Biology subjects

Ota, M.

Publications and source records attributed to Ota, M..

25 records · Page 2Linked to original sources

bioRxiv2022

An Autoimmune Transcriptional Circuit Driving Foxp3+ Regulatory T cell Dysfunction

Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. While CD4+Foxp3+ regulatory T cells (Tregs) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of Tregs in the autoimmune disease multiple sclerosis (MS) to identify central transcriptional programs regulating human autoimmunity. We discovered that upregulation of a primate-specific short PRDM1 isoform (PRDM1-S) induces SGK1 independent from evolutionally conserved long PRDM1, leading to destabilization of Foxp3 and Treg dysfunction. This aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases. Furthermore, by chromatin landscape profiling in MS Tregs we identified a PRDM1-S specific cis-regulatory element associated with enriched binding of AP-1/IRF transcription factors. Our study identifies evolutionally emerged PRDM1-S and epigenetic priming of AP-1/IRF as key drivers of pathogenic Treg programs leading to human autoimmune disease.

immunology↗

bioRxiv2021

Autotaxin may play a Critical Role between the Genetic Risk Factors and Pathogenesis of SLE in Plasmacytoid Dendritic Cells

BackgroundThe importance of autotaxin, an enzyme that catalyzes lysophospholipid production, has recently been recognized in various diseases, including cancer and autoimmune diseases. Herein, we examined the role of autotaxin in systemic lupus erythematosus (SLE), utilizing data from ImmuNexUT, a comprehensive database consisting of transcriptome data and expression quantitative trait locus (eQTL) data of immune cells from patients with immune-mediated disorders. MethodsSerum autotaxin concentrations in patients with SLE and healthy controls (HCs) were compared. The transcriptome data of patients with SLE and age-and sex-matched HCs were obtained from ImmuNexUT. The expression of ENPP2, the gene encoding autotaxin, was examined in peripheral blood immune cells. Next, weighted gene correlation network analysis (WGCNA) was performed to identify genes with expression patterns similar to ENPP2. The ImmuNexUT eQTL database and public epigenomic databases were used to infer the relationship between autotaxin and pathogenesis of SLE. ResultsAutotaxin levels were elevated in the serum of patients with SLE compared to HCs. Furthermore, the expression of ENPP2 was higher in plasmacytoid dendritic cells (pDCs) than in other immune cell subsets, and its expression was elevated in pDCs of patients with SLE compared to HCs. In WGCNA, ENPP2 belonged to a module that correlated with disease activity. This module was enriched in interferon-associated genes and included genes whose expression was influenced by single-nucleotide polymorphisms associated with SLE, suggesting that it is a key module connecting genetic risk factors of SLE with disease pathogenesis. Analysis utilizing the ImmuNexUT eQTL database and public epigenomic databases suggested that the increased expression of ENPP2 in pDCs from patients with SLE may be caused by increased expression of interferon-associated genes and increased binding of STAT3 complexes to the regulatory region of ENPP2. ConclusionsAutotaxin may play a critical role in connecting genetic risk factors of SLE to disease pathogenesis in pDCs.

immunology↗

bioRxiv2021

Immune cell multi-omics analysis reveals contribution of oxidative phosphorylation to B cell functions and organ damage of lupus

ObjectiveSystemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease, with a poor long-term prognosis. The type I interferon (IFN) signature, a prominent feature of SLE, is not an ideal therapeutic target or outcome predictor. To explore immunological pathways in SLE more precisely, we performed integrative analysis of transcriptomics, epigenomics, and genomics using each immune cell subset from peripheral blood. MethodsWe sorted 18 immune cell subsets and identified the mRNA expression profiles and genetic polymorphisms in 107 SLE patients and 92 healthy controls. Open chromatin information was also taken by ATAC-seq analysis. Combined differentially expressed genes (DEGs) and expression quantitative trait loci (eQTL) analysis was conducted to find key driver genes in SLE pathogenesis. ResultsWe found transcriptomic, epigenetic, and genetic importance of oxidative phosphorylation (OXPHOS)/mitochondrial dysfunction in SLE memory B cells. Particularly, we identified an OXPHOS-regulating gene, PRDX6, as a key driver in SLE B cells. Prdx6-deficient B cells showed upregulated mitochondrial respiration as well as antibody production. We revealed OXPHOS signature was associated with type I IFN signaling-related genes (ISRGs) signature in SLE memory B cells. Furthermore, the gene sets related to innate immune signaling among ISRGs presented correlation with OXPHOS and these two signatures showed associations with SLE organ damage as well as specific clinical phenotypes. ConclusionThis work elucidated the potential prognostic marker for SLE. Since OXPHOS consists of the electron transport chain, a functional unit in mitochondria, these findings suggest the importance of mitochondrial dysfunction as a key immunological pathway involved in SLE.

immunology↗

bioRxiv2021

The cerebellum as a moderator of negative bias of facial expression processing in depressive patients

BackgroundNegative bias--a mood-congruent bias in emotion processing--is an important aspect of major depressive disorder (MDD), and such a bias in facial expression recognition has a significant effect on patients social lives. Neuroscience research shows abnormal activity in emotion-processing systems regarding facial expressions in MDD. However, the neural basis of negative bias in facial expression processing has not been explored directly. MethodsSixteen patients with MDD and twenty-three healthy controls (HC) who underwent an fMRI scan during an explicit facial emotion task with happy to sad faces were selected. We identified brain areas in which the MDD and HC groups showed different correlations between the behavioral negative bias scores and functional activities. ResultsBehavioral data confirmed the existence of a higher negative bias in the MDD group. Regarding the relationship with neural activity, higher activity of happy faces in the posterior cerebellum was related to a higher negative bias in the MDD group, but lower negative bias in the HC group. LimitationsThe sample size was small, and the possible effects of medication were not controlled for in this study. ConclusionsWe confirmed a negative bias in the recognition of facial expressions in patients with MDD. fMRI data suggest the cerebellum as a moderator of facial emotion processing, which biases the recognition of facial expressions toward their own mood.

neuroscience↗

bioRxiv2020

Hypoxia-tolerant vascular endothelial growth factor-A (VEGF-A) and the genetic variations of VEGFA in Sherpa highlanders

Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, partly by one of the adaptation mechanisms promoting increases of microcirculatory blood flow and capillary density at high altitude for restoring oxygen supply to tissues. Hypoxia stimulates vascular endothelial growth factor (VEGF), which is an important signaling protein involved in hypoxia-stimulated vasculogenesis and angiogenesis. Our present study included 51 Sherpas dwelling in Namche Bazaar village (3440 m) and 76 non-Sherpa lowlanders residing in Kathmandu (1300 m) in Nepal. In these participants, we measured plasma VEGF-A concentrations and genotyped five single-nucleotide polymorphisms (SNPs) of VEGFA: rs699947, rs8333061, rs1570360, and rs2010963 in the 5'-untranslated region (5'-UTR); and rs3025039 in the 3'-UTR. The average circulating VEGF-A level in Sherpas did not respond to hypoxia at the high altitude in 3440 m, remaining equivalent to the level in non-Sherpa lowlanders at low altitude. Allele discriminations for the analyzed SNPs revealed significant genetic divergences of rs699947, rs8333061, and rs2010963 in Sherpa highlanders compared with non-Sherpa lowlanders, East Asians, South Asians, and the global population; however, consistency with the indigenous Tibetan highlanders from the Tibet Plateau. On the other hand, the SNP rs3025039 in the 3'-UTR presented constant preserved genetic variation among global populations. Our findings indicated that the physiological sea-level VEGF-A concentration in Sherpa highlanders at high altitude was probably linked with the significant variations of VEGFA in Sherpas that regulate the gene expression in a manner of tolerance to hypoxia through production of the optimal biological level of VEGF-A at high altitudes. Precise angiogenesis at high altitude contributes to the adaptive levels of capillary density and microcirculation, providing efficient and effective diffusion of oxygen to tissues and representing human adaptation to high-altitude hypoxia environment. Author summarySherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, partly by one of the adaptation mechanisms promoting increases of microcirculatory blood flow and capillary density at high altitude for restoring oxygen supply to tissues. Vascular endothelial growth factor (VEGF) is mainly stimulated by hypoxia, and is an important signaling protein involved in hypoxia-stimulated vasculogenesis and angiogenesis. Interestingly, we found that the circulating VEGF-A level in Sherpa highlanders did not respond to hypoxia at high altitude. Furthermore, allele discrimination of the single nucleotide polymorphisms (SNPs) of VEGFA revealed significant divergences of rs699947, rs8333061, and rs2010963 within the VEGFA regulation region in Sherpa highlanders compared to the non-Sherpa lowlanders, East Asians, South Asians, and the global population; however, consistency with Tibetan highlanders from the Tibet Plateau. We propose that the hypoxia-tolerant circulating VEGF-A level in Sherpa highlanders is linked with the genetic variations of VEGFA, contributing to human adaptation to high-altitude hypoxic environments.

genetics↗

bioRxiv2019

Synovial fibroblasts contribute to the genetic risk of rheumatoid arthritis through the synergistic action of cytokines

ObjectivesSynovial fibroblasts (SFs) produce a variety of pathogenic molecules in the inflamed synovium of rheumatoid arthritis (RA). We aimed to gain insight into the pathogenic mechanisms of SFs through elucidating the genetic contribution to molecular regulatory networks under inflammatory condition. MethodsSFs from RA and osteoarthritis (OA) patients (n=30 each) were stimulated with 8 different cytokines (IFN-, IFN-{gamma}, TNF-, IL-1{beta}, IL-6/sIL-6R, IL-17, TGF-{beta}1, IL-18) or a combination of all 8 (8-mix). Peripheral blood mononuclear cells (PBMCs) from the same patients were fractioned into five major immune cell subsets (CD4+ T cells, CD8+ T cells, B cells, NK cells, monocytes). Integrative analyses including mRNA expression, histone modifications (H3K27ac, H3K4me1, H3K4me3), 3D genome architecture and genetic variations of SNPs were performed. ResultsSFs exposed to synergistically acting cytokines produced markedly higher levels of pathogenic molecules, including CD40 whose expression was significantly affected by a RA risk SNP (rs6074022). Upon chromatin remodeling in activated SFs, RA risk loci were enriched in clusters of enhancers (super-enhancers; SEs) induced by synergistic proinflammatory cytokines. A RA risk SNP (rs28411362), located in a SE under synergistically acting cytokines, formed three-dimensional contact with the promoter of MTF1 gene, whose binding motif showed significant enrichment in stimulation specific-SEs. Consistently, inhibition of MTF1 suppressed cytokine and chemokine production from SFs and ameliorated mice model of arthritis. ConclusionsOur findings established the dynamic landscape of activated SFs, and yielded potential therapeutic targets associated with genetic risk of RA. Key messagesO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIIn rheumatoid arthritis (RA), a variety of dysregulated molecules from immune cells and mesenchymal cells drive disease progression. Synovial fibroblasts (SFs), the most abundant resident mesenchymal cells in the inflamed synovium, produce a variety of pathogenic molecules including IL-6. C_LIO_LIGenome-wide association studies (GWAS) have identified more than 100 RA susceptibility loci. To gain insight into the pathogenic mechanisms of SFs, understanding the genetic contribution to molecular regulatory networks under inflammatory condition is crucial. C_LI What does this study add?O_LIIntegrated analyses of activated SFs demonstrated that SFs exposed to synergistically acting cytokines produced markedly higher levels of pathogenic molecules. Some of which were significantly affected by RA risk loci in a stimulation-specific manner. C_LIO_LIChromatin remodeling induced by synergistic proinflammatory cytokines were associated with RA heritability. Some transcription factors (MTF1, RUNX1) could be crucial for this structural rearrangement and the formation of inflammatory arthritis. C_LI How might this impact on clinical practice or future developments?O_LIOur findings established the dynamic landscape of activated SFs, and yielded potential therapeutic targets associated with genetic risk of RA. C_LI

immunology↗

bioRxiv2019

Within-Host Diversity and Vertical Transmission of Group B Streptococcus Among Mother-infant Dyads in The Gambia

IntroductionUnderstanding mother-to-infant transmission of Group B Streptococcus (GBS) is vital to the prevention and control of GBS disease. We investigated the transmission and phylogenetic relationships of mothers colonised by GBS and their infants in a peri-urban setting in The Gambia.\n\nMethodsWe collected nasopharyngeal swabs from 35 mother-infant dyads at weekly intervals from birth until six weeks post-partum. GBS was isolated by conventional microbiology techniques. Whole-genome sequencing was performed on GBS isolates from one mother-infant dyad (dyad 17).\n\nResultsWe recovered 85 GBS isolates from the 245 nasopharyngeal swabs. GBS was isolated from 16.33% and 18.37% of sampled mothers and infants, respectively. In 87% of cultured swabs, the culture status of an infant agreed with that of the mother (Kappa p-value <0.001). In dyad 17, phylogenetic analysis revealed within-host strain diversity in the mother and clone to her infant.\n\nConclusionGBS colonisation in mothers presents a significant risk of colonisation in their infants. We confirm vertical transmission from mother to child in dyad 17, accompanied by within-host diversity.

microbiology↗