Mouse model underestimates the critical role of Tyk2 in human immune system

A new study identifies a human Tyk2 deficiency and definitively links this molecule with multiple cytokine signals that are critical for the human immune responses. The research, published online in October 2006 by the journal Immunity, highlights the importance of Tyk2 function in humans and its differences in mice.

Dr. Yoshiyuki Minegishi from Tokyo Medical and Dental University and colleagues investigated immunological abnormalities in a patient diagnosed with a unique primary immunodeficiency called hyper IgE syndrome (HIES). The researchers observed that the patient showed some symptoms not frequently associated with HIES and found that the signaling pathways of two different soluble proteins (cytokines), IL-12 and IFN-, were defective in the patient. The researchers subsequently discovered that the patient carried a mutation in both copies of the gene for Tyk2. Tyk2, a non-receptor tyrosine kinase that belongs to the Janus kinase (Jak) family, is an enzyme shared by both IL-12 and IFN- signaling pathways.

Surprisingly, the patient's cells displayed severe defects in signaling pathways not only for IL-12 and IFN- but also for other cytokines including IL-6, IL-10 and IL-23, an observation that is in stark contrast to earlier studies with Tyk2-deficient mice that exhibited partially impaired IFN signaling and normal IL-6 and IL-10 signaling. This discrepancy is most likely due to a species difference between humans and mice. When normal Tyk2 was given to the patient's cells, it restored IL-12 and type I IFN signaling. In contrast, inhibition of Tyk2 expression in a normal human cell line disrupted IFN- signaling. Therefore, unlike what has been observed in mice, Tyk2 appears to be critical for the multiple cytokine signals involved in the immune system in humans.

The researchers conclude that the absence of functional Tyk2 caused the defects in the multiple cytokine signals that were observed in the patient and identify human Tyk2 mutation as a unique type of primary immunodeficiency with characteristics similar to autosomal recessive HIES. "This study is the first to identify human Tyk2 deficiency and demonstrates the unique and indispensable role played by Tyk2 in the innate and acquired immune response in human," says Dr. Minegishi.

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The researchers include Yoshiyuki Minegishi, Masako Saito, Tomohiro Morio, Ken Watanabe, Norio Shimizu, Sheik Mizutani, and Hajime Karasuyama of Tokyo Medical and Dental University, Tokyo, Japan; Kazunaga Agematsu of Shinshu University, Matsumoto, Japan; Shigeru Tsuchiya of Tohoku University, Sendai, Japan; Hidetoshi Takada and Toshiro Hara of Kyushu University, Fukuoka, Japan; Nobuaki Kawamura and Tadashi Ariga of Hokkaido University Graduate School of Medicine, Sapporo, Japan; Hideo Kaneko and Naomi Kondo of Gifu University, Gifu, Japan; Ikuya Tsuge of Fujita Health University, Nagoya, Japan; Akihiro Yachie of Kanazawa University, Kanazawa, Japan; Yukio Sakiyama of Teine-Keijinkai Hospital, Pediatric Science, Sapporo, Japan; Tsutomu Iwata of Tokyo Kasei University, Tokyo, Japan; Fumio Bessho of Kyorin University School of Medicine, Tokyo, Japan; Tsutomu Ohishi and Kosuke Joh of Saitama Children's Medical Center, Saitama, Japan; Kohsuke Imai, Kazuhiro Kogawa, and Shigeaki Nonoyama of National Defense Medical College, Saitama, Japan; Miwa Shinohara, Mikiya Fujieda, and Hiroshi Wakiguchi of Kochi Medical School, Kochi, Japan; Srdjan Pasic of Mother and Child Health Institute, Belgrade, Serbia and Montenegro; Mario Abinun of Newcastle General Hospital, UK; Hans D Ochs of University of Washington and Children's Hospital, Seattle, USA; Eleonore D Renner of University of Washington and Children's Hospital, Seattle, USA and Ludwig Maximilian University, Munich, Germany; Annette Jansson and Bernd H Belohradsky of Ludwig Maximilian University, Munich, Germany; Ayse Metin of SB Ankara Diskapi Children's Hospital, Ankara, Turkey; Toshio Miyawaki of University of Toyama, Japan.

This work is supported by Grants-in-Aid 16616004 and 17047013, 18659299 from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and Grants-in-Aid 2212131 and 2211932 from the Japanese Ministry of Health, Labor and Welfare. Publishing in Immunity, Vol. 25, Issue 5 November, 2006. http://www.immunity.com/


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