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

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autorinnen und Autoren: Boisson-Dupuis S, Ramirez-Alejo N, Li Z, Patin E, Rao G, Kerner G, Lim CK, Krementsov DN, Hernandez N, Ma CS, Zhang Q, Markle J, Martinez-Barricarte R, Payne K, Fisch R, Deswarte C, Halpern J, Bouaziz M, Mulwa J, Sivanesan D, Lazarov T, Naves R, Garcia P, Itan Y, Boisson B, Checchi A, Jabot-Hanin F, Cobat A, Guennoun A, Jackson CC, Pekcan S, Caliskaner Z, Inostroza J, Costa-Carvalho BT, Tavares De Albuquerque JA, Garcia-Ortiz H, Orozco L, Ozcelik T, Abid A, Rhorfi IA, Souhi H, Amrani HN, Zegmout A, Geissmann F, Michnick SW, Muller-Fleckenstein I, Fleckenstein B, Puel A, Ciancanelli MJ, Marr N, Abolhassani H, Elvira Balcells M, Condino-Neto A, Strickler A, Abarca K, Teuscher C, Ochs HD, Reisli I, Sayar EH, El-Baghdadi J, Bustamante J, Hammarstrom L, Tangye SG, Pellegrini S, Quintana-Murci L, Abel L, Casanova JL
Zeitschrift: Science immunology
Jahr der Veröffentlichung: 2018
Band: 3
Heftnummer: 30
ISSN: 2470-9468


Abstract

Inherited IL-12R beta 1 and TYK2 deficiencies impair both IL-12- and IL-23 -dependent IFN-gamma 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 x 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-alpha, IL-10, or even IL-12, which, like IL-23, induces IFN-gamma 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-gamma by IL-23 and is a common monogenic etiology of tuberculosis.


FAU-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Fleckenstein, Bernhard Prof. Dr.
Medizinische Fakultät


Einrichtungen weiterer Autorinnen und Autoren

Bilkent University / Bilkent Üniversitesi
Federal University of São Paulo / Universidade Federal de São Paulo (UNIFESP)
Garvan Institute of Medical Research
Institut Pasteur
Karolinska Institute
Memorial Sloan Kettering Cancer Center
Military Hospital Mohammed V
National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM)
National Institute of Genomic Medicine / Instituto Nacional de Medicina Genómica (INMEGEN)
Necmettin Erbakan Üniversitesi
Pontificia Universidad Católica de Chile
Rockefeller University
San Sebastián University / Universidad San Sebastián
Sidra Medical and Research Center
Universidad de Santiago de Chile (USACH) / University of Santiago, Chile
Université de Montréal
University of São Paulo / Universidade de São Paulo (USP)
University of the Frontier / Universidad de La Frontera (UFRO)
University of Vermont
University of Washington


Zitierweisen

APA:
Boisson-Dupuis, S., Ramirez-Alejo, N., Li, Z., Patin, E., Rao, G., Kerner, G.,... Casanova, J.-L. (2018). Tuberculosis and impaired IL-23-dependent IFN-gamma immunity in humans homozygous for a common TYK2 missense variant. Science immunology, 3(30). https://dx.doi.org/10.1126/sciimmunol.aau8714

MLA:
Boisson-Dupuis, Stephanie, et al. "Tuberculosis and impaired IL-23-dependent IFN-gamma immunity in humans homozygous for a common TYK2 missense variant." Science immunology 3.30 (2018).

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Zuletzt aktualisiert 2019-01-02 um 08:23