Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.
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.
Minegishi
Yoshiyuki
Y
Department of Immune Regulation, Graduate School, Tokyo Medical and Dental University, Yushima, Tokyo, Japan. yminegishi.mbch@tmd.ac.jp
Saito
Masako
M
Morio
Tomohiro
T
Watanabe
Ken
K
Agematsu
Kazunaga
K
Tsuchiya
Shigeru
S
Takada
Hidetoshi
H
Hara
Toshiro
T
Kawamura
Nobuaki
N
Ariga
Tadashi
T
Kaneko
Hideo
H
Kondo
Naomi
N
Tsuge
Ikuya
I
Yachie
Akihiro
A
Sakiyama
Yukio
Y
Iwata
Tsutomu
T
Bessho
Fumio
F
Ohishi
Tsutomu
T
Joh
Kosuke
K
Imai
Kohsuke
K
Kogawa
Kazuhiro
K
Shinohara
Miwa
M
Fujieda
Mikiya
M
Wakiguchi
Hiroshi
H
Pasic
Srdjan
S
Abinun
Mario
M
Ochs
Hans D
HD
Renner
Eleonore D
ED
Jansson
Annette
A
Belohradsky
Bernd H
BH
Metin
Ayse
A
Shimizu
Norio
N
Mizutani
Shuki
S
Miyawaki
Toshio
T
Nonoyama
Shigeaki
S
Karasuyama
Hajime
H
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
D016207:Cytokines; D053634:TYK2 Kinase