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

Author:

Sacco, Keith [ORCID]

Kuehn, Hye Sun [ORCID]

Kawai, Tomoki [ORCID]

Alsaati, Nouf

Smith, Lauren

Davila, Blachy [ORCID]

Bundy, Vanessa [ORCID]

Kuhns,Doug [ORCID]

Dobbs, Kerry [ORCID]

Delmonte, Ottavia [ORCID]

Notarangelo, Luigi D [ORCID]

Rosenzweig, Sergio D [ORCID]

Keller, Michael D [ORCID]
Author Address

Laboratory of Clinical Immunology and Microbiology, Immune Deficiency Genetics Section, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, 10 Center Dr, Rm 5-3840W, Bethesda, MD, 20914, USA. keith.sacco@nih.gov., Division of Pulmonology, Section of Allergy-Immunology, Phoenix Children 39;s Hospital, Phoenix, AZ, USA. keith.sacco@nih.gov., Immunology Service, Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, MD, USA., Division of Allergy and Immunology, Children 39;s National Hospital, Washington, DC, USA., Eastern Virginia Medical School, Children 39;s Hospital of the King 39;s Daughters, Norfolk, VA, USA., Division of Blood and Marrow Transplantation, Children 39;s National Hospital, Washington, DC, USA., Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.,

Abstract:

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. 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. A patient with two heterozygous IKBKB variants (E518K and T559M) presents with previously undescribed autoimmune cytopenias and autoinflammation. He had decreased TNF-a-induced IkBa 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 IKKa/b and p65, and higher degradation of IkBa suggesting a GOF mechanism. No significant changes were observed in Jurkat cells transduced with the E518K variant. A GOF variant in IKBKB may associate with autoinflammation and autoimmunity highlighting a novel clinical phenotype. © 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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