Novel mutations of TYK2 leading to divergent clinical phenotypes

Abstract

Background: TYK2 deficiency is a rare primary immunodeficiency disease caused by loss-of-function mutations of TYK2 gene, which is initially proposed as a subset of hyper-IgE syndrome (HIES). However, accumulating evidence suggests TYK2-deficient patients do not necessarily present with HIES characteristics, indicating a vacuum of knowledge on the exact roles of TYK2 in human immune system.

Method: Pathogenic effects of patients were confirmed by qRT-PCR, Western blot, and protein stability assays. The responses to cytokines including IFN-α/β/γ, IL-6, IL-10, IL-12, and IL-23 of peripheral blood mononuclear cells (PBMCs) from these patients were detected by Western blot, qRT-PCR, and flow cytometry. The differentiation of T and B cells was detected by flow cytometry.

Results: We described five more TYK2-deficient cases presenting with or without hyper-IgE levels, atopy, and distinct pathogen infection profile, which are caused by novel TYK2 mutations. These mutations were all found by high-throughput sequencing and confirmed by Sanger sequencing. The patients showed heterogeneous responses to various cytokine treatments, including IFN-α/β/γ, IL-6, IL-10, IL-12, and IL-23. The homeostasis of lymphocytes is also disrupted.

Conclusion: Based on our findings, we propose that TYK2 works as a multi-tasker in orchestrating various cytokine signaling pathways, differentially combined defects which account for the expressed clinical manifestations.

Keywords: JAK-STAT; TYK2 deficiency; hyper-IgE syndrome; primary immunodeficiency; recurrent infection.