Abstract
Background: NF-κB1 is a master regulator of both acquired and innate responses. NFKB1 loss-of-function mutations elicit a wide clinical phenotype with asymptomatic individuals at one end of the spectrum and patients with common variable immunodeficiency, combined immunodeficiency or autoinflammation at the other. Impairment of acquired and innate immunity and disseminated Mycobacterium genavense infection expands the clinical and immunological phenotype of NF-κB1 deficiency.Objective: Functional and molecular characterization of a patient with a novel phenotype of NF-κB1 deficiency.Methods: Circulating T, B, dendritic cell subsets and innate or unconventional T-cells were quantified. The cytokine production in stimulated whole blood samples was assessed and molecular characterization by next generation sequencing and gene expression assays were also performed.Results: We report a patient presenting with features of combined immunodeficiency (CID) and disseminated Mycobacterium genavense infection. Sequencing of genomic DNA identified a novel synonymous mutation (c.705G > A) in NFKB1 gene which resulted in exon 8 skipping and haploinsufficiency of the NF-κB1 subunit p50. The susceptibility to atypical mycobacterial infection has not been previously reported and may be the result of a dendritic cell deficiency. A selective deficiency of circulating follicular helper T (cTFH) cells responsible for mediating the differentiation of naive B cells into memory and plasma cells was also present in the patient. It could affect the maturation of innate or unconventional T cells where NF-κB1 could also be involved.Conclusion: These findings showed that the role of NF-κB1 in humans could be critical for the development of acquired and innate immunity and further highlights the role of human T cells in anti-mycobacterial immunity.
Highlights
The nuclear factor kappa light-chain enhancer of activated B-cells (NF-κB) is a pleiotropic transcription factor present in almost all cell types and represents the endpoint of a series of signal transduction events initiated by a vast array of stimuli related to many biological processes such as inflammation, apoptosis, differentiation, cell growth, tumorigenesis, and immunity [1]
We report a patient presenting with features of combined immunodeficiency (CID) and disseminated Mycobacterium genavense infection
Sequencing of genomic DNA identified a novel synonymous mutation (c.705G > A) in NFKB1 gene which resulted in exon 8 skipping and haploinsufficiency of the NF-κB1 subunit p50
Summary
The nuclear factor kappa light-chain enhancer of activated B-cells (NF-κB) is a pleiotropic transcription factor present in almost all cell types and represents the endpoint of a series of signal transduction events initiated by a vast array of stimuli related to many biological processes such as inflammation, apoptosis, differentiation, cell growth, tumorigenesis, and immunity [1]. Heterozygous mutations of NFKB1 gene lead to haploinsufficiency of NF-κB1. It was initially described in patients with common variable immunodeficiency (CVID) [5]. The presentation of NF-κB1 deficiency has since expanded to include more diverse immunologic phenotypes ranging from combined immunodeficiency(CID) [6, 7] to autoinflammatory disease [8, 9], broadening the clinical phenotype. NFKB1 loss-of-function mutations elicit a wide clinical phenotype with asymptomatic individuals at one end of the spectrum and patients with common variable immunodeficiency, combined immunodeficiency or autoinflammation at the other. Impairment of acquired and innate immunity and disseminated Mycobacterium genavense infection expands the clinical and immunological phenotype of NF-κB1 deficiency
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