A novel functional IKBKE variant activating NFAT in a patient with polyarthritis and a remittent fever

Front Immunol. 2024 Oct 25:15:1475179. doi: 10.3389/fimmu.2024.1475179. eCollection 2024.

Abstract

Background: IKBKE is a negative regulator of T cell activation and one of the key activators of type I interferon (IFN) and NFκB signaling via non-classical pathways. The upstream single nucleotide polymorphism of IKBKE (rs2297550-G) is a genome-wide association study risk variant of systemic lupus erythematosus, and is associated with decreased IKBKE expression in T cells by expression quantitative trait locus analysis.

Case presentation: A 48-year-old female had a remittent fever, arthritis, and oral ulcers for 20 years. She had a poor response to corticosteroids or disease-modifying antirheumatic drugs, including the tumor necrosis factor-α antagonist, etanercept, and the anti-interleukin-6 receptor antibody, tocilizumab.

Method: She participated in the Initiative on Rare and Undiagnosed Disease (IRUD), and whole-exome sequencing (WES) was performed. Functional analyses were conducted by transfecting the identified variants into reporter cells to assess the activation of NFAT and NFκB signaling. Additionally, peripheral blood RNA- sequencing (RNA-seq) data were compared with those from healthy individuals to evaluate the gene expression profiles of immune cells.

Result: WES identified a novel heterozygous c.1877G>A, p(Cys626Tyr) variant in IKBKE. Functional analysis indicated that this variant led to increased activity of NFAT (p = 0.015) and decreased activity of NFκB and type I IFN (p = 0.00068 and 0.00044, respectively). The patient had a remarkably low proportion of Naïve CD4 T cells. RNA-seq of peripheral blood immune cell subsets revealed significant differences in gene expression, especially in T cells.

Conclusion: A novel functional heterozygous variant in IKBKE is described in a patient with a remittent fever and arthritis. The data suggest that IKBKE is an important negative regulator of inflammation, particularly in T cells, and this IKBKE variant might be the underlying cause of a novel autoinflammatory pathology.

Keywords: IKBKE; NFκB; T cell; rare variant; the inhibitor of κB kinase ϵ (IKKϵ); type I IFN.

Publication types

  • Case Reports

MeSH terms

  • Arthritis* / genetics
  • Exome Sequencing
  • Female
  • Fever*
  • Genetic Predisposition to Disease
  • Humans
  • I-kappa B Kinase* / genetics
  • Middle Aged
  • NF-kappa B / metabolism
  • NFATC Transcription Factors* / genetics
  • NFATC Transcription Factors* / metabolism
  • Polymorphism, Single Nucleotide
  • Signal Transduction

Substances

  • I-kappa B Kinase
  • NFATC Transcription Factors
  • IKBKE protein, human
  • NF-kappa B

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was supported by Initiative on Rare and Undiagnosed Diseases (grant number JP24ek0109760) from the Japan Agency for Medical Research and Development (to KK). The authors declare that this study received funding from Chugai Pharmaceutical. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.