Kreins, Alexandra Y.Ciancanelli, Michael J.Okada, SatoshiKong, Xiao-FeiRamirez-Alejo, NoeKılıç, Sara ŞebnemEl Baghdadi, JamilaNonoyama, ShigeakiMahdaviani, Seyed AlirezaAilal, FatimaBousfiha, AzizMansouri, DavoodNievas, ElmaMa, Cindy S.Rao, GeethaBernasconi, AndreaKuehn, Hye SunNiemela, JulieStoddard, JenniferDeveau, PaulCobat, AurelieEl Azbaoui, SafaSabri, AyoubLim, Che KangSundin, MikaelAvery, Danielle T.Halwani, RabihGrant, Audrey V.Boisson, BertrandBogunovic, DusanItan, YuvalMoncada-Velez, MarcelaMartinez-Barricarte, RubenMigaud, MelanieDeswarte, CarolineAlsina, LaiaKotlarz, DanielKlein, ChristophMuller-Fleckenstein, IngridFleckenstein, BernhardCormier-Daire, ValerieRose-John, StefanPicard, CapucineHammarstrom, LennartPuel, AnneAl-Muhsen, SalehAbel, LaurentChaussabel, DamienRosenzweig, Sergio D.Minegishi, YoshiyukiTangye, Stuart G.Bustamante, JacintaCasanova, Jean-LaurentBoisson-Dupuis, Stephanie2024-08-132024-08-132015-09-210022-1007https://doi.org/10.1084/jem.20140280https://rupress.org/jem/article/212/10/1641/41672/Human-TYK2-deficiency-Mycobacterial-and-viralhttps://europepmc.org/backend/ptpmcrender.fcgihttps://hdl.handle.net/11452/43981Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-alpha/beta, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-gamma, IL-28/29 (IFN-lambda), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-alpha/beta. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.eninfo:eu-repo/semantics/openAccessProtein-tyrosine kinaseInborn-errorsIfn-gammaInterferon-alpha/betaClinical-featuresSignal transducerB10.q/j miceMendelian susceptibilityCytokine responsesPartial impairmentScience & technologyLife sciences & biomedicineImmunologyMedicine, research & experimentalResearch & experimental medicineArticle000365135200014164116622121010.1084/jem.201402801540-9538