Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity.

Nature communications (2014-11-20)
Katharina L Willmann, Stefanie Klaver, Figen Doğu, Elisangela Santos-Valente, Wojciech Garncarz, Ivan Bilic, Emily Mace, Elisabeth Salzer, Cecilia Domínguez Conde, Heiko Sic, Peter Májek, Pinaki P Banerjee, Gregory I Vladimer, Sule Haskoloğlu, Musa Gökalp Bolkent, Alphan Küpesiz, Antonio Condino-Neto, Jacques Colinge, Giulio Superti-Furga, Winfried F Pickl, Menno C van Zelm, Hermann Eibel, Jordan S Orange, Aydan Ikincioğulları, Kaan Boztuğ

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.

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Anti-HA−Peroxidase antibody, Mouse monoclonal antibody produced in mouse, clone HA-7, purified from hybridoma cell culture