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

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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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Abbreviations

AIHA:

Autoimmune hemolytic anemia

AIN:

Autoimmune neutropenia

SCID:

Severe combined immunodeficiency

IKK2:

Inhibitor kappa B kinase 2

IVIG:

Intravenous immunoglobulin

NF-κB:

Nuclear factor kappa B

PBMC:

Peripheral blood mononuclear Cells

WT:

Wild-type

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Acknowledgements

Molecular graphics and analyses performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311.

Funding

This research was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH).

Author information

Author notes

  1. Keith Sacco, Hye Sun Kuehn and Tomoki Kawai contributed equally.

Authors and Affiliations

  1. 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, Tomoki Kawai, Kerry Dobbs, Ottavia Delmonte & Luigi D. Notarangelo

  2. Division of Pulmonology, Section of Allergy-Immunology, Phoenix Children’s Hospital, Phoenix, AZ, USA

    Keith Sacco

  3. Immunology Service, Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, MD, USA

    Hye Sun Kuehn & Sergio D. Rosenzweig

  4. Division of Allergy and Immunology, Children’s National Hospital, Washington, DC, USA

    Nouf Alsaati, Blachy Davila, Vanessa Bundy & Michael D. Keller

  5. Eastern Virginia Medical School, Children’s Hospital of the King’s Daughters, Norfolk, VA, USA

    Lauren Smith

  6. Division of Blood and Marrow Transplantation, Children’s National Hospital, Washington, DC, USA

    Blachy Davila

  7. Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    Douglas B. Kuhns

Authors
  1. Keith Sacco
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  2. Hye Sun Kuehn
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  3. Tomoki Kawai
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  4. Nouf Alsaati
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  5. Lauren Smith
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  6. Blachy Davila
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  7. Vanessa Bundy
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  8. Douglas B. Kuhns
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  9. Kerry Dobbs
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  10. Ottavia Delmonte
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  11. Luigi D. Notarangelo
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  12. Sergio D. Rosenzweig
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  13. Michael D. Keller
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Contributions

KS, HSK, TK, NA, KDBK, KD, OD, LDN, SDR, and MDK performed the research, analyzed data, and wrote the manuscript.

LS, BD, and VB contributed data and edited the manuscript.

Corresponding author

Correspondence to Keith Sacco.

Ethics declarations

Ethics Approval

The patient’s family provided informed consent for study participation and dissemination of results on a protocol that was approved by the IRBs of both the National Institutes of Health and Children’s National Hospital in accordance with the Declaration of Helsinki.

Consent to Participate

Consent for publication was obtained from parents.

Conflict of Interest

MDK has received income from Uptodate, which was not felt to be in conflict with this research. All other authors declare no conflicts of interest related to this work.

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Cite this article

Sacco, K., Kuehn, H.S., Kawai, T. et al. A Heterozygous Gain-of-Function Variant in IKBKB Associated with Autoimmunity and Autoinflammation. J Clin Immunol 43, 512–520 (2023). https://doi.org/10.1007/s10875-022-01395-2

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  • DOI: https://doi.org/10.1007/s10875-022-01395-2

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