18 results on '"Hyun Mu Shin"'
Search Results
2. Longitudinal Analysis of Human Memory T-Cell Response According to the Severity of Illness up to 8 Months After Severe Acute Respiratory Syndrome Coronavirus 2 Infection
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Minji Kim, Keehoon Jung, Pyoeng Gyun Choe, Wan Beom Park, Hyun Mu Shin, Myoung Don Oh, Gwanghun Kim, Nam Joong Kim, Ik Soo Kim, Soojin Lee, Dong Sup Lee, Chang-Han Lee, Hang Rae Kim, and Chang Kyung Kang
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Male ,0301 basic medicine ,Time Factors ,Epitopes, T-Lymphocyte ,severity ,medicine.disease_cause ,Severity of Illness Index ,0302 clinical medicine ,Immunophenotyping ,T-cell ,T-Lymphocyte Subsets ,Immunology and Allergy ,Medicine ,Longitudinal Studies ,030212 general & internal medicine ,Respiratory system ,Antigens, Viral ,Coronavirus ,Immunity, Cellular ,Memory response ,Disease Management ,Middle Aged ,AcademicSubjects/MED00290 ,Infectious Diseases ,medicine.anatomical_structure ,Host-Pathogen Interactions ,Cytokines ,Female ,Symptom Assessment ,medicine.symptom ,Adult ,T cell ,Asymptomatic ,03 medical and health sciences ,Antigen ,Severity of illness ,Major Article ,Humans ,Aged ,SARS-CoV-2 ,business.industry ,COVID-19 ,8 months ,030104 developmental biology ,Case-Control Studies ,Immunology ,Leukocytes, Mononuclear ,business ,Immunologic Memory ,Biomarkers ,CD8 - Abstract
Background Understanding the memory T-cell response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for assessing the longevity of protective immunity after SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) vaccination. However, the longitudinal memory T-cell response up to 8 months post–symptom onset (PSO) according to the severity of illness is unknown. Methods We analyzed peripheral blood mononuclear cells (PBMCs) from healthy volunteers or patients with COVID-19 who experienced asymptomatic, mild, or severe illness at 2, 5, and 8 months PSO. SARS-CoV-2 spike, nucleocapsid, and membrane protein-stimulated PBMCs were subjected to flow cytometry analysis. Results A total of 24 patients (7 asymptomatic, 9 with mild disease, and 8 with severe disease) and 6 healthy volunteers were analyzed. SARS-CoV-2–specific OX40+CD137+CD4+ T cells and CD69+CD137+CD8+ T cells persisted at 8 months PSO. Also, antigen-specific cytokine-producing or polyfunctional CD4+ T cells were maintained for up to 8 months PSO. Memory CD4+ T-cell responses tended to be greater in patients who had severe illness than in those with mild or asymptomatic disease. Conclusions Memory response to SARS-CoV-2, based on the frequency and functionality, persists for 8 months PSO. Further investigations involving its longevity and protective effect from reinfection are warranted.
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- 2021
3. Broad humoral and cellular immunity elicited by one-dose mRNA vaccination 18 months after SARS-CoV-2 infection
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Chang Kyung Kang, Hyun Mu Shin, Pyoeng Gyun Choe, Jiyoung Park, Jisu Hong, Jung Seon Seo, Yung Hie Lee, Euijin Chang, Nam Joong Kim, Minji Kim, Yong-Woo Kim, Hang-Rae Kim, Chang-Han Lee, Jun-Young Seo, Wan Beom Park, and Myoung-don Oh
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Immunity, Cellular ,Vaccines, Synthetic ,COVID-19 Testing ,COVID-19 Vaccines ,SARS-CoV-2 ,Vaccination ,COVID-19 ,Humans ,General Medicine ,RNA, Messenger ,mRNA Vaccines ,Antibodies, Viral - Abstract
Background Practical guidance is needed regarding the vaccination of coronavirus disease 2019 (COVID-19) convalescent individuals in resource-limited countries. It includes the number of vaccine doses that should be given to unvaccinated patients who experienced COVID-19 early in the pandemic. Methods We recruited COVID-19 convalescent individuals who received one or two doses of an mRNA vaccine within 6 or around 18 months after a diagnosis of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Their samples were assessed for IgG-binding or neutralizing activity and cell-mediated immune responses against SARS-CoV-2 wild-type and variants of concern. Results A total of 43 COVID-19 convalescent individuals were analyzed in the present study. The results showed that humoral and cellular immune responses against SARS-CoV-2 wild-type and variants of concern, including the Omicron variant, were comparable among patients vaccinated within 6 versus around 18 months. A second dose of vaccine did not significantly increase immune responses. Conclusion One dose of mRNA vaccine should be considered sufficient to elicit a broad immune response even around 18 months after a COVID-19 diagnosis.
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- 2022
4. Why are children less affected than adults by severe acute respiratory syndrome coronavirus 2 infection?
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Chang Kyung Kang, Hyun Mu Shin, Wan Beom Park, and Hang-Rae Kim
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Adult ,SARS-CoV-2 ,Viral infection ,Immunology ,Adaptive immunity ,Immunology and Allergy ,COVID-19 ,Humans ,Infectious diseases ,Child ,Article - Abstract
SARS-CoV-2 infection is generally mild or asymptomatic in children but a biological basis for this outcome is unclear. Here we compare antibody and cellular immunity in children (aged 3–11 years) and adults. Antibody responses against spike protein were high in children and seroconversion boosted responses against seasonal Beta-coronaviruses through cross-recognition of the S2 domain. Neutralization of viral variants was comparable between children and adults. Spike-specific T cell responses were more than twice as high in children and were also detected in many seronegative children, indicating pre-existing cross-reactive responses to seasonal coronaviruses. Importantly, children retained antibody and cellular responses 6 months after infection, whereas relative waning occurred in adults. Spike-specific responses were also broadly stable beyond 12 months. Therefore, children generate robust, cross-reactive and sustained immune responses to SARS-CoV-2 with focused specificity for the spike protein. These findings provide insight into the relative clinical protection that occurs in most children and might help to guide the design of pediatric vaccination regimens., SARS-CoV-2 infection is milder in children, but direct comparison with adults is rare. Here the authors show that immune responses are higher in children, retained for 12 months or longer and can neutralize Alpha, Beta and Delta variants.
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- 2022
5. Aberrant hyperactivation of cytotoxic T-cell as a potential determinant of COVID-19 severity
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Myoung Don Oh, Gi Chan Han, Pyoeng Gyun Choe, Wan Beom Park, Kyoung Ho Song, Gwanghun Kim, Eu Suk Kim, Chang Kyung Kang, Hong Bin Kim, Hyun Mu Shin, Hang Rae Kim, Nam Joong Kim, and Minji Kim
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CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,Programmed Cell Death 1 Receptor ,severity ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Granzymes ,0302 clinical medicine ,granzyme B ,Cytotoxic T cell ,Medicine ,030212 general & internal medicine ,perforin ,Aged, 80 and over ,Immunity, Cellular ,education.field_of_study ,biology ,General Medicine ,Middle Aged ,Infectious Diseases ,Cytokines ,Female ,Coronavirus Infections ,Adult ,Microbiology (medical) ,Pneumonia, Viral ,030106 microbiology ,Population ,macromolecular substances ,Peripheral blood mononuclear cell ,Article ,lcsh:Infectious and parasitic diseases ,Betacoronavirus ,03 medical and health sciences ,Immune system ,Humans ,lcsh:RC109-216 ,Lymphocyte Count ,education ,Pandemics ,Aged ,SARS-CoV-2 ,business.industry ,COVID-19 ,contraction ,Granzyme B ,Ki-67 Antigen ,Perforin ,Granzyme ,Immunology ,Leukocytes, Mononuclear ,biology.protein ,business ,CD8 ,cytotoxic T cell ,T-Lymphocytes, Cytotoxic - Abstract
Highlights • COVID-19 can deteriorate at the 2nd week of illness despite of decreasing viral loads • We analyzed PBMCs of severe or mild COVID-19 cases at the 1st and 3rd week of illness • Cellular responses were not different between two groups at the 1st week of illness • Higher T-cell proliferation, activation, and cytotoxicity was noted in severe cases at the 3rd week • Aberrant hyperactivation of cytotoxic T-cell may contribute to severe COVID-19 pneumonia, Objectives We hypothesized that immune response may contribute to progression of coronavirus disease-19 (COVID-19) at the second week of illness. Therefore, we compared cell-mediated immune (CMI) responses between severe and mild COVID-19 cases. Methods We examined peripheral blood mononuclear cells of laboratory-confirmed COVID-19 patients from their first and third weeks of illness. Severe pneumonia was defined as an oxygen saturation ≤ 93% at room air. Expressions of molecules related to T-cell activation and functions were analyzed by flow cytometry. Results The population dynamics of T cells at the first week were not different between the two groups. However, total numbers of CD4+ and CD8 + T cells tended to be lower in the severe group at the third week of illness. Expressions of Ki-67, PD-1, perforin, and granzyme B in CD4+ or CD8+ T cells were significantly higher in the severe group than in the mild group at the third week. In contrast to the mild group, the levels of their expression did not decrease in severe group. Conclusions Severe COVID-19 had higher degree of proliferation, activation, and cytotoxicity of T-cells at the late phase of illness without cytotoxic T-cell contraction, which might contribute to the development of severe COVID-19.
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- 2020
6. The acidic tumor microenvironment enhances PD-L1 expression via activation of STAT3 in MDA-MB-231 breast cancer cells
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Yong-Jin Kwon, Eun-Bi Seo, Ae Jin Jeong, Song-Hee Lee, Kum Hee Noh, Sangsik Lee, Chung-Hyun Cho, Chang-Han Lee, Hyun Mu Shin, Hang-Rae Kim, Hyeong-Gon Moon, and Sang-Kyu Ye
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STAT3 Transcription Factor ,Cancer Research ,Oncology ,Cell Line, Tumor ,Genetics ,Tumor Microenvironment ,Humans ,Breast Neoplasms ,Female ,Breast ,B7-H1 Antigen ,Signal Transduction - Abstract
Tumor acidosis, a common phenomenon in solid cancers such as breast cancer, is caused by the abnormal metabolism of cancer cells. The low pH affects cells surrounding the cancer, and tumor acidosis has been shown to inhibit the activity of immune cells. Despite many previous studies, the immune surveillance mechanisms are not fully understood. We found that the expression of PD-L1 was significantly increased under conditions of extracellular acidosis in MDA-MB-231 cells. We also confirmed that the increased expression of PD-L1 mediated by extracellular acidosis was decreased when the pH was raised to the normal range. Gene set enrichment analysis (GSEA) of public breast cancer patient databases showed that PD-L1 expression was also highly correlated with IL-6/JAK/STAT3 signaling. Surprisingly, the expression of both phospho-tyrosine STAT3 and PD-L1 was significantly increased under conditions of extracellular acidosis, and inhibition of STAT3 did not increase the expression of PD-L1 even under acidic conditions in MDA-MB-231 cells. Based on these results, we suggest that the expression of PD-L1 is increased by tumor acidosis via activation of STAT3 in MDA-MB-231 cells.
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- 2022
7. Hyperglycemia-induced oxidative stress promotes tumor metastasis by upregulating vWF expression in endothelial cells through the transcription factor GATA1
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Han-Seok Jeong, Da-Hye Lee, Seung-Hoon Kim, Chang-Han Lee, Hyun Mu Shin, Hang-Rae Kim, and Chung-Hyun Cho
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Cancer Research ,Lung Neoplasms ,Endothelial Cells ,Carcinoma, Lewis Lung ,Disease Models, Animal ,Mice ,Oxidative Stress ,Hyperglycemia ,Genetics ,Diabetes Mellitus ,Animals ,Humans ,GATA1 Transcription Factor ,Molecular Biology - Abstract
Diabetes mellitus (DM) characterized by hyperglycemia is a chronic metabolic disorder that leads to many symptoms and vascular complications. Despite the close association between DM and cancer progression, the response and role of endothelial cells (ECs) under diabetic conditions in tumor metastasis remain to be elucidated. In this study, we sought to determine whether and how ECs under diabetic conditions contribute to tumor metastasis. We have taken advantage of syngeneic mouse tumor models of Lewis lung carcinoma (LLC) and melanoma (B16F10) cells and a streptozotocin (STZ)-induced hyperglycemia model. We demonstrated that hyperglycemia increased the metastasis of LLC and B16F10 cells in an experimental metastasis model with an intravenous injection of the tumor cells. We also found that hyperglycemia promoted lung metastasis of tumor cells by increasing the adhesiveness of ECs to facilitate the adhesion of tumor cells to ECs rather than affecting the metastatic behavior of tumor cells themselves. From the analysis of gene expression in primary lung ECs from STZ-treated mice, we identified that vWF promoted the adhesion of tumor cells to ECs and the transendothelial migration of tumor cells. Mechanistically, hyperglycemia-induced oxidative stress in ECs, and increased oxidative stress enhanced vWF expression in ECs through an increase in the transcription factor GATA1. These results provide evidence for the role of vWF in ECs in promoting hyperglycemia-induced tumor metastasis and potential therapeutic targets for the regulation of vWF expression in ECs and hyperglycemia-induced tumor metastasis.
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- 2021
8. Metallic Fe–Au Barcode Nanowires as a Simultaneous T Cell Capturing and Cytokine Sensing Platform for Immunoassay at the Single-Cell Level
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Hyun Mu Shin, Yu Jin Kim, Eunmin Yoo, Da Yeon Nam, Bum Chul Park, Hang Rae Kim, Young Keun Kim, and Yoo Sang Jeon
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Materials science ,Iron ,T cell ,Nanowire ,Nanotechnology ,Cell Separation ,02 engineering and technology ,CD8-Positive T-Lymphocytes ,Barcode ,Sensitivity and Specificity ,01 natural sciences ,Epitope ,law.invention ,Metal ,Interferon-gamma ,law ,medicine ,Humans ,Cytotoxic T cell ,General Materials Science ,Immunoassay ,chemistry.chemical_classification ,medicine.diagnostic_test ,Nanowires ,Biomolecule ,010401 analytical chemistry ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,medicine.anatomical_structure ,chemistry ,visual_art ,visual_art.visual_art_medium ,Gold ,0210 nano-technology - Abstract
Barcode nanowires (BNWs) composed of multiple layered segments of different materials are attractive to bioengineering field due to their characteristics that allow the adjustment of physicochemical properties and conjugation with two or more types of biomolecules to facilitate multiple tasks. Here, we report a metallic Fe (iron)-Au (gold) BNW-based platform for capturing CD8 T cells and the interferon-γ (γ) they secrete, both of which play key roles in controlling infectious diseases such as tuberculosis, at the single-cell level. We also describe an efficient approach for conjugating distinct antibodies, which recognize different epitopes to appropriate materials. The platform achieved detection even with 4.45-35.6 μg mL-1 of BNWs. The T cell capture efficiency was close to 100% and the detection limit for interferon-γ was 460 pg mL-1. This work presents a potential guideline for the design of single-cell immunoassay platforms for eliminating diagnostic errors by unambiguously identifying disease-relevant immune mediators.
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- 2019
9. Interleukin-7 Contributes to the Invasiveness of Prostate Cancer Cells by Promoting Epithelial–Mesenchymal Transition
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Bo Yeon Seo, Gwanghun Kim, Hyun Mu Shin, Keunhee Oh, Insoo Kang, Ja-Lok Ku, Dong Sup Lee, Myung Won Seo, Young Kyoung Shin, Jin Hee Kim, Hang Rae Kim, Ji Hyun Sim, Min A. Seol, Serk In Park, and Ilkyu Han
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0301 basic medicine ,Male ,Epithelial-Mesenchymal Transition ,lcsh:Medicine ,Biology ,Article ,Metastasis ,03 medical and health sciences ,Prostate cancer ,Mice ,0302 clinical medicine ,Cell Movement ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Epithelial–mesenchymal transition ,Neoplasm Metastasis ,lcsh:Science ,Protein kinase B ,Multidisciplinary ,Receptors, Interleukin-7 ,Kinase ,Bone metastases ,Interleukin-7 ,lcsh:R ,Bone metastasis ,Prostatic Neoplasms ,medicine.disease ,030104 developmental biology ,Cancer cell ,PC-3 Cells ,Cancer research ,STAT protein ,lcsh:Q ,030217 neurology & neurosurgery - Abstract
Precise mechanisms underlying interleukin-7 (IL-7)-mediated tumor invasion remain unclear. Thus, we investigated the role of IL-7 in tumor invasiveness using metastatic prostate cancer PC-3 cell line derivatives, and assessed the potential of IL-7 as a clinical target using a Janus kinase (JAK) inhibitor and an IL-7-blocking antibody. We found that IL-7 stimulated wound-healing migration and invasion of PC-3 cells, increased phosphorylation of signal transducer and activator of transcription 5, Akt, and extracellular signal-regulated kinase. On the other hand, a JAK inhibitor and an IL-7-blocking antibody decreased the invasiveness of PC-3 cells. IL-7 increased tumor sphere formation and expression of epithelial–mesenchymal transition (EMT) markers. Importantly, lentiviral delivery of IL-7Rα to PC-3 cells significantly increased bone metastasis in an experimental murine metastasis model compared to controls. The gene expression profile of human prostate cancer cells from The Cancer Genome Atlas revealed that EMT pathways are strongly associated with prostate cancers that highly express both IL-7 and IL-7Rα. Collectively, these data suggest that IL-7 and/or IL-7Rα are promising targets of inhibiting tumor metastasis.
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- 2019
10. Chromatin accessibility of circulating CD8
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Hyun Mu, Shin, Gwanghun, Kim, Sangjib, Kim, Ji Hyun, Sim, Jiyeob, Choi, Minji, Kim, Minsuk, Kwon, Sang-Kyu, Ye, Dong-Sup, Lee, Seung Woo, Cho, Seung Tae, Kim, Jeeyun, Lee, and Hang-Rae, Kim
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Genome ,Programmed Cell Death 1 Receptor ,Transposases ,Sequence Analysis, DNA ,CD8-Positive T-Lymphocytes ,Translational research ,Chromatin ,Article ,Stomach Neoplasms ,Biomarkers, Tumor ,Chromatin Immunoprecipitation Sequencing ,Humans ,Gastric cancer ,Sequence Alignment ,Cell Proliferation - Abstract
Although tumor genomic profiling has identified small subsets of gastric cancer (GC) patients with clinical benefit from anti-PD-1 treatment, not all responses can be explained by tumor sequencing alone. We investigate epigenetic elements responsible for the differential response to anti-PD-1 therapy by quantitatively assessing the genome-wide chromatin accessibility of circulating CD8+ T cells in patients’ peripheral blood. Using an assay for transposase-accessible chromatin using sequencing (ATAC-seq), we identify unique open regions of chromatin that significantly distinguish anti-PD-1 therapy responders from non-responders. GC patients with high chromatin openness of circulating CD8+ T cells are significantly enriched in the responder group. Concordantly, patients with high chromatin openness at specific genomic positions of their circulating CD8+ T cells demonstrate significantly better survival than those with closed chromatin. Here we reveal that epigenetic characteristics of baseline CD8+ T cells can be used to identify metastatic GC patients who may benefit from anti-PD-1 therapy., Anti-PD-1 therapy could induce a durable response in patients with gastric cancer, however biomarkers to predict response to immunotherapy are generally lacking. Here the authors report that openness of chromatin in circulating CD8+ T cells predicts treatment outcome in patients with metastatic gastric cancer treated with pembrolizumab.
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- 2020
11. IL-7Rα
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Ji Hyun, Sim, Jin-Hee, Kim, Ae Kyung, Park, Jeeyun, Lee, Kyoung-Mee, Kim, Hyun Mu, Shin, Minji, Kim, Kyungho, Choi, Eun Young, Choi, Insoo, Kang, Dong-Sup, Lee, and Hang-Rae, Kim
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Interleukin-15 ,Receptors, Interleukin-7 ,GATA3 Transcription Factor ,CD8-Positive T-Lymphocytes ,Healthy Volunteers ,Proto-Oncogene Proteins c-myc ,Jurkat Cells ,Cell Line, Tumor ,Humans ,Glycolysis ,Immunologic Memory ,Cells, Cultured ,Cell Proliferation ,Signal Transduction - Abstract
Effector memory (EM) CD8
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- 2019
12. Immunological dynamics associated with rapid virological response duringthe early phase of type I interferon therapy in patients with chronichepatitis C
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Hyun Mu Shin, Byeong Gwan Kim, Jaewon Lee, Myung Sik Choi, Eun Kyung Kwon, Donghyun Kim, Chan Ki Min, Won Woo Lee, Won Kim, Yuri Kim, Ji Yeob Choi, and Nam Hyuk Cho
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0301 basic medicine ,Male ,RNA viruses ,Cellular immunity ,Physiology ,Hepacivirus ,Cancer Treatment ,lcsh:Medicine ,medicine.disease_cause ,Biochemistry ,chemistry.chemical_compound ,White Blood Cells ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Public and Occupational Health ,Prospective Studies ,lcsh:Science ,Immune Response ,Pathology and laboratory medicine ,Innate Immune System ,Multidisciplinary ,biology ,T Cells ,Hepatitis C virus ,Innate lymphoid cell ,Hepatitis C ,Regulatory T cells ,Middle Aged ,Viral Load ,Medical microbiology ,Vaccination and Immunization ,Treatment Outcome ,Oncology ,Interferon Type I ,Viruses ,Cytokines ,Drug Therapy, Combination ,Female ,Cellular Types ,Pathogens ,Viral load ,Research Article ,Genotype ,Immune Cells ,Immunology ,Cytokine Therapy ,Antiviral Agents ,Microbiology ,03 medical and health sciences ,Immune system ,Antiviral Therapy ,Republic of Korea ,Ribavirin ,medicine ,Humans ,Aged ,Blood Cells ,Flaviviruses ,business.industry ,Interleukins ,lcsh:R ,Organisms ,Viral pathogens ,Biology and Life Sciences ,Proteins ,Cell Biology ,Hepatitis C, Chronic ,Molecular Development ,biology.organism_classification ,medicine.disease ,Hepatitis viruses ,Microbial pathogens ,030104 developmental biology ,chemistry ,Gene Expression Regulation ,Immune System ,lcsh:Q ,Preventive Medicine ,Interferons ,business ,Developmental Biology - Abstract
Type I interferons (IFNs) play an important role in antiviral immunity as well as immunopathogenesis of diverse chronic viral infections. However, the precise mechanisms regulating the multifaceted effects of type I IFNs on the immune system and pathological inflammation still remain unclear. In order to assess the immunological dynamics associated with rapid viral clearance in chronic hepatitis C patients during the acute phase of type I IFN therapy, we analyzed multiple parameters of virological and immunological responses in a cohort of 59 Korean hepatitis C patients who received pegylated IFN-alpha and ribavirin (IFN/RBV). Most of the Korean patients had favorable alleles in the IFN-lambda loci for responsiveness to IFN/RBV (i.e., C/C in rs12979860, T/T in rs8099917, and TT/TT in rs368234815). Rapid virological response (RVR) was determined mainly by the hepatitis C virus genotype. Among the cytokines analyzed, higher plasma levels of IL-17A and FGF were observed in non-RVR patients infected with viral genotype 1 and IP-10 was consistently elevated in RVR group infected with genotype 2 during the early phase of antiviral therapy. In addition, these three cytokines were correlated each other, suggesting a functional linkage of the cytokines in antiviral responses during IFN/RBV therapy. A low baseline frequencies of regulatory T cells and.d T cells, but high level of group 2 innate lymphoid cells, in peripheral bloods were also significantly associated with the RVR group, implicating a potential role of the cellular immunity during the early phase of IFN/RBV therapy. Therefore, the immunological programs established by chronic hepatitis C and rapid disruption of the delicate balance by exogenous type I IFN might be associated with the subsequent virological outcomes in chronic hepatitis C patients.
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- 2017
13. Epigenetic Modifications Induced by Blimp-1 Regulate CD8+ T Cell Memory Progression during Acute Virus Infection
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Leslie J. Berg, Varun N. Kapoor, Hyun Mu Shin, Raymond M. Welsh, Tianxia Guan, and Susan M. Kaech
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Molecular Sequence Data ,Immunology ,Histone Deacetylase 2 ,Mice, Transgenic ,CD8-Positive T-Lymphocytes ,Lymphocytic Choriomeningitis ,Biology ,Methylation ,Article ,Epigenesis, Genetic ,Histones ,Mice ,Animals ,Humans ,Lymphocytic choriomeningitis virus ,Gene silencing ,Cytotoxic T cell ,Immunology and Allergy ,Amino Acid Sequence ,Epigenetics ,IL-2 receptor ,RNA, Small Interfering ,Histone H3 acetylation ,Histone deacetylase 2 ,Interleukin-2 Receptor alpha Subunit ,Histone-Lysine N-Methyltransferase ,Tumor Necrosis Factor Receptor Superfamily, Member 7 ,Histone ,Infectious Diseases ,Disease Progression ,Cancer research ,biology.protein ,Positive Regulatory Domain I-Binding Factor 1 ,Immunologic Memory ,Chromatin immunoprecipitation ,Signal Transduction ,Transcription Factors - Abstract
The transcription factor Blimp-1 regulates the overall accumulation of virus-specific CD8+ T cells during acute viral infections. We found that increased proliferation and survival of Blimp-1-deficient CD8+ T cells resulted from sustained expression of CD25 and CD27 and persistent cytokine responsiveness. Silencing of these genes reduced the Blimp-1-deficient CD8+ T cell response. Genome-wide Chromatin immunoprecipitation (ChIP) sequencing analysis identified Il2ra and Cd27 genes as direct targets of Blimp-1. At the peak of the anti-viral response, but not earlier, Blimp-1 recruited the histone modifying enzymes G9a and HDAC2 to the Il2ra and Cd27 loci, thereby repressing expression of these genes. In the absence of Blimp-1, the Il2ra and Cd27 genes exhibited enhanced histone H3-acetylation and reduced histone H3K9-trimethylation. These data elucidate a central mechanism by which Blimp-1 acts as an epigenetic regulator, enhancing the numbers of short-lived effector cells while suppressing the development of memory precursor CD8+ T cells.
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- 2013
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14. Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity
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Abdimadiyeva Aigerim, Kyung Mok Sohn, Shinhye Cheon, Ji Yeob Choi, Kyung-Soo Inn, Jae Young Moon, Yeon Sook Kim, Chan Ki Min, Yuri Kim, Hyun Mu Shin, Na Young Ha, Nam Hyuk Cho, Jin Hwan Kim, and Myung Sik Choi
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0301 basic medicine ,Adult ,Male ,Middle East respiratory syndrome coronavirus ,Leukocytosis ,Lymphocyte ,medicine.disease_cause ,Severity of Illness Index ,Article ,03 medical and health sciences ,Immunity ,Lymphopenia ,Severity of illness ,Medicine ,Humans ,Viral shedding ,Aged ,Aged, 80 and over ,Multidisciplinary ,Epidermal Growth Factor ,business.industry ,Pneumonia ,Middle Aged ,Viral Load ,medicine.disease ,Thrombocytopenia ,Virus Shedding ,Kinetics ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,Middle East Respiratory Syndrome Coronavirus ,Cytokines ,Female ,medicine.symptom ,business ,Coronavirus Infections ,Viral load - Abstract
Despite the ongoing spread of MERS, there is limited knowledge of the factors affecting its severity and outcomes. We analyzed clinical data and specimens from fourteen MERS patients treated in a hospital who collectively represent a wide spectrum of disease severity, ranging from mild febrile illness to fatal pneumonia, and classified the patients into four groups based on severity and mortality. Comparative and kinetic analyses revealed that high viral loads, weak antibody responses, and lymphopenia accompanying thrombocytopenia were associated with disease mortality, whereas persistent and gradual increases in lymphocyte responses might be required for effective immunity against MERS-CoV infection. Leukocytosis, primarily due to increased neutrophils and monocytes, was generally observed in more severe and fatal cases. The blood levels of cytokines such as IL-10, IL-15, TGF-β, and EGF were either positively or negatively correlated with disease mortality. Robust induction of various chemokines with differential kinetics was more prominent in patients that recovered from pneumonia than in patients with mild febrile illness or deceased patients. The correlation of the virological and immunological responses with disease severity and mortality, as well as their responses to current antiviral therapy, may have prognostic significance during the early phase of MERS.
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- 2016
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15. Spread of Mutant Middle East Respiratory Syndrome Coronavirus with Reduced Affinity to Human CD26 during the South Korean Outbreak
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Chan Ki Min, Hyun Soo Cho, Na Young Ha, Young Je Cha, Abdimadiyeva Aigerim, Yeon Sook Kim, Nam Hyuk Cho, Yuri Kim, Sanguk Kim, Seong Kyu Han, Hyun Mu Shin, Gwanghun Kim, Shinhye Cheon, Kyung Mok Sohn, Ying Jin Kang, Myung Sik Choi, and Ju Il Kang
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0301 basic medicine ,Middle East respiratory syndrome coronavirus ,Dipeptidyl Peptidase 4 ,viruses ,Adaptation, Biological ,Mutation, Missense ,Virus Attachment ,Genome, Viral ,Biology ,medicine.disease_cause ,Microbiology ,Virus ,Disease Outbreaks ,03 medical and health sciences ,Virology ,Republic of Korea ,medicine ,Missense mutation ,Humans ,Point Mutation ,Selection, Genetic ,Mutation ,Point mutation ,Outbreak ,Respiratory infection ,Sequence Analysis, DNA ,Surface Plasmon Resonance ,Entry into host ,QR1-502 ,030104 developmental biology ,Spike Glycoprotein, Coronavirus ,Middle East Respiratory Syndrome Coronavirus ,Receptors, Virus ,Mutant Proteins ,Coronavirus Infections ,Protein Binding ,Research Article - Abstract
The newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes a severe respiratory infection with a high mortality rate (~35%). MERS-CoV has been a global threat due to continuous outbreaks in the Arabian peninsula and international spread by infected travelers since 2012. From May to July 2015, a large outbreak initiated by an infected traveler from the Arabian peninsula swept South Korea and resulted in 186 confirmed cases with 38 deaths (case fatality rate, 20.4%). Here, we show the rapid emergence and spread of a mutant MERS-CoV with reduced affinity to the human CD26 receptor during the South Korean outbreak. We isolated 13 new viral genomes from 14 infected patients treated at a hospital and found that 12 of these genomes possess a point mutation in the receptor-binding domain (RBD) of viral spike (S) protein. Specifically, 11 of these genomes have an I529T mutation in RBD, and 1 has a D510G mutation. Strikingly, both mutations result in reduced affinity of RBD to human CD26 compared to wild-type RBD, as measured by surface plasmon resonance analysis and cellular binding assay. Additionally, pseudotyped virus bearing an I529T mutation in S protein showed reduced entry into host cells compared to virus with wild-type S protein. These unexpected findings suggest that MERS-CoV adaptation during human-to-human spread may be driven by host immunological pressure such as neutralizing antibodies, resulting in reduced affinity to host receptor, and thereby impairs viral fitness and virulence, rather than positive selection for a better affinity to CD26., IMPORTANCE Recently, a large outbreak initiated by an MERS-CoV-infected traveler from the Middle East swept South Korea and resulted in 186 confirmed cases with 38 deaths. This is the largest outbreak outside the Middle East, and it raised strong concerns about the possible emergence of MERS-CoV mutations. Here, we isolated 13 new viral genomes and found that 12 of them possess a point mutation in the receptor-binding domain of viral spike protein, resulting in reduced affinity to the human cognate receptor, CD26, compared to the wild-type virus. These unexpected findings suggest that MERS-CoV adaptation in humans may be driven by host immunological pressure.
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- 2016
16. Synergistic interaction of MEF2D and Sp1 in activation of the CD14 promoter
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Hyun-Mu Shin, Tae Hee Han, and So-Youn Park
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Mef2 ,Sp1 Transcription Factor ,HL60 ,Cellular differentiation ,CD14 ,Immunology ,Lipopolysaccharide Receptors ,MADS Domain Proteins ,Biology ,chemistry.chemical_compound ,Downregulation and upregulation ,medicine ,Humans ,Binding site ,Promoter Regions, Genetic ,Receptor ,Molecular Biology ,MEF2 Transcription Factors ,Monocyte ,Cell Differentiation ,U937 Cells ,Molecular biology ,DNA-Binding Proteins ,medicine.anatomical_structure ,Myogenic Regulatory Factors ,chemistry ,Transcription Factors - Abstract
The expression of CD14, a monocyte receptor for the bacterial lipopolysaccharide (LPS), is upregulated during monocytic cell differentiation. Although a Sp1 site at −110 bp of the CD14 promoter was shown to be critical for activation of the promoter during the differentiation, how the Sp1 site is regulated has not been well understood. We have recently reported that expression of MEF2D protein increases during the differentiation of HL60 promyeloid cells to monocyte and that the upregulation of the protein is required for CD14 expression during the differentiation [Mol. Immunol. 36 (1999) 1209]. However, there is no obvious MEF2 binding site in the critical region of the CD14 promoter. In this study, which aimed to determine the regulatory role of MEF2D in monocytic cell differentiation, MEF2D was found to form a complex with Sp1 in U937 promyeloid cells. Transient transfection experiments showed that co-expression of MEF2D and Sp1 synergistically activated the CD14 promoter. The results support a model in which increased MEF2D protein during monocytic cell differentiation activates the CD14 promoter through interaction with Sp1.
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- 2002
17. Requirement of MEF2D in the induced differentiation of HL60 promyeloid cells
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Myong Joon Hahn, Hyun Mu Shin, Jae Seung Kang, So Joung Choi, Ju Young Seoh, Hee Yong Chung, Tae Hee Han, and Myung Sik Choi
- Subjects
Mef2 ,CD14 ,Immunology ,Cell ,Lipopolysaccharide Receptors ,HL-60 Cells ,MADS Domain Proteins ,Biology ,Monocytes ,Cell Line ,Transactivation ,Enhancer binding ,medicine ,Humans ,Macrophage ,Molecular Biology ,Cholecalciferol ,Base Sequence ,U937 cell ,MEF2 Transcription Factors ,Macrophages ,Monocyte ,Gene Expression Regulation, Developmental ,Cell Differentiation ,U937 Cells ,Cell biology ,DNA-Binding Proteins ,medicine.anatomical_structure ,Myogenic Regulatory Factors ,Tetradecanoylphorbol Acetate ,Plasmids ,Transcription Factors - Abstract
The regulatory role of MEF2 (myocyte enhancer binding factor 2) proteins in nonmuscle tissues has not been well characterized. We examined the expression of MEF2 family members, namely, MEF2A, -B, -C, and -D, in the differentiation of HL60 promyeloid cells and observed the remarkable increase in the expressions of MEF2A and MEF2D proteins during the differentiation process into monocytes. To examine the role of MEF2, we expressed a dominant-negative form of MEF2D, without its transactivation domain, in HL60 cells. When the HL60 cell line expressing the mutant MEF2D was induced to differentiate by VitD(3) treatment, cell surface expression of CD14 and the ability to reduce NBT, which are important characteristics of differentiated monocytes, were significantly decreased compared with control HL60 cells. These results show that MEF2D is required in the differentiation process along the monocyte/macrophage lineage
- Published
- 1999
18. CD28-mediated regulation of the c-jun promoter involves the MEF2 transcription factor in Jurkat T cells
- Author
-
Tae Hee Han and Hyun Mu Shin
- Subjects
T cell ,Immunology ,MADS Domain Proteins ,Biology ,Regulatory Sequences, Nucleic Acid ,CREB ,Jurkat cells ,Wortmannin ,chemistry.chemical_compound ,Jurkat Cells ,Phosphatidylinositol 3-Kinases ,CD28 Antigens ,Genes, jun ,medicine ,Humans ,Binding site ,Promoter Regions, Genetic ,Molecular Biology ,Transcription factor ,Binding Sites ,MEF2 Transcription Factors ,CD28 ,hemic and immune systems ,Promoter ,Molecular biology ,DNA-Binding Proteins ,medicine.anatomical_structure ,Sphingomyelin Phosphodiesterase ,chemistry ,Gene Expression Regulation ,Myogenic Regulatory Factors ,biology.protein ,Signal Transduction ,Transcription Factors - Abstract
Within a few minutes of T-cell activation, transcription of a set of genes including c-fos and c-jun is activated. For maximal induction of c-jun, at least two major signal pathways are required. One can be triggered by T-cell receptor engagement or phorbol esters and the other by anti-CD28 engagement. The c-jun promoter region between -117 and -50 contains binding sites for the transcription factors Spl, CTF, ATF/CREB, and MEF2. In this study, we sought to map the sequences in the c-jun promoter responsible for CD28-mediated induction in activated Jurkat T cell by point mutational analysis. We found that mutation of the c-jun MEF2 site strongly reduces CD28 induction of the promoter in Jurkat T cells and that MEF2D is the major binding molecule to the c-jun MEF2 site in Jurkat T cells. Mutation of the c-jun ATF site also partially reduced CD28 induction of the promoter. In addition, pretreatment with an endolysomotropic agent NH4Cl, an acidic sphingomyelinase inhibitor, completely inhibited the activation of the c-jun promoter by anti-CD28 antibody treatment, whereas pretreatment with wortmannin, a PI3-kinase inhibitor, did not affect the induction of the c-jun promoter. These results suggest that CD28 signaling leading to the c-jun promoter involves acidic sphingomyelinase, but not PI3-kinase, to activate factors binding to the MEF2 and ATF sites.
- Published
- 1999
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