Human Tyrosine Kinase 2 Deficiency Reveals Its Requisite Roles in Multiple Cytokine Signals Involved in Innate and Acquired Immunity

Yoshiyuki Minegishi, Masako Saito, Tomohiro Morio, Ken Watanabe, Kazunaga Agematsu, Shigeru Tsuchiya, Hidetoshi Takada, Toshiro Hara, Nobuaki Kawamura, Tadashi Ariga, Hideo Kaneko, Naomi Kondo, Ikuya Tsuge, Akihiro Yachie, Yukio Sakiyama, Tsutomu Iwata, Fumio Bessho, Tsutomu Ohishi, Kosuke Joh, Kohsuke ImaiKazuhiro Kogawa, Miwa Shinohara, Mikiya Fujieda, Hiroshi Wakiguchi, Srdjan Pasic, Mario Abinun, Hans D. Ochs, Eleonore D. Renner, Annette Jansson, Bernd H. Belohradsky, Ayse Metin, Norio Shimizu, Shuki Mizutani, Toshio Miyawaki, Shigeaki Nonoyama, Hajime Karasuyama

Research output: Contribution to journalArticle

387 Citations (Scopus)

Abstract

Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.

Original languageEnglish
Pages (from-to)745-755
Number of pages11
JournalImmunity
Volume25
Issue number5
DOIs
Publication statusPublished - Nov 1 2006

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TYK2 Kinase
Adaptive Immunity
Innate Immunity
Cytokines
Job Syndrome
Janus Kinases
Interleukin-23
Interferon Type I
Atopic Dermatitis
Interleukin-12
Mycobacterium
Interleukin-10
Protein-Tyrosine Kinases
Immunoglobulin E
Interleukin-6
Fungi
Tyrosine Kinase 2 Deficiency
human TYK2 protein
Viruses
Phenotype

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Minegishi, Y., Saito, M., Morio, T., Watanabe, K., Agematsu, K., Tsuchiya, S., ... Karasuyama, H. (2006). Human Tyrosine Kinase 2 Deficiency Reveals Its Requisite Roles in Multiple Cytokine Signals Involved in Innate and Acquired Immunity. Immunity, 25(5), 745-755. https://doi.org/10.1016/j.immuni.2006.09.009

Human Tyrosine Kinase 2 Deficiency Reveals Its Requisite Roles in Multiple Cytokine Signals Involved in Innate and Acquired Immunity. / Minegishi, Yoshiyuki; Saito, Masako; Morio, Tomohiro; Watanabe, Ken; Agematsu, Kazunaga; Tsuchiya, Shigeru; Takada, Hidetoshi; Hara, Toshiro; Kawamura, Nobuaki; Ariga, Tadashi; Kaneko, Hideo; Kondo, Naomi; Tsuge, Ikuya; Yachie, Akihiro; Sakiyama, Yukio; Iwata, Tsutomu; Bessho, Fumio; Ohishi, Tsutomu; Joh, Kosuke; Imai, Kohsuke; Kogawa, Kazuhiro; Shinohara, Miwa; Fujieda, Mikiya; Wakiguchi, Hiroshi; Pasic, Srdjan; Abinun, Mario; Ochs, Hans D.; Renner, Eleonore D.; Jansson, Annette; Belohradsky, Bernd H.; Metin, Ayse; Shimizu, Norio; Mizutani, Shuki; Miyawaki, Toshio; Nonoyama, Shigeaki; Karasuyama, Hajime.

In: Immunity, Vol. 25, No. 5, 01.11.2006, p. 745-755.

Research output: Contribution to journalArticle

Minegishi, Y, Saito, M, Morio, T, Watanabe, K, Agematsu, K, Tsuchiya, S, Takada, H, Hara, T, Kawamura, N, Ariga, T, Kaneko, H, Kondo, N, Tsuge, I, Yachie, A, Sakiyama, Y, Iwata, T, Bessho, F, Ohishi, T, Joh, K, Imai, K, Kogawa, K, Shinohara, M, Fujieda, M, Wakiguchi, H, Pasic, S, Abinun, M, Ochs, HD, Renner, ED, Jansson, A, Belohradsky, BH, Metin, A, Shimizu, N, Mizutani, S, Miyawaki, T, Nonoyama, S & Karasuyama, H 2006, 'Human Tyrosine Kinase 2 Deficiency Reveals Its Requisite Roles in Multiple Cytokine Signals Involved in Innate and Acquired Immunity', Immunity, vol. 25, no. 5, pp. 745-755. https://doi.org/10.1016/j.immuni.2006.09.009
Minegishi, Yoshiyuki ; Saito, Masako ; Morio, Tomohiro ; Watanabe, Ken ; Agematsu, Kazunaga ; Tsuchiya, Shigeru ; Takada, Hidetoshi ; Hara, Toshiro ; Kawamura, Nobuaki ; Ariga, Tadashi ; Kaneko, Hideo ; Kondo, Naomi ; Tsuge, Ikuya ; Yachie, Akihiro ; Sakiyama, Yukio ; Iwata, Tsutomu ; Bessho, Fumio ; Ohishi, Tsutomu ; Joh, Kosuke ; Imai, Kohsuke ; Kogawa, Kazuhiro ; Shinohara, Miwa ; Fujieda, Mikiya ; Wakiguchi, Hiroshi ; Pasic, Srdjan ; Abinun, Mario ; Ochs, Hans D. ; Renner, Eleonore D. ; Jansson, Annette ; Belohradsky, Bernd H. ; Metin, Ayse ; Shimizu, Norio ; Mizutani, Shuki ; Miyawaki, Toshio ; Nonoyama, Shigeaki ; Karasuyama, Hajime. / Human Tyrosine Kinase 2 Deficiency Reveals Its Requisite Roles in Multiple Cytokine Signals Involved in Innate and Acquired Immunity. In: Immunity. 2006 ; Vol. 25, No. 5. pp. 745-755.
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T1 - Human Tyrosine Kinase 2 Deficiency Reveals Its Requisite Roles in Multiple Cytokine Signals Involved in Innate and Acquired Immunity

AU - Minegishi, Yoshiyuki

AU - Saito, Masako

AU - Morio, Tomohiro

AU - Watanabe, Ken

AU - Agematsu, Kazunaga

AU - Tsuchiya, Shigeru

AU - Takada, Hidetoshi

AU - Hara, Toshiro

AU - Kawamura, Nobuaki

AU - Ariga, Tadashi

AU - Kaneko, Hideo

AU - Kondo, Naomi

AU - Tsuge, Ikuya

AU - Yachie, Akihiro

AU - Sakiyama, Yukio

AU - Iwata, Tsutomu

AU - Bessho, Fumio

AU - Ohishi, Tsutomu

AU - Joh, Kosuke

AU - Imai, Kohsuke

AU - Kogawa, Kazuhiro

AU - Shinohara, Miwa

AU - Fujieda, Mikiya

AU - Wakiguchi, Hiroshi

AU - Pasic, Srdjan

AU - Abinun, Mario

AU - Ochs, Hans D.

AU - Renner, Eleonore D.

AU - Jansson, Annette

AU - Belohradsky, Bernd H.

AU - Metin, Ayse

AU - Shimizu, Norio

AU - Mizutani, Shuki

AU - Miyawaki, Toshio

AU - Nonoyama, Shigeaki

AU - Karasuyama, Hajime

PY - 2006/11/1

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N2 - Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.

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