Our laboratory aims to elucidate the genetic basis of autoimmunity. We 34recently conducted a large-scale transcriptome study of systemic lupus erythematosus (SLE) patients (Nakano et al. Cell 2022). SLE is a prototype au-toimmune disease with a clear genetic etiology and involves multiple immune cells. To elucidate SLE pathogenesis, it is essential to understand the dysregu-lated gene expression pattern linked to various clinical statuses with a high cel-lular resolution. For this aim, we analyzed 6,386 RNA sequencing data covering 27 immune cell types from 136 SLE and 89 healthy donors. We profiled two distinct cell-type-specific transcriptomic signatures: disease-state signature (case-control contrast reflecting disease establishment) and disease-activity sig-nature (case-case contrast reflecting disease exacerbation). We then identified candidate biological processes unique to each signature and demonstrated the value of these signatures in multiple applications: transferability to independent transcriptome datasets, association with clinical manifestations, and shared components with drug responses. For example, the disease-activity signature was associated with organ involvement and therapeutic responses, suggesting its clinical value. This study revealed the underappreciated cell-type-specific mechanisms driving these signatures, most of which were not identified in pre-vious single cell RNA-seq studies, emphasizing the advantage of bulk RNA-seq study coupled with fine sorting of multiple immune cells.We for the first time investigated the genetic basis of clinical transcriptome abnormalities. Intriguingly, we found that SLE risk variants are more enriched around disease-state signature genes than disease-activity signature genes. These results suggested that current genetic studies, most of them based on case-control comparisons, does not well capture disease-activity signatures, which point to clinically vital biology. Together, we identified comprehensive gene signatures of SLE that will provide essential foundations for future genom-ic and genetic studies.Figure: The study design of our SLE transcrip-tome studyWe identified two distinct categories of disease-relevant signatures in a cell-type-specific manner (middle im-age) and performed extensive downstream analyses (i–v). HCs, healthy controls; LDA, low disease activity; MDA, moderate disease activity; HDA, high disease activity; BLM, belimumab; TF, transcription factor; EAS, East Asian; EUR, European.Recent Major PublicationsIshigaki K, Sakaue S, Terao C, Luo Y, Sonehara K, Yama-guchi K, Amariuta T, Too CL, Laufer VA, Scott IC, Viatte S, Takahashi M, Ohmura K, Murasawa A, Hashimoto M, Ito H, Hammoudeh M, Emadi SA, Masri BK, Halabi H, Badsha H, Uthman IW, Wu X, Lin L, Li T, Plant D, Barton A, Orozco G, Verstappen SMM, Bowes J, MacGregor AJ, Honda S, Koido M, Tomizuka K, Kamatani Y, Tanaka H, Tanaka E, Suzuki A, Maeda Y, Yamamoto K, Miyawaki S, Xie G, Zhang J, Amos CI, Keystone E, Wolbink G, van der Horst-Bruinsma I, Cui J, Liao KP, Carroll RJ, et al. Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis. Nat Genet 54, 1640-1651 (2022)Nakano M, Ota M, Takeshima Y, Iwasaki Y, Hatano H, Nagafuchi Y, Itamiya T, Maeda J, Yoshida R, Yamada S, Nishiwaki A, Takahashi H, Takahashi H, Akutsu Y, Kusuda T, Suetsugu H, Liu L, Kim K, Yin X, Bang SY, Cui Y, Lee HS, Shoda H, Zhang X, Bae SC, Terao C, Yamamoto K, Okamura T, Ishigaki K (co-corresponding author), Fujio K. Distinct transcriptome architectures underlying lupus establishment and exacerbation. Cell 185, 3375-3389.e21 (2022)Ishigaki K, Lagattuta KA, Luo Y, James EA, Buckner JH, Raychaudhuri S. HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors. Nat Genet 54, 393-402 (2022)Invited presentationsNakano M & Ishigaki K. “Genetic factors influencing chronic inflammation” The 96th Annual Meeting of the Japanese Biochemical Society (Fukuoka, Japan) Novem-ber 2023Ishigaki K. “Autoimmunity pathology elucidated by functional genetics studies” Human Genetics Asia 2023 (Tokyo, Japan) October 2023Laboratory for Human ImmunogeneticsTeam Leader: Kazuyoshi Ishigaki
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