Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity
Résumé
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-kappaB-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-kappaB 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.
Mots clés
Humans
Female
Mutation
Computer Simulation
Infant
Recurrence
Child
Preschool
Immunoglobulin Class Switching
Pedigree
Agammaglobulinemia/*genetics/immunology
B-Lymphocytes/immunology
Bacterial Infections/immunology
Cryptosporidiosis/immunology
Immunologic Deficiency Syndromes/genetics
Immunologic Memory
Inducible T-Cell Co-Stimulator Ligand/metabolism
Killer Cells
Natural/immunology
Leukocyte Count
Lymphocyte Count
Lymphopenia/*genetics/immunology
Protein-Serine-Threonine Kinases/*genetics
T-Lymphocytes
Helper-Inducer/immunology
Virus Diseases/immunology
Domaines
Cancer| Origine | Fichiers éditeurs autorisés sur une archive ouverte |
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