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

Katharina L Willmann,Cecilia Domínguez Conde,Musa Gökalp Bolkent,Elisabeth Salzer,Jordan S Orange,Alphan Küpesiz,Wojciech Garncarz,Elisangela Santos-Valente,Kaan Boztuğ,Stefanie Klaver,Heiko Sic,Figen Doğu,Pinaki P Banerjee,Menno C Van Zelm,Hermann Eibel,Gregory I Vladimer,Şule Haskoloğlu,Jacques Colinge,Winfried F Pickl,Ivan Bilić ,Emily M Mace ,Giulio Superti‐Furga ,Antônio Condino‐Neto ,Peter Marynen ,Aydan İkincioğulları

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.

Highlights

Primary immunodeficiency disorders enable identification of genes with crucial roles in the human immune system
Absolute blood cell counts revealed B lymphopenia in p52 I-2 (P2), while B-cell numbers in P1 were in the agematched lower normal range (Supplementary Table 3)
As NIK is an integral component of the non-canonical nuclear factor-kB (NF-kB) pathway downstream of the BAFF receptor (BAFFR), which plays a key role in mature B-cell survival[29], we investigated whether functional NIK deficiency resembles phenotypes found in BAFFR deficiency[2,30]

Summary

Introduction

Primary immunodeficiency disorders enable identification of genes with crucial roles in the human immune system. We study patients suffering from recurrent bacterial, viral and Cryptosporidium infections, and identify a biallelic mutation in the MAP3K14 gene encoding NIK (NF-kB-inducing kinase). 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. BAFFR, CD40 and LTb receptors transmit signals through the non-canonical nuclear factor-kB (NF-kB) pathway We report a combined immunodeficiency syndrome caused by biallelic mutations in the gene encoding NIK, encompassing B-cell lymphopenia and impaired memory B-cell differentiation. We identify abnormal NK-cell development and function, as well as aberrant T-cell responses, indicating that biallelic loss-of-function mutations in NIK cause a hitherto unrecognized, pervasive combined immunodeficiency syndrome

Methods

Results

Conclusion