Saeko Yamada ¹ Yasuo Nagafuchi ^1,2* Mamiko Yamada ³ Hisato Suzuki ^3,4 Bunki Natsumoto ¹ Mineto Ota ^1,2 Ikuo Takazawa ¹ Hiroaki Hatano ¹ Masanori Kono ¹ Hiroaki Harada ¹ Hirofumi Shoda ¹ Tomohisa Okamura ¹ Kenjiro Kosaki ³ Keishi Fujio ^1*

• ¹ Department of Allergy and Rheumatology, Faculty of Medicine, The University of Tokyo, Bunkyo, Japan
• ² Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Bunkyo, Tōkyō, Japan
• ³ Center for Medical Genetics, School of Medicine, Keio University, Tokyo, Japan
• ⁴ Department of Medical Genetics, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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.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.