Human NF-κB1 Haploinsufficiency and Epstein–Barr Virus-Induced Disease—Molecular Mechanisms and Consequences

Abstract

Nuclear factor kappa-light-chain-enhancer of activated B cells 1 (NF-κB1)-related human primary immune deficiencies have initially been characterized as defining a subgroup of common variable immunodeficiencies (CVIDs), representing intrinsic B-cell disorders with antibody deficiency and recurrent infections of various kind. Recent evidence indicates that NF-κB1 haploinsufficiency underlies a variable type of combined immunodeficiency (CID) affecting both B and T lymphocyte compartments, with a broadened spectrum of disease manifestations, including Epstein–Barr virus (EBV)-induced lymphoproliferative disease and immediate life-threatening consequences. As part of this review series focused on EBV-related primary immunodeficiencies, we discuss the current clinical and molecular understanding of monoallelic NFKB1 germline mutations with special focus on the emerging context of EBV-associated disease. We outline mechanistic implications of dysfunctional NF-κB1 in B and T cells and discuss the fatal relation of impaired T-cell function with the inability to clear EBV infections. Finally, we compare common and suggested treatment angles in the context of this complex disease.

Nuclear factor κB mutations in human subjects: The devil is in the details

“…In a first step to understand the pathogenic potential of the identified NFKB1 sequence variants, Tuijnenburg et al 2 classified them into ''high-effect'' and ''moderate-effect'' variants according to probability predictions. Among the 13 high-effect variants, 10 mutations were predicted to cause expression of severely truncated nonfunctional proteins, which probably undergo rapid decay and thus cause p50 haploinsufficiency, in analogy with previous published NFKB1 mutations (as reviewed in Hoeger et al 1 ). Consistently, Western blotting showed reduced total amounts of wild-type p50 in patient-derived cells.…”

“…Consistent with previous reports, Tuijnenburg et al 2 observed a wide expressivity and highly variable penetrance associated with NFKB1 mutations. (as reviewed in Hoeger et al 1 ). Symptoms range from mild-to-severe immunophenotypic manifestations even within a single CVID family, but apparently asymptomatic mutation carriers are also common.…”

Late-Onset Antibody Deficiency Due to Monoallelic Alterations in NFKB1

“…In contrast to haploinsufficiency mutations, frameshift mutations in the central part of p105 (typically on the C-terminal side of the NLS), lead to skipping of the precursor stage and expression of p50-like mutant proteins as previously suggested (23, 32). The mutation (p.I567Nfs * 6) in Family D (S7) also predicts the expression of a p50-like protein, however with a molecular mass of ~89 kDa (which probably processed to p50) and which retains the NLS and translocates into the nucleus upon expression in HEK293T cells (Figure 3).…”

Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2

“…Importantly, monogenetic defects may represent distinct disease entities with particular phenotypes. Following identification in 2013 and 2015, heterozygous mutations in NFKB1 and NFKB2 now represent the largest CVID subgroups with known monogenetic mutations ( 5 , 6 ).…”