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 suggest 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,
IL12 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 were detected by flow cytometry.
Results: We describe 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 throughout sequencing and confirmed by Sanger sequencing. The
patients showed heterogenous responses to various cytokine treatments,
including IFN-α/β/γ, IL-6, IL-10, IL12 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
cytokines signaling pathways, differentially combined defects of which
account for the expressed clinical manifestations.