NF-κB1 Haploinsufficiency Causing Immunodeficiency and EBV-Driven Lymphoproliferation

Abstract

PurposeNF-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 ResultsWe 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.ConclusionsDeficiency 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10875-016-0306-1) contains supplementary material, which is available to authorized users.

NFKB1 regulates human NK cell maturation and effector functions

“…Besides an increased proportion of autoimmune multiorgan manifestations, which is consistent with observations in p50-deficient mice [26], our cohort of patients with heterozygous NFKB1 mutations presents with an increased prevalence of viral infections, including herpes zoster, JC virus, CMV, Norovirus and EBV, a finding which has previously not been described and which may indicate a broader susceptibility to viral infections in this disorder. Recently, another patient with NFKB1 haploinsufficiency was recently reported with EBV-driven lymphoproliferation, further suggesting a susceptibility to viral infections in NFKB1 mutated patients [27].…”

The Expanding Spectrum of NFkB1 Deficiency

“…This report by Boztug et al [6] extends the clinical and immunological phenotype of NFkB1 deficient patients, thereby expanding the spectrum of this newly described rare PID. And while EBV-induced lymphoproliferation was not previously reported for individuals with p50 haploinsufficiency [2], the current finding suggests an important role for canonical NFkB signaling in controlling EBV infection and subsequent lymphoproliferation [6].…”

“…The authors demonstrated that the mutation was also present in the proband's father, who had a milder clinical phenotype, consistent with a diagnosis of probable CVID. Peripheral blood mononuclear cells from both individuals demonstrated severe reductions in expression of p105 and p50, and the complete absence of mutant p50 following mitogenic stimulation [6].…”

“…In this issue of the Journal of Clinical Immunology, Boztug et al describe a young adult patient who presented with hypogammaglobulinemia, parapharyngeal abscesses, cervical lymphadenopathy and-most strikingly-EBV-driven lymphoproliferation [6]. Laboratory investigations revealed impaired T cell function in response to tetanus antigen and TCR stimulation and reduced memory B cells, a phenotype resembling classic CID [6].…”

“…Laboratory investigations revealed impaired T cell function in response to tetanus antigen and TCR stimulation and reduced memory B cells, a phenotype resembling classic CID [6]. While no mutations were identified in known EBV-associated genes, a custom next generation sequencing panel that assessed 419 known pathogenic as well as additional candidate PID genes revealed a novel heterozygous mutation in NFKB1 that results in a severely truncated non-functional protein, similar to one described in the original report of NFkB1 deficiency by Fleigauf et al [2].…”