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

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- B-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- B 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

Long-Lived Plasma Cells and Memory B Cells Produce Pathogenic Anti-GAD65 Autoantibodies in Stiff Person Syndrome

Stiff person syndrome (SPS) is a rare, neurological disorder characterized by sudden cramps and spasms. High titers of enzyme-inhibiting IgG autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GAD65) are a hallmark of SPS, implicating an autoimmune component in the pathology of the syndrome. Studying the B cell compartment and the anti-GAD65 B cell response in two monozygotic twins suffering from SPS, who were treated with the B cell-depleting monoclonal anti-CD20 antibody rituximab, we found that the humoral autoimmune response in SPS is composed of a rituximab-sensitive part that is rapidly cleared after treatment, and a rituximab-resistant component, which persists and acts as a reservoir for autoantibodies inhibiting GAD65 enzyme activity. Our data show that these potentially pathogenic anti-GAD65 autoantibodies are secreted by long-lived plasma cells, which may either be persistent or develop from rituximab-resistant memory B lymphocytes. Both subsets represent only a fraction of anti-GAD65 autoantibody secreting cells. Therefore, the identification and targeting of this compartment is a key factor for successful treatment planning of SPS and of similar autoimmune diseases

Making Science Fun - A Tribute to Our Colleague and Friend, Prof. Antonius G. Rolink (1953-2017)

This Research Topic honors the memory of Prof. Antonius “Ton” G. Rolink (April 19, 1953–August 06, 2017), our colleague, mentor and friend in immunology. It is now over a year since Ton left us. This article collection, authored by many of Ton’s friends and colleagues, reflects the huge contribution to cellular and molecular immunology that work emanating directly from Ton’s own hands and laboratory have made to the understanding of lymphocyte development. Ton’s hard work, expertise, generosity, passion for science and infectious humor were legendary and for all of those lucky enough to have been his colleague, he ensured that science was fun. We take this opportunity of thanking all contributors for submitting their manuscripts; we are sure that Ton would have enjoyed reading and making his own insightful comments on them. In the form of original research and review articles, these papers cover many of Ton’s scientific interests in different aspects of lymphocyte development in mouse and man. In the first section, Development of hematopoietic cells and lymphocytes, Klein et al. describe the accumulation of multipotent hematopoietic progenitors in peripheral lymphoid organs of IL-7xFlt3L double transgenic mice and Pang et al. the role of the transcription factor PU.1 on the development of Common Lymphoid Progenitors. In Early B cell development, Winkler and Mårtensson review the role of the Pre-B cell receptor in B cell development and papers by Hobeika et al. and Brennecke et al. describe models of inducible B cell development. For B cell selection, survival and tolerance, Smulski and Eibel review the role of BAFF and Kowalczyk-Quintans et al. analyse the role of membrane-bound BAFF. The impact of BIM on B cell homeostasis is discussed by Liu et al. The role of the MEK-ERK pathway in B cell tolerance is discussed by Greaves et al. and the transcriptional regulation of germinal center development is reviewed by Song and Matthias. For Hematological diseases, Ghia reviews how studies of B cell development help the understanding of Leukemia development, Kim and Schaniel review how iPS technology helps the understanding of hematological diseases and Hellmann et al. describe development of new therapeutic antibody drug conjugates. Finally, in T cell development, homeostasis and graft vs. host disease, Heiler et al. describe the therapeutic effects of IL-2/anti-IL-2 immune complexes in GvHD, Calvo-Asensio et al. describe the DNA damage response of thymocyte progenitors and Mori and Pieters review the role of Coronin 1 in T cell survival

Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels

Background: Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans