AUTHOR=Yamada Saeko , Nagafuchi Yasuo , Yamada Mamiko , Suzuki Hisato , Natsumoto Bunki , Ota Mineto , Takazawa Ikuo , Hatano Hiroaki , Kono Masanori , Harada Hiroaki , Shoda Hirofumi , Okamura Tomohisa , Kosaki Kenjiro , Fujio Keishi 

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

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1475179

DOI=10.3389/fimmu.2024.1475179

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p><italic>IKBKE</italic> 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 <italic>IKBKE</italic> (rs2297550-G) is a genome-wide association study risk variant of systemic lupus erythematosus, and is associated with decreased <italic>IKBKE</italic> expression in T cells by expression quantitative trait locus analysis.</p></sec><sec><title>Case presentation</title><p>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.</p></sec><sec><title>Method</title><p>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.</p></sec><sec><title>Result</title><p>WES identified a novel heterozygous c.1877G&gt;A, p(Cys626Tyr) variant in <italic>IKBKE</italic>. Functional analysis indicated that this variant led to increased activity of NFAT (<italic>p</italic> = 0.015) and decreased activity of NFκB and type I IFN (<italic>p</italic> = 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.</p></sec><sec><title>Conclusion</title><p>A novel functional heterozygous variant in <italic>IKBKE</italic> is described in a patient with a remittent fever and arthritis. The data suggest that <italic>IKBKE</italic> is an important negative regulator of inflammation, particularly in T cells, and this <italic>IKBKE</italic> variant might be the underlying cause of a novel autoinflammatory pathology.</p></sec>