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.

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