Biology subjects

Ogishi, M.

Publications and source records attributed to Ogishi, M..

7 recordsLinked to original sources

bioRxiv2026

Homozygosity for rare or common hypomorphic IL23R variants confers a predisposition to tuberculosis in humans

Homozygosity for rare loss-of-function IL23R variants abolishes IL-23-dependent IFN-{gamma} production by lymphocytes, including NK and innate-like T cells, thereby underlying clinical disease due to weakly virulent mycobacterial species. We report selective enrichment in homozygosity for four hypomorphic IL23R variants in our cohort of patients with tuberculosis. Three of these IL23R alleles are rare (G300V, G149R, and L372F), with a minor allele frequency (MAF) under 1%, but the fourth (R381Q) is surprisingly common, with an MAF as high as 10.2% in certain populations. The other 15 missense alleles found in the homozygous state in public databases are isomorphic. The four hypomorphic IL-23R variants identified dimerize with IL-12R{beta}1 and bind IL-23. However, their function is impaired by low levels of cell surface expression (R381Q, G300V) and/or as a consequence of conformational changes altering agonist efficacy. IFN-{gamma} production in response to IL-23 is impaired in innate-like T cells and NK cells. These data suggest that recessive partial IL-23R deficiency, whether due to rare or common variants, confers a predisposition to tuberculosis while preserving immunity to less virulent mycobacteria. One sentence summaryHomozygous hypomorphic IL23R variants impair IL-23-dependent IFN-{gamma} production and underlie tuberculosis.

genetics↗

bioRxiv2026

Selective Immune Silencing by Targeted TGF-β Agonists

Depletion of pathogenic T and B cells is a pillar of therapies for autoimmune, inflammatory, and transplantation-related immunological diseases. However, adverse events, safety concerns in immunocompromised patients, and disease relapse limit clinical utility. Here, we exploit the immunosuppressive properties of a transforming growth factor beta (TGF-{beta}) mimic repurposed from helminths for cell type-specific therapeutic silencing, as a new approach to complement existing therapies. Mouse CD4 and CD8 T cell-targeted TGF-{beta} agonists selectively and potently silence antigen-specific T cell responses in OVA-immunized mice by suppressing pro-inflammatory effector, cytotoxic, and T follicular helper programs, while skewing cells toward a quiescent state biased toward regulatory and type 17 T cell phenotypes. Similarly, human CD4 and CD8 T cell-targeted TGF-{beta} agonists precisely and effectively suppress live-attenuated influenza vaccine (LAIV)-induced T cell activation and expansion in human spleen organoids. Correspondingly, CD4 T cell-targeted TGF-{beta} agonist effectively ameliorated disease activity and promoted disease remission in CD4 T cell-driven models of autoimmune neuroinflammation and allergic airway inflammation, demonstrating efficacy in both prophylactic and established inflammatory settings. Moreover, both CD4 and CD8 T cell-targeted TGF-{beta} agonists ameliorated disease activity in graft-versus-host disease. Additionally, a human CD19 B cell-targeted TGF-{beta} agonist robustly inhibits germinal center B cell-to-plasmablast maturation and antibody responses in LAIV-stimulated human spleen organoids. These early-stage results suggest that cell-selective TGF-{beta} agonism merits further investigation as a versatile therapeutic approach for the precise silencing of pathogenic adaptive immune responses.

immunology↗

bioRxiv2024

Mechanism of neurodegeneration mediated by clonal inflammatory microglia

Langerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and an increased risk of neurodegeneration. Surprisingly, we found pervasive PU.1+ microglia mutant clones across the brain of LCH and ECD patients with and without neurological symptoms, associated with microgliosis, reactive astrocytosis, and neuronal loss. The disease predominated in the grey nuclei of the rhombencephalon, a topography attributable to a local proliferative advantage of mutant microglia. Presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1+ clones (p= 0.0003). Genetic lineage tracing of PU.1+ clones suggest a resident macrophage lineage or a bone marrow precursor origin depending on patients. Finally, a CSF1R-inhibitor depleted mutant microglia and limited neuronal loss in mice suggesting an alternative to MAPK inhibitors. These studies characterize a progressive neurodegenerative disease, caused by clonal proliferation of inflammatory microglia (CPIM), with a decade(s)-long preclinical stage of incipient disease that represent a therapeutic window for prevention of neuronal death.

immunology↗

bioRxiv2024

A microglia clonal inflammatory disorder in Alzheimer's Disease

Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however few studies have investigated its role in neurodegenerative processes such as Alzheimers Disease (AD). Here we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in human, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients. One-Sentence SummaryA subset of Alzheimer Disease patients carry mutant microglia somatic clones which promote neuro-inflammation.

neuroscience↗

bioRxiv2020

Multi-batch cytometry data integration for optimal immunophenotyping

We describe the integration of multi-batch cytometry datasets (iMUBAC), a flexible, robust, and scalable computational framework for unsupervised cell-type identification across multiple batches of high-dimensional cytometry datasets. After overlaying cells from healthy controls across multiple batches, iMUBAC learns batch-specific cell-type classification boundaries and identifies aberrant immunophenotypes in patient samples. We illustrate unbiased and streamlined immunophenotyping, using both in-house and public mass and flow cytometry datasets.

bioinformatics↗

bioRxiv2019

Prioritizing putatively etiological T cell epitopes across autoimmune diseases

Autoimmune diseases remain a leading cause of mortality among adolescents and young adults worldwide. Despite their clinical impact, there are still significant knowledge gaps in our understanding of immunological tolerance and its breach that characterizes the onset of autoimmune diseases. Genetic associations between the histocompatibility leukocyte antigen (HLA) loci and various autoimmune diseases have been well established. The HLA class I and class II molecules present epitopes to T cells, and T cells play indispensable roles both in the maintenance of tolerance and the pathogenesis of autoimmune diseases. Although a vast number of epitopes and reactive T cell clones have been identified from animal model studies and observational studies, however, only a few have been proven to be causally relevant to disease pathogenesis. Here, we propose a computational framework to prioritize etiologically relevant epitopes by integrating the putatively causal associations between HLA alleles and disease risk identified from population genetics; we define a metric, termed \"differential presentation index (DPI),\" which principally reflects the relative difference of epitope abundance presented onto HLA molecules whose alleles are genetically predisposing to or protective against the specific disease. We systematically examined publicly available epitope sequence data previously studied in the context of autoimmune diseases. Self-epitopes were generally more stably presented on disease-protective HLAs than non-self epitopes, and hence had a negative DPI. Conversely, proteome-wide sequence alignment revealed that epitopes with highly positive DPI were less similar to self. As a case study, we performed a focused analysis of multiple sclerosis (MS), and identified epitopes from myelin basic protein (MBP), a well-established MS autoantigen, based on DPI-guided prioritization. Moreover, we found several non-MBP-derived self-epitopes with high DPI that are potentially involved in the pathogenesis of MS. Our framework facilitates the identification of etiologically relevant epitopes across autoimmune diseases with known HLA allele association, which in turn expedites the development of epitope-specific disease monitoring and intervention strategies.

immunology↗

bioRxiv2017

TCR-peptide contact profile determines immunogenicity in pathogen/tumor-derived MHC-I epitopes

The existence of population-wide T cell immunity is widely recognized for multiple pathogen-derived immunodominant epitopes, despite the vast diversity and individualized nature of T cell receptor (TCR) repertoire. We thus hypothesized that population-wide epitope immunogenicity could be probabilistically defined by exploiting public TCR features. To gain a proof-of-concept, here we describe a machine learning framework yielding probabilistic estimates of immunogenicity, termed \"immunogenicity scores\", by utilizing features designed to mimic thermodynamic interactions between peptides bound to major histocompatibility complex (MHC) and TCR repertoire. Immunogenicity score dynamics among observed and computationally simulated single amino acid mutants delineated the landscape of position- and residue-specific mutational impacts, and even quantitatively estimated escaping potentials of known epitopes with remarkable positional specificity. This study illustrates that the population-wide aspect of adaptive immunity is predictable via non-individualized approach, possibly indicating antigen-guided convergence of human T cell reactivity.

immunology↗