Laboratory for Human Immunogenetics

Our laboratory aims to elucidate the genetic basis of autoimmunity, with a focus on three major research themes. The first theme centers on the T cell receptor (TCR). We previously developed a novel analytical pipeline for TCR repertoire analysis and demonstrated that HLA risk alleles influence thymic selection, resulting in an increased frequency of autoreactive TCRs. We have since extended the framework to systematically investigate TCR features across multiple autoimmune diseases. In parallel, we are developing a high-throughput experimental platform for TCR repertoire analysis that enables the sequencing of thousands of samples and the identification of cognate epitopes recognized by disease-associated TCR clonotypes. The second theme focuses on functional genetics. Our laboratory has established a state-of-the-art genome-editing platform based on prime editing in primary human T cells and has developed UNIChro-seq, a targeted chromatin accessibility assay that digitally quantifies accessible chromatin molecules at predefined loci. UNIChro-seq enables accurate, sensitive, and efficient measurement of allelic effects compared with conventional approaches. Using this method, we systematically evaluated the effects of 57 autoimmunity-associated risk alleles on chromatin accessibility, providing experimental validation of the molecular functions of fine-mapped variants (Kono & Hatano et al., medRxiv, 2025). The last theme is large-scale multi-omics study using clinical samples. By analyzing one of the largest single-cell transcriptomic datasets in systemic lupus erythematosus (SLE)—comprising approximately 2.1 million peripheral blood mononuclear cells from 232 SLE patients and 114 healthy controls—we performed fine mapping of cellular and molecular pathology and identified previously unrecognized disease-relevant cell states. Through integrated multimodal in silico analyses, CRISPR-based perturbation experiments, and functional cellular assays, we further identified cell-state-specific transcriptional regulators that play key roles in SLE pathogenesis (Nakano & Kono et al., medRxiv, 2025). Collectively, these research activities advance our understanding of the genetic and cellular mechanisms underlying human autoimmune diseases.