V., Deveau, A.P., Lin, Y., Del Bel, K.L., Orben, F., Ragotte, R.J., Saferali, A., Mostafavi, S., Dinh, L., Dai, D., Weinacht, K.G., Dobbs, K., Ott de Bruin, L., Sharma, M., Tsai, K., Priatel, J.J., Schreiber, R.A., Rozmus, J., Hosking, M.C., Shopsowitz, K.E., McKinnon, M.L., Vercauteren, S., Seear, M., Notarangelo, L.D., Lynn, F.C., Berman, J.N., Turvey, S.E.
- ID
- ZDB-PUB-221223-4
- Date
- 2022
- Source
- JCI insight 7(24): (Journal)
- Registered Authors
- Berman, Jason
- Keywords
- Allergy, Bone marrow differentiation, Hematology, Immunology
- MeSH Terms
-
- Animals
- Child
- Eosinophilia*/genetics
- Gain of Function Mutation
- Humans
- Hypersensitivity*/genetics
- Hypersensitivity, Immediate*
- Induced Pluripotent Stem Cells*
- Inflammation/genetics
- Janus Kinase 1/genetics
- Zebrafish
- PubMed
- 36546480 Full text @ JCI Insight
Citation
Biggs, C.M., Cordeiro-Santanach, A., Prykhozhij, S.V., Deveau, A.P., Lin, Y., Del Bel, K.L., Orben, F., Ragotte, R.J., Saferali, A., Mostafavi, S., Dinh, L., Dai, D., Weinacht, K.G., Dobbs, K., Ott de Bruin, L., Sharma, M., Tsai, K., Priatel, J.J., Schreiber, R.A., Rozmus, J., Hosking, M.C., Shopsowitz, K.E., McKinnon, M.L., Vercauteren, S., Seear, M., Notarangelo, L.D., Lynn, F.C., Berman, J.N., Turvey, S.E. (2022) Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation. JCI insight. 7(24):.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping