| Added by | mollevi |
|---|---|
| Last modified by | jacques.colinge |
| Group name | EquipeJC |
| Item Type | Journal Article |
| Title | Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity |
| Creator | Willmann et al. |
| Author | K. L. Willmann |
| Author | S. Klaver |
| Author | F. Dogu |
| Author | E. Santos-Valente |
| Author | W. Garncarz |
| Author | I. Bilic |
| Author | E. Mace |
| Author | E. Salzer |
| Author | C. D. Conde |
| Author | H. Sic |
| Author | P. Majek |
| Author | P. P. Banerjee |
| Author | G. I. Vladimer |
| Author | S. Haskologlu |
| Author | M. G. Bolkent |
| Author | A. Kupesiz |
| Author | A. Condino-Neto |
| Author | J. Colinge |
| Author | G. Superti-Furga |
| Author | W. F. Pickl |
| Author | M. C. van Zelm |
| Author | H. Eibel |
| Author | J. S. Orange |
| Author | A. Ikinciogullari |
| Author | K. Boztug |
| 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-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. |
| Publication | Nat Commun |
| Volume | 5 |
| Pages | 5360 |
| Date | 2014 |
| Journal Abbr | Nature communications |
| DOI | 10.1038/ncomms6360 |
| ISSN | 2041-1723 (Electronic) 2041-1723 (Linking) |
| Tags | Agammaglobulinemia/*genetics/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/immunology, Mutation, original, Pedigree, Protein-Serine-Threonine Kinases/*genetics, Recurrence, T-Lymphocytes, Helper-Inducer/immunology, Virus Diseases/immunology |
| Date Added | 2018/11/14 - 11:48:35 |
| Date Modified | 2019/05/14 - 20:57:54 |
| Notes and Attachments | (Note) (Note) 25406581 (Attachment) |
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