Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant

buir.contributor.authorÖzçelik, Tayfun
dc.citation.issueNumber30en_US
dc.citation.volumeNumber3en_US
dc.contributor.authorBoisson-Dupuis, S.en_US
dc.contributor.authorRamirez-Alejo, N.en_US
dc.contributor.authorLi, Z.en_US
dc.contributor.authorPatin, E.en_US
dc.contributor.authorRao, G.en_US
dc.contributor.authorKerner, G.en_US
dc.contributor.authorLim, C. K.en_US
dc.contributor.authorKrementsov, D. N.en_US
dc.contributor.authorHernandez, N.en_US
dc.contributor.authorMa, C. S.en_US
dc.contributor.authorZhang, Q.en_US
dc.contributor.authorMarkle, J.en_US
dc.contributor.authorMartinez-Barricarte, R.en_US
dc.contributor.authorPayne, K.en_US
dc.contributor.authorFisch, R.en_US
dc.contributor.authorDeswarte, C.en_US
dc.contributor.authorHalpern, J.en_US
dc.contributor.authorBouaziz, M.en_US
dc.contributor.authorMulwa, J.en_US
dc.contributor.authorSivanesan, D.en_US
dc.contributor.authorLazarov, T.en_US
dc.contributor.authorNaves, R.en_US
dc.contributor.authorGarcia, P.en_US
dc.contributor.authorItan, Y.en_US
dc.contributor.authorBoisson, B.en_US
dc.contributor.authorChecchi, A.en_US
dc.contributor.authorJabot-Hanin, F.en_US
dc.contributor.authorCobat, A.en_US
dc.contributor.authorGuennoun, A.en_US
dc.contributor.authorJackson, C. C.en_US
dc.contributor.authorPekcan, S.en_US
dc.contributor.authorÇalışkaner, Z.en_US
dc.contributor.authorInostroza, J.en_US
dc.contributor.authorCosta-Carvalho, B. T.en_US
dc.contributor.authorDe Albuquerque, J. A. T.en_US
dc.contributor.authorGarcia-Ortiz, H.en_US
dc.contributor.authorOrozco, L.en_US
dc.contributor.authorÖzçelik, Tayfunen_US
dc.contributor.authorAbid, A.en_US
dc.contributor.authorRhorfi, I. A.en_US
dc.contributor.authorSouhi, H.en_US
dc.contributor.authorAmrani, H. N.en_US
dc.contributor.authorZegmout, A.en_US
dc.contributor.authorGeissmann, F.en_US
dc.contributor.authorMichnick, S. W.en_US
dc.contributor.authorMuller-Fleckenstein, I.en_US
dc.contributor.authorFleckenstein, B.en_US
dc.contributor.authorPuel, A.en_US
dc.contributor.authorCiancanelli, M. J.en_US
dc.contributor.authorMarr, N.en_US
dc.contributor.authorAbolhassani, H.en_US
dc.contributor.authorBalcells, M. E.en_US
dc.contributor.authorCondino-Neto, A.en_US
dc.contributor.authorStrickler, A.en_US
dc.contributor.authorAbarca, K.en_US
dc.contributor.authorTeuscher, C.en_US
dc.contributor.authorOchs, H. D.en_US
dc.contributor.authorReisli, I.en_US
dc.contributor.authorSayar, E. H.en_US
dc.contributor.authorEl-Baghdadi, J.en_US
dc.contributor.authorBustamante, J.en_US
dc.contributor.authorHammarström, L.en_US
dc.contributor.authorTangye, S. G.en_US
dc.contributor.authorPellegrini, S.en_US
dc.contributor.authorQuintana-Murci, L.en_US
dc.contributor.authorAbel, L.en_US
dc.contributor.authorCasanova, J. -L.en_US
dc.date.accessioned2019-02-21T16:06:34Z
dc.date.available2019-02-21T16:06:34Z
dc.date.issued2018en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractInherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls (P = 8.37 × 10-8; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis. Copyright
dc.description.provenanceMade available in DSpace on 2019-02-21T16:06:34Z (GMT). No. of bitstreams: 1 Bilkent-research-paper.pdf: 222869 bytes, checksum: 842af2b9bd649e7f548593affdbafbb3 (MD5) Previous issue date: 2018en
dc.identifier.doi10.1126/sciimmunol.aau8714
dc.identifier.issn2470-9468
dc.identifier.urihttp://hdl.handle.net/11693/50318
dc.language.isoEnglish
dc.publisherNLM (Medline)
dc.relation.isversionofhttps://doi.org/10.1126/sciimmunol.aau8714
dc.source.titleScience immunologyen_US
dc.titleTuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common TYK2 missense varianten_US
dc.typeArticleen_US

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
Tuberculosis_and_impaired_IL-23-dependent_IFN-γ_immunity_in_humans_homozygous_for_a_common_TYK2_missense_variant.pdf
Size:
1.65 MB
Format:
Adobe Portable Document Format
Description:
Full printable version