NF-κB1 Haploinsufficiency Causing Immunodeficiency and EBV-Driven Lymphoproliferation

Abstract

Purpose: NF-κB signaling is critically important for regulation of both innate and adaptive immune responses. While activation of NF-κB has been implicated in malignancies such as leukemia and lymphoma, loss-of-function mutations affecting different NF-κB pathway components have been shown to cause primary immunodeficiency disorders. Recently, haploinsufficiency of NF-κB1 has been described in three families with common variable immunodeficiency (CVID).

Methods and results: We studied a patient with recurrent respiratory infections and bacterial parapharyngeal abscess. Immunological investigations revealed normal total B- cell numbers, but hypogammaglobulinemia, decreased frequencies of class-switched B cells and impaired T-cell proliferation. Targeted next-generation sequencing using a custom-designed panel comprising all known PID genes (IUIS 2014 classification) and novel candidate genes identified a novel heterozygous frameshift mutation in the NFKB1 gene leading to a premature stop codon (c.491delG; p.G165A*31). We could show that the mutation leads to reduced phosphorylation of p105 upon stimulation, resulting in decreased protein levels of p50. The further disease course was mainly characterized by two episodes of severe EBV-associated lymphoproliferative disease responsive to rituximab treatment. Due to disease severity, the patient is considered for allogeneic hematopoietic stem cell transplantation. Interestingly, the father carries the same heterozygous NFKB1 mutation and also shows decreased frequencies of memory B cells but has a much milder clinical phenotype, in line with a considerable phenotypic disease heterogeneity.

Conclusions: Deficiency of NF-κB1 leads to immunodeficiency with a wider phenotypic spectrum of disease manifestation than previously appreciated, including EBV lymphoproliferative diseases as a hitherto unrecognized feature of the disease.

Keywords: Combined immunodeficiency; EBV lymphoproliferative disease; NF-κB1; haploinsufficiency.

Fig. 1

Clinical and immunological phenotype. Initially, the index patient presented with a parapharyngeal abscess which was surgically drained (a). Immunological assessment revealed normal total number of B cells (b) but decreased numbers of non-switched (CD27⁺IgD⁺) and switched (CD27⁺IgD⁻) memory B cells in comparison to healthy donor. c At the age of 18 years, the patient showed EBV lymphoproliferative diseases including EBV reactivation, cervical lymphadenopathy (d), splenomegaly (e), and multiple splenic lesions (f), all of which normalized upon treatment with anti-CD20 (rituximab)

Fig. 2

Identification of a disease-causing mutation in. Disease severity and complications increased over time with two severe episodes of EBV-associated lymphoproliferation within one year (a). The patient was assessed using a targeted, next-generation sequencing-based gene panel with high on-target coverage (b). A heterozygous mutation in the RHD domain of the NFKB1 gene was identified, leading to a frameshift and a subsequent stop codon (c.491delG; p.G165A*31). The patient’s father was found to be a carrier of the disease (c) and shows an aberrant B cell immunophenotype despite his mild clinical manifestation (Table 1). The mutation leads to reduced phosphorylation of p105 upon stimulation in both index patient (II-1) and father (I-2), resulting in decreased protein levels of p50 (d)