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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinemia / genetics*
  • Agammaglobulinemia / immunology
  • B-Lymphocytes / immunology
  • Bacterial Infections / immunology
  • Child, Preschool
  • Computer Simulation
  • Cryptosporidiosis / immunology
  • Female
  • Humans
  • Immunoglobulin Class Switching
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Memory
  • Inducible T-Cell Co-Stimulator Ligand / metabolism
  • Infant
  • Killer Cells, Natural / immunology
  • Leukocyte Count
  • Lymphocyte Count
  • Lymphopenia / genetics*
  • Lymphopenia / immunology
  • Mutation
  • Pedigree
  • Protein-Serine-Threonine Kinases / genetics*
  • Recurrence
  • T-Lymphocytes, Helper-Inducer / immunology
  • Virus Diseases / immunology

Substances

  • ICOSLG protein, human
  • Inducible T-Cell Co-Stimulator Ligand
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase