Our laboratory aims to elucidate the genetic control of immune func-39tions and autoimmunity risk. Our recent research focuses on human leukocyte antigen (HLA) genetic risks for autoimmunity. Polymorphisms in the HLA genes strongly influence autoimmune disease risk. HLA risk alleles may influence thymic selection to increase the frequency of T cell receptors (TCRs) reactive with autoantigens (central hypothesis). However, research in human autoimmunity has provided little evidence supporting the central hypothesis. We recently investigated the influence of HLA alleles on TCR composition at the highly diverse complementarity determining region 3 (CDR3), which con-fers antigen recognition. We demonstrated unexpectedly powerful HLA-CDR3 associations (see figure below). We showed that the CDR3 features promoted by HLA risk alleles were more enriched in candidate pathogenic TCRs than in control TCRs (e.g., citrullinated-epitope-specific TCRs in rheumatoid arthritis patients). We thus provided novel genetic evidence supporting the central hy-pothesis (Ishigaki K et al., Nat Genet 2022).In another project, we recently developed a novel analytic strategy for TCRs that assesses TCR features of regulatory T cells (T-reg). We showed that the hydrophobicity of CDR3 and the usage of some TCR V genes increase the like-lihood that thymic T cells will acquire a T-reg phenotype (Kaitlyn L et al., Nat Immunol 2022).Our laboratory is also committed to multiple new research areas: i) func-tional genetics studies using CRISPR-based genome editing, ii) development of a novel analytic pipeline to integrate ATAC-seq and RNA-seq data, iii) devel-opment of a novel polygenic risk score (PRS) calculation strategy. All of these research directions have the promise of improving our understanding of the genetic basis of autoimmunity risk.Figure: P values of the HLA-CDR3 association analysisP values for all CDR3 amino acid compositions are plot-ted at each HLA site. The HLA site with the lowest P value (HLA-DRB1 site 13) is highlighted by a diamond. The dashed line indicates the significance threshold with the Bonferroni multiple testing correction (P < 0.05/24,360 total tests).Recent Major PublicationsIshigaki K. Beyond GWAS: from simple associations to functional insights. Semin Immunopathol 44, 3-14 (2022)Ishigaki K, Akiyama M, Kanai M, Takahashi A, Kawakami E, Sugishita H, Sakaue S, Matoba N, Low SK, Okada Y, Terao C, Amariuta T, Gazal S, Kochi Y, Horikoshi M, Suzuki K, Ito K, Koyama S, Ozaki K, Niida S, Sakata Y, Sakata Y, Kohno T, Shiraishi K, Momozawa Y, Hirata M, Matsuda K, Ikeda M, Iwata N, Ikegawa S, Kou I, Tanaka T, Nakagawa H, Suzuki A, Hirota T, Tamari M, Chayama K, Miki D, Mori M, Nagayama S, Daigo Y, Miki Y, Katagiri T, Ogawa O, Obara W, Ito H, Yoshida T, Imoto I, Takahashi T, Tanikawa C, et al. Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases. Nat Genet 52, 669–679 (2020)Amariuta T, Ishigaki K (co-first author), Sugishita H, Ohta T, Koido M, Dey KK, Matsuda K, Murakami Y, Price AL, Kawakami E, Terao C, Raychaudhuri S. Improving the trans-ancestry portability of polygenic risk scores by prioritizing variants in predicted cell-type-specific regulatory elements. Nat Genet 52,1346-1354 (2020)Invited presentationsIshigaki K. “Immune system variation induced by ge-netic risk of autoimmunity” The 50th Annual Meeting of the Japanese Society for Immunology (Nara, Japan) December 2021Ishigaki K. “Investigation of HLA genetic risk of autoim-munity” The 8th Japan College of Rheumatology, Basic Research Conference (Tokyo, Japan) November 2021Laboratory for Human ImmunogeneticsTeam Leader: Kazuyoshi Ishigaki
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