Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation
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
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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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 8

JAK1GOF drives IL-4, IL-13, and IFN signaling across species.

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JAK1GOF drives IL-4, IL-13, and IFN signaling across species. (A) Diagr...
(A) Diagrammatic explanation of analysis pipeline for comparing differential gene expression between zebrafish, induced pluripotent stem cells (iPSC), and human whole blood. (B) Analysis of differentially expressed orthologous genes identified 25 genes that were common between human JAK1GOF iPSCs, human JAK1GOF whole blood, and JAK1GOF transgenic zebrafish. (C and D) Reactome Pathway analysis and STRING protein-to-protein interactions of the 25 differentially expressed genes in JAK1GOF-affected patients, iPSCs, and transgenic zebrafish reveals significantly enriched protein-to-protein interactions, as well as IFN and IL-4/IL-13 signaling. The 5 most significantly upregulated Reactome Pathways are displayed in C. The y axis indicates Reactome Pathway, and the x axis corresponds to ratio of upregulated genes to the number of genes in each pathway; the size of each dot corresponds to number of genes identified. Color corresponds to the adjusted P value with red being more significant. The upregulated Reactome Pathway corresponding proteins are annotated in D, revealing the shared expression of SOCS proteins in both IFN and IL-4/IL-13 signaling.