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 2

JAK1GOF BM and iPSC reveal skewing toward myelopoiesis.

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JAK1GOF BM and iPSC reveal skewing toward myelopoiesis. (A) BM biopsy s...
(A) BM biopsy slide obtained from JAK1GOF patient demonstrates an increase in the eosinophil lineage compared with healthy control BM biopsy (Ctrl). Images are at 50× magnification. (B) Representative photographs of JAK1GOF and XY control (Ctrl) iPSCs, demonstrating normal morphology for iPSCs grown in feeder-free culture, including tightly packed iPSCs with well-defined edges. (C) Embryoid body (EB) differentiation of JAK1GOF and Ctrl iPSCs. Images obtained on day 10 of EB differentiation. (D) Representative methylcellulose plates with hematopoietic precursor CFUs, demonstrating increased proportion of hemoglobinized erythroid precursor CFUs in Ctrl compared with JAK1GOF. Experiments represented in B–D were performed 3 times. (E) Decreased proportion of erythroid (CFU-E, BFU-E) CFUs in JAK1GOF compared with Ctrl, with an increased proportion of granulocyte/monocyte precursors (CFU-G, CFU-M, CFU-GM). Average percentage of total CFUs (data presented as mean ± SEM) was compared using a 2-tailed unpaired t test with Welch’s correction. (F) Increased myeloid/erythroid ratio (data presented as mean ± SEM) in JAK1GOF compared with Ctrl using a 2-tailed unpaired t test with Welch’s correction.