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 3

Enhanced Th2 phenotype and T cell activation in JAK1GOF.

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Enhanced Th2 phenotype and T cell activation in JAK1GOF. (A) Representat...
(A) Representative flow cytometry plots of healthy controls (Ctrl) and JAK1GOF patient (II-2) Th2, Th17, Th1, and Th1/17 cell subsets as a proportion of live CD3+CD4+ T cells, identified as CCR4+CXCR3–CCR10–CCR6–, CCR4+CXCR3–CCR10–CCR6+, CCR4–CXCR3+CCR10–CCR6–, and CCR4–CXCR3+CCR10–CCR6+, respectively. The red rectangles highlight the cell population gated on for the subsequent plot identified by the red arrow. This experiment was performed twice with patient samples. (B) Average frequency of Th subsets (data presented as mean ± SEM). Subset frequency calculated by multiplying the proportion of each subset by the sample’s number of CD4+ T cells. (C) PCA of Th subset gene expression from whole blood RNA-Seq data. First principal component (PC) values (data presented as mean ± SEM) were compared between groups using 1-way ANOVA with Bonferri multiple comparisons correction. (D) Decreased proportion of naive CD4+ JAK1GOF T cells. Representative flow cytometry of and (E) proportions of naive, effector memory (TEM), effector memory reexpressing CD45RA (TEMRA), and central memory (TCM) CD4+ T cells. This experiment was performed once with patient cells. (F) Increased frequency of IL-4–, IFN-γ–, and IL-17–secreting JAK1GOF CD4+ T cells and IL-4–, IL-9–, and IL-17–secreting JAK1GOF CD8+ T cells (identified as CD3+CD4– T cells) compared with control. (G) Increased IL4 gene expression in expanded and activated JAK1GOF T cells. Measured using qPCR after 4 hours of stimulation with DMSO control, IL-2, and IL-2 plus ruxolitinib (1 mM). Relative gene expression Ctrl and JAK1GOF were calculated using the Livak method (2–ΔΔCt).