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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-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.
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https://hal.umontpellier.fr/hal-02181338
Contributor : Cécile Nowak <>
Submitted on : Friday, July 12, 2019 - 9:18:06 AM
Last modification on : Thursday, April 30, 2020 - 2:22:02 PM

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K. L. Willmann, S. Klaver, F. Dogu, E. Santos-Valente, W. Garncarz, et al.. Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity. Nature Communications, Nature Publishing Group, 2014, 5, pp.5360. ⟨10.1038/ncomms6360⟩. ⟨hal-02181338⟩

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