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15.11.2022 | Original Article

A Heterozygous Gain-of-Function Variant in IKBKB Associated with Autoimmunity and Autoinflammation

verfasst von: Keith Sacco, Hye Sun Kuehn, Tomoki Kawai, Nouf Alsaati, Lauren Smith, Blachy Davila, Vanessa Bundy, Douglas B. Kuhns, Kerry Dobbs, Ottavia Delmonte, Luigi D. Notarangelo, Sergio D. Rosenzweig, Michael D. Keller

Erschienen in: Journal of Clinical Immunology

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Abstract

Purpose

Biallelic loss-of-function variants in IKBKB cause severe combined immunodeficiency. We describe a case of autoimmunity and autoinflammation in a male infant with a heterozygous gain-of-function (GOF) IKBKB variant.

Methods

Case report and review of the literature. We performed in silico variant analysis, measurement of plasma soluble biomarkers associated with immune activation, functional stimulation of patient peripheral blood mononuclear cells, and functional validation of variants transduced in Jurkat cells.

Results

A patient with two heterozygous IKBKB variants (E518K and T559M) presents with previously undescribed autoimmune cytopenias and autoinflammation. He had decreased TNF-α-induced IkBα degradation in vitro, and had increased serum biomarkers associated with macrophage recruitment and activation. Jurkat cells transduced with the IKKb T559M variant showed increased basal levels of phosphorylation of IKKα/b and p65, and higher degradation of IkBα suggesting a GOF mechanism. No significant changes were observed in Jurkat cells transduced with the E518K variant.

Conclusions

A GOF variant in IKBKB may associate with autoinflammation and autoimmunity highlighting a novel clinical phenotype.
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Metadaten
Titel
A Heterozygous Gain-of-Function Variant in IKBKB Associated with Autoimmunity and Autoinflammation
verfasst von
Keith Sacco
Hye Sun Kuehn
Tomoki Kawai
Nouf Alsaati
Lauren Smith
Blachy Davila
Vanessa Bundy
Douglas B. Kuhns
Kerry Dobbs
Ottavia Delmonte
Luigi D. Notarangelo
Sergio D. Rosenzweig
Michael D. Keller
Publikationsdatum
15.11.2022
Verlag
Springer US
Erschienen in
Journal of Clinical Immunology
Print ISSN: 0271-9142
Elektronische ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-022-01395-2

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