2. Academic Validation
  3. Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity

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

  • Nat Commun. 2014 Nov 19:5:5360. doi: 10.1038/ncomms6360.
Katharina L Willmann 1,  Stefanie Klaver 2,  Figen Doğu 3,  Elisangela Santos-Valente 1,  Wojciech Garncarz 1,  Ivan Bilic 1,  Emily Mace 4,  Elisabeth Salzer 1,  Cecilia Domínguez Conde 1,  Heiko Sic 5,  Peter Májek 1,  Pinaki P Banerjee 4,  Gregory I Vladimer 1,  Sule Haskoloğlu 3,  Musa Gökalp Bolkent 3,  Alphan Küpesiz 6,  Antonio Condino-Neto 7,  Jacques Colinge 1,  Giulio Superti-Furga 1,  Winfried F Pickl 8,  Menno C van Zelm 9,  Hermann Eibel 5,  Jordan S Orange 4,  Aydan Ikincioğulları 3,  Kaan Boztuğ 10
Affiliations

Affiliations

  • 1 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
  • 2 1] CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria [2] Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil.
  • 3 Department of Pediatric Immunology and Allergy, Ankara University Medical School, Ankara 06100, Turkey.
  • 4 Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas 77030, USA.
  • 5 Centre of Chronic Immunodeficiency, University Medical Centre Freiburg, Freiburg 79180, Germany.
  • 6 Department of Pediatric Hematology, Akdeniz University Medical School, Antalya 07985, Turkey.
  • 7 Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil.
  • 8 Christian Doppler Laboratory for Immunomodulation and Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna 1090, Austria.
  • 9 Department of Immunology, Erasmus MC, University Medical Center, Rotterdam 3015GE, The Netherlands.
  • 10 1] CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria [2] Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna 1090, Austria.
PMID: 25406581 DOI: 10.1038/ncomms6360
Abstract

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 Cryptosporidium infections, and identify a biallelic mutation in the MAP3K14 gene encoding NIK (NF-κB-inducing kinase). Loss of kinase activity of mutant NIK, predicted by in silico analysis and confirmed by functional assays, leads to defective activation of both canonical and non-canonical NF-κB signalling. Patients with mutated NIK 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 NIK can cause multiple aberrations of lymphoid immunity.

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