title: Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity.
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.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Katharina L
authors.initials: KL
authors.lastname: Willmann
authors.affiliation: 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.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Klaver
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University Medical School, Ankara 06100, Turkey.
authors.forename: Figen
authors.initials: F
authors.lastname: Doğu
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Elisangela
authors.initials: E
authors.lastname: Santos-Valente
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Garncarz
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bilic
authors.affiliation: Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Mace
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Salzer
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Cecilia Domínguez
authors.initials: CD
authors.lastname: Conde
authors.affiliation: Centre of Chronic Immunodeficiency, University Medical Centre Freiburg, Freiburg 79180, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Sic
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Májek
authors.affiliation: Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Pinaki P
authors.initials: PP
authors.lastname: Banerjee
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Vladimer
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University Medical School, Ankara 06100, Turkey.
authors.forename: Sule
authors.initials: S
authors.lastname: Haskoloğlu
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University Medical School, Ankara 06100, Turkey.
authors.forename: Musa Gökalp
authors.initials: MG
authors.lastname: Bolkent
authors.affiliation: Department of Pediatric Hematology, Akdeniz University Medical School, Antalya 07985, Turkey.
authors.forename: Alphan
authors.initials: A
authors.lastname: Küpesiz
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil.
authors.forename: Antonio
authors.initials: A
authors.lastname: Condino-Neto
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.affiliation: Christian Doppler Laboratory for Immunomodulation and Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna 1090, Austria.
authors.forename: Winfried F
authors.initials: WF
authors.lastname: Pickl
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, Rotterdam 3015GE, The Netherlands.
authors.forename: Menno C
authors.initials: MC
authors.lastname: van Zelm
authors.affiliation: Centre of Chronic Immunodeficiency, University Medical Centre Freiburg, Freiburg 79180, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Eibel
authors.affiliation: Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University Medical School, Ankara 06100, Turkey.
authors.forename: Aydan
authors.initials: A
authors.lastname: Ikincioğulları
authors.affiliation: 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.
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztuğ
mesh_terms: D000361:Agammaglobulinemia / Q000235:genetics* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D001424:Bacterial Infections / Q000276:immunology; D002675:Child, Preschool; D003198:Computer Simulation; D003457:Cryptosporidiosis / Q000276:immunology; D005260:Female; D006801:Humans; D017578:Immunoglobulin Class Switching; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D007156:Immunologic Memory; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000378:metabolism; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology; D007958:Leukocyte Count; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000235:genetics* / Q000276:immunology; D009154:Mutation; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012008:Recurrence; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D060945:Inducible T-Cell Co-Stimulator Ligand; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C498514:ICOSLG protein, human