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Clinical and laboratory characterization of allergic immune dysregulation caused by a heterozygous gain-of-function mutation in JAK1

University of British Columbia

Monogenic immune disorders are a group of conditions caused by single gene mutations affecting how the immune system develops, functions, or both. It is now appreciated that certain monogenic immune disorders can present with severe allergic disease, such as asthma, food allergy, elevated eosinophil counts and/or atopic dermatitis. Studying single-gene defects that lead to atopy has identified critical molecules in the pathogenesis of allergic inflammation. These discoveries have created new therapeutic targets for allergic diseases, which carry an immense health and economic burden in Canada. Germline gain-of-function mutations in JAK1 are a newly described monogenic cause of severe atopy, with affected patients demonstrating profound eosinophilia and allergic inflammation. The initial report identified a dramatic clinical response to the combined JAK1/2 inhibitor ruxolitinib. We sought to determine the long-term clinical outcomes and response to ruxolitinib of patients carrying a germline JAK1 gain-of-function mutation. We further aimed to characterize the mechanisms behind JAK1-mediated atopic immune dysregulation, including its effect on T lymphocytes–key regulators in allergic inflammation–and hematopoiesis. We demonstrate that long-term ruxolitinib use is associated with improvements in growth, eosinophilia, and allergic inflammation, however, anemia represents a dose-limiting adverse effect. T cell immunophenotypic analysis revealed severe skewing towards a TH2 phenotype pre-ruxolitinib treatment, in keeping with the allergic clinical manifestations. RNA sequencing data from patients and a transgenic zebrafish model both containing the same JAK1 gain-of-function mutation identified increased expression of genes involved in cytokine signaling, type 1 interferon and antiviral immune responses, and alternative macrophage activation, as well as genes whose role in allergic immune dysregulation warrants further investigation. In conclusion, this work demonstrates a critical role for JAK1 in atopic immune dysregulation, specifically driving lymphocyte responses towards a TH2 phenotype. Combined JAK1/2 inhibition can reverse much of the allergic inflammation, with dramatic clinical effects. This has important implications for our understanding of the pathogenesis and potential therapeutic targets for early life allergic immune dysregulation.

Text

2023-02-28

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71461

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/