Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation
Catherine M. Biggs, … , Jason N. Berman, Stuart E. Turvey
Catherine M. Biggs, … , Jason N. Berman, Stuart E. Turvey
Published December 22, 2022
Citation Information: JCI Insight. 2022;7(24):e150849. https://doi.org/10.1172/jci.insight.150849.
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Research Article Hematology Immunology

Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation

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.

Authors

Catherine M. Biggs, Anna Cordeiro-Santanach, Sergey V. Prykhozhij, Adam P. Deveau, Yi Lin, Kate L. Del Bel, Felix Orben, Robert J. Ragotte, Aabida Saferali, Sara Mostafavi, Louie Dinh, Darlene Dai, Katja G. Weinacht, Kerry Dobbs, Lisa Ott de Bruin, Mehul Sharma, Kevin Tsai, John J. Priatel, Richard A. Schreiber, Jacob Rozmus, Martin C.K. Hosking, Kevin E. Shopsowitz, Margaret L. McKinnon, Suzanne Vercauteren, Michael Seear, Luigi D. Notarangelo, Francis C. Lynn, Jason N. Berman, Stuart E. Turvey

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Figure 6

Characterization of the hematological phenotype of the human JAK1WT and JAK1GOF transgenic fish lines.

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Characterization of the hematological phenotype of the human JAK1WT and ...
(A) Whole-mount in situ hybridization (WISH) using digoxigenin-labeled RNA antisense probes for stem cells and differentiated myeloid cells in zebrafish embryos of JAK1WT and JAK1GOF transgenic genotypes. A panel of representative micrographs shows runx1/c-myb staining for hematopoietic stem cells at 48hpf, pu.1 staining for early myeloid cells at 28 hpf, mpx staining for neutrophils at 48 hpf, and cpa5 staining for mast cells at 48 hpf. Total numbers of imaged and quantified embryos are shown on the representative images, and arrowheads indicate main sites of marker expression. (B) Plots of marker-positive cell counts for runx1/c-myb at 48 hpf, pu.1 at 28 hpf, and mpx and cpa5 at 48 hpf. Each individual embryo count is indicated by a filled circle, and the box plot shows quartile distribution with whiskers covering 95% CI. Black circles denote location of outlier counts. One-way ANOVA was used to quantify the statistical differences between the groups. ***P ≤ 0.001; ****P ≤ 0.0001.