Late-Onset Antibody Deficiency Due to Monoallelic Alterations in NFKB1

Abstract

Adult-onset primary immunodeficiency is characterized by recurrent infections, hypogammaglobulinemia, and poor antibody response to vaccines. In this study, we have analyzed targeted gene panel sequencing results of 270 patients diagnosed with antibody deficiency and identified five disease-associated variants in NFKB1 in five unrelated families. We detected two single base pair deletions and two single base pair insertions, causing severe protein truncations, and one missense mutation. Immunoblotting, lymphocyte stimulation, immunophenotyping, and ectopic expression assays demonstrated the functional relevance of NFKB1 mutations. Besides antibody deficiency, clinical manifestations included infections, autoimmune features, lymphoproliferation, lymphoma, Addison's disease, type 2 diabetes and asthma. Although partial clinical penetrance was observed in almost all pedigrees, all carriers presented a deficiency in certain serum immunoglobulins and the majority showed a lack of memory B cells (CD19+CD27+). Among all tested genes, NFKB1 alterations were the most common monoallelic cause of antibody deficiency in our cohort.

A Pathogenic Missense Variant in NFKB1 Causes Common Variable Immunodeficiency Due to Detrimental Protein Damage

“…We concluded, neither the mutant p105 precursor nor the mutant p50, are maintained at high levels in transfected cells (resulting from forced CMV-promoter-driven overexpression) but instead undergo rapid cytoplasmic decay or proteotoxic aggregation within the nucleus, respectively. The subnuclear deposition of severely damaged p50 proteins upon experimental overexpression has previously been observed with other mutations (12,24,34). Severely damaged proteins undergoing enhanced decay, typically gain substantially lower fluorescence signals, which might further decrease over time during the experiment.…”

“…Western blotting using isolated PBMCs has successfully been applied to confirm reduced levels of p105 and p50 associated with pathogenic truncating variants, precursor skipping variants and several missense variants ( 12 – 14 , 22 , 23 , 34 ). EBV-transformed B lymphocytes might be used as an alternative ( 12 , 14 ; Supplementary Figure 3 ), e.g.…”

Peripheral Blood Lymphocyte Phenotype Differentiates Secondary Antibody Deficiency in Rheumatic Disease from Primary Antibody Deficiency

“…In other words, the diagnosis of a PID is clear in case the diagnosis of hypogammaglobulinemia precedes immunosuppressive treatment of autoimmune or lymphoproliferative conditions. However, autoimmunity or lymphoproliferative disease and introduction of immunosuppressive treatment could precede the diagnosis of hypogammaglobulinemia [8][9][10][11][12]. The relatively recent discovery of monogenic disorders manifesting as CVID and subsequent studies of cohorts of patients with common monogenic defects revealed that hypogammaglobulinemia in primary immunodeficiency may have a later onset than autoimmunity or lymphoproliferative disease, which can phenotypically prevail [13][14][15][16].…”

Case Report: Post-Partum Complications of NFκB1 Deficiency Underscore a Need to Better Understand Primary Immunodeficiency Management During Pregnancy

“…Among patients with NFκB1 haploinsufficiency there is a wide phenotypic spectrum with variable expressivity even within the same family unit (10). Clinical presentations may include recurrent infections, autoimmune disease, and malignancy; in particular, Evans Syndrome (ES) should trigger concern for NFkB1-related disease (11)(12)(13). Notably, the phenotypic features continue to evolve as a description of recurrent necrotizing cellulitis following a dental procedure has just been described within the spectrum of NFkB1 deficiency (14).…”