title: Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.
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.
authors.affiliation: Department of Immune Regulation, Graduate School, Tokyo Medical and Dental University, Yushima, Tokyo, Japan. yminegishi.mbch@tmd.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Minegishi
authors.forename: Masako
authors.initials: M
authors.lastname: Saito
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.forename: Ken
authors.initials: K
authors.lastname: Watanabe
authors.forename: Kazunaga
authors.initials: K
authors.lastname: Agematsu
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tsuchiya
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takada
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Kawamura
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ariga
authors.forename: Hideo
authors.initials: H
authors.lastname: Kaneko
authors.forename: Naomi
authors.initials: N
authors.lastname: Kondo
authors.forename: Ikuya
authors.initials: I
authors.lastname: Tsuge
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yachie
authors.forename: Yukio
authors.initials: Y
authors.lastname: Sakiyama
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Iwata
authors.forename: Fumio
authors.initials: F
authors.lastname: Bessho
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ohishi
authors.forename: Kosuke
authors.initials: K
authors.lastname: Joh
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kogawa
authors.forename: Miwa
authors.initials: M
authors.lastname: Shinohara
authors.forename: Mikiya
authors.initials: M
authors.lastname: Fujieda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wakiguchi
authors.forename: Srdjan
authors.initials: S
authors.lastname: Pasic
authors.forename: Mario
authors.initials: M
authors.lastname: Abinun
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Eleonore D
authors.initials: ED
authors.lastname: Renner
authors.forename: Annette
authors.initials: A
authors.lastname: Jansson
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Belohradsky
authors.forename: Ayse
authors.initials: A
authors.lastname: Metin
authors.forename: Norio
authors.initials: N
authors.lastname: Shimizu
authors.forename: Shuki
authors.initials: S
authors.lastname: Mizutani
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyawaki
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.forename: Hajime
authors.initials: H
authors.lastname: Karasuyama
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D016207:Cytokines / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate; D015151:Immunoblotting; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D007223:Infant; D007589:Job Syndrome / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D053634:TYK2 Kinase / Q000172:deficiency* / Q000235:genetics
chemical_list: D016207:Cytokines; D053634:TYK2 Kinase