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 Ck Hosking; Kevin E Shopsowitz; Margaret L McKinnon; Suzanne Vercauteren; Michael Seear; Luigi D Notarangelo; Francis C Lynn; Jason N Berman; Stuart E Turvey

doi:10.1172/jci.insight.150849

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

JCI Insight. 2022 Dec 22;7(24):e150849. doi: 10.1172/jci.insight.150849.

Authors

Catherine M Biggs^{1

2}, Anna Cordeiro-Santanach³, Sergey V Prykhozhij⁴, Adam P Deveau⁵, Yi Lin², Kate L Del Bel^{1

2}, Felix Orben^{1

2}, Robert J Ragotte^{1

2}, Aabida Saferali^{1

2

6}, Sara Mostafavi^{7

8}, Louie Dinh^{7

8}, Darlene Dai², Katja G Weinacht⁹, Kerry Dobbs¹⁰, Lisa Ott de Bruin¹¹, Mehul Sharma^{1

2}, Kevin Tsai^{2

12}, John J Priatel^{2

12}, Richard A Schreiber^{1

2}, Jacob Rozmus^{1

2}, Martin Ck Hosking^{1

2}, Kevin E Shopsowitz^{2

12}, Margaret L McKinnon⁷, Suzanne Vercauteren¹², Michael Seear^{1

2}, Luigi D Notarangelo¹⁰, Francis C Lynn^{2

13}, Jason N Berman^{4

14}, Stuart E Turvey^{1

2}

Affiliations

¹ Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
² BC Children's Hospital, Vancouver, British Columbia, Canada.
³ AGADA Biosciences Inc., Halifax, Nova Scotia, Canada.
⁴ CHEO Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
⁵ Department of Internal Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
⁶ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁷ Department of Medical Genetics and.
⁸ Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada.
⁹ Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford, California, USA.
¹⁰ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
¹¹ Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹² Department of Pathology and Laboratory Medicine and.
¹³ Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁴ Departments of Pediatrics and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.

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.

Keywords: Allergy; Bone marrow differentiation; Hematology; Immunology.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

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

Substances

JAK1 protein, human
Janus Kinase 1

Grants and funding

U54 AI082973/AI/NIAID NIH HHS/United States