Compound heterozygous TYK2 mutations underlie primary immunodeficiency with T-cell lymphopenia

Michiko Nemoto, Hiroyoshi Hattori, Naoko Maeda, Nobuhiro Akita, Hideki Muramatsu, Suzuko Moritani, Tomonori Kawasaki, Masami Maejima, Hirotaka Ode, Atsuko Hachiya, Wataru Sugiura, Yoshiyuki Yokomaku, Keizo Horibe, Yasumasa Iwatani

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Abstract

Complete tyrosine kinase 2 (TYK2) deficiency has been previously described in patients with primary immunodeficiency diseases. The patients were infected with various pathogens, including mycobacteria and/or viruses, and one of the patients developed hyper-IgE syndrome. A detailed immunological investigation of these patients revealed impaired responses to type I IFN, IL-10, IL-12 and IL-23, which are associated with increased susceptibility to mycobacterial and/or viral infections. Herein, we report a recessive partial TYK2 deficiency in two siblings who presented with T-cell lymphopenia characterized by low naïve CD4+ T-cell counts and who developed Epstein-Barr virus (EBV)-associated B-cell lymphoma. Targeted exome-sequencing of the siblings' genomes demonstrated that both patients carried novel compound heterozygous mutations (c.209-212delGCTT/c.691C > T, p.Cys70Serfs∗21/p.Arg231Trp) in the TYK2. The TYK2 protein levels were reduced by 35% in the T cells of the patient. Unlike the response under complete TYK2 deficiency, the patient's T cells responded normally to type I IFN, IL-6, IL-10 and IL-12, whereas the cells displayed an impaired response to IL-23. Furthermore, the level of STAT1 was low in the cells of the patient. These studies reveal a new clinical entity of a primary immunodeficiency with T-cell lymphopenia that is associated with compound heterozygous TYK2 mutations in the patients.

Original languageEnglish
Article number6956
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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    Nemoto, M., Hattori, H., Maeda, N., Akita, N., Muramatsu, H., Moritani, S., Kawasaki, T., Maejima, M., Ode, H., Hachiya, A., Sugiura, W., Yokomaku, Y., Horibe, K., & Iwatani, Y. (2018). Compound heterozygous TYK2 mutations underlie primary immunodeficiency with T-cell lymphopenia. Scientific reports, 8(1), [6956]. https://doi.org/10.1038/s41598-018-25260-8