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Willmann, Katharina L.; Klaver, Stefanie; Doğu, Figen; Santos-Valente, Elisangela; Garncarz, Wojciech; Bilic, Ivan; Mace, Emily; Salzer, Elisabeth; Domínguez Conde, Cecilia; Sic, Heiko; Májek, Peter; Banerjee, Pinaki P.; Vladimer, Gregory I.; Haskoloğlu, Şule; Gökalp Bolkent, Musa; Küpesiz, Alphan; Condino-Neto, Antonio; Colinge, Jacques; Superti-Furga, Giulio; Pickl, Winfried F.; van Zelm, Menno C.; Eibel, Hermann; Orange, Jordan S.; Ikincioğulları, Aydan;

Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity

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  • Medientyp: E-Artikel
  • Titel: Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity
  • Beteiligte: Willmann, Katharina L.; Klaver, Stefanie; Doğu, Figen; Santos-Valente, Elisangela; Garncarz, Wojciech; Bilic, Ivan; Mace, Emily; Salzer, Elisabeth; Domínguez Conde, Cecilia; Sic, Heiko; Májek, Peter; Banerjee, Pinaki P.; Vladimer, Gregory I.; Haskoloğlu, Şule; Gökalp Bolkent, Musa; Küpesiz, Alphan; Condino-Neto, Antonio; Colinge, Jacques; Superti-Furga, Giulio; Pickl, Winfried F.; van Zelm, Menno C.; Eibel, Hermann; Orange, Jordan S.; Ikincioğulları, Aydan;
  • Erschienen: Springer Science and Business Media LLC, 2014
  • Erschienen in: Nature Communications
  • Sprache: Englisch
  • DOI: 10.1038/ncomms6360
  • ISSN: 2041-1723
  • Schlagwörter: General Physics and Astronomy ; General Biochemistry, Genetics and Molecular Biology ; General Chemistry ; Multidisciplinary
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Primary immunodeficiency disorders enable identification of genes with crucial roles in the human immune system. Here we study patients suffering from recurrent bacterial, viral and <jats:italic>Cryptosporidium</jats:italic> infections, and identify a biallelic mutation in the <jats:italic>MAP3K14</jats:italic> gene encoding NIK (NF-κB-inducing kinase). Loss of kinase activity of mutant NIK, predicted by <jats:italic>in silico</jats:italic> analysis and confirmed by functional assays, leads to defective activation of both canonical and non-canonical NF-κB signalling. Patients with mutated <jats:italic>NIK</jats:italic> exhibit B-cell lymphopenia, decreased frequencies of class-switched memory B cells and hypogammaglobulinemia due to impaired B-cell survival, and impaired ICOSL expression. Although overall T-cell numbers are normal, both follicular helper and memory T cells are perturbed. Natural killer (NK) cells are decreased and exhibit defective activation, leading to impaired formation of NK-cell immunological synapses. Collectively, our data illustrate the non-redundant role for NIK in human immune responses, demonstrating that loss-of-function mutations in <jats:italic>NIK</jats:italic> can cause multiple aberrations of lymphoid immunity.</jats:p>
  • Zugangsstatus: Freier Zugang