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2. Just not himself these days: an invitation to submit papers on the topic of inflammation and immunity in organ systems physiology and pathophysiology
- Author
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David G. Harrison
- Subjects
Inflammation ,Publishing ,Phrase ,Physiology ,Interpretation (philosophy) ,media_common.quotation_subject ,Immunity ,Autoimmunity ,Adaptive Immunity ,Immunity, Innate ,Reflexive pronoun ,Autoimmune Diseases ,Disease Models, Animal ,Physiology (medical) ,Distraction ,Personality ,Animals ,Humans ,Psychology ,Organ system ,media_common - Abstract
when someone is acting oddly, it is often said that she or he is “not herself” or “not himself.” This generally refers to a change is personality, either due to distraction, stress, or some other emotional alteration. During the past decade, a new interpretation of this phrase has arisen.
- Published
- 2011
3. Differences in the dynamics of the <scp>tandem‐SH2</scp> modules of the Syk and <scp>ZAP</scp> ‐70 tyrosine kinases
- Author
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Neel H. Shah, Christine L. Gee, John Kuriyan, Jean M. Badroos, Helen T. Hobbs, and Susan Marqusee
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Protein Conformation, alpha-Helical ,Conformational change ,Full‐Length Papers ,T-Lymphocytes ,Genetic Vectors ,Gene Expression ,Syk ,chemical and pharmacologic phenomena ,Adaptive Immunity ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,SH2 domain ,Biochemistry ,Full‐Length Paper ,evolution ,Immunoreceptor tyrosine-based activation motif ,Escherichia coli ,Animals ,Humans ,Syk Kinase ,Protein Interaction Domains and Motifs ,Cloning, Molecular ,Tyrosine ,Molecular Biology ,B-Lymphocytes ,Binding Sites ,ZAP-70 Protein-Tyrosine Kinase ,Chemistry ,conformational landscape ,hydrogen–deuterium exchange mass spectrometry ,tyrosine kinase signaling ,Deuterium Exchange Measurement ,hemic and immune systems ,Biological Evolution ,Recombinant Proteins ,Protein kinase domain ,protein dynamics ,Biophysics ,Phosphorylation ,Protein Conformation, beta-Strand ,Tyrosine kinase ,Protein Binding ,Signal Transduction - Abstract
The catalytic activity of Syk‐family tyrosine kinases is regulated by a tandem Src homology 2 module (tSH2 module). In the autoinhibited state, this module adopts a conformation that stabilizes an inactive conformation of the kinase domain. The binding of the tSH2 module to phosphorylated immunoreceptor tyrosine‐based activation motifs necessitates a conformational change, thereby relieving kinase inhibition and promoting activation. We determined the crystal structure of the isolated tSH2 module of Syk and find, in contrast to ZAP‐70, that its conformation more closely resembles that of the peptide‐bound state, rather than the autoinhibited state. Hydrogen–deuterium exchange by mass spectrometry, as well as molecular dynamics simulations, reveal that the dynamics of the tSH2 modules of Syk and ZAP‐70 differ, with most of these differences occurring in the C‐terminal SH2 domain. Our data suggest that the conformational landscapes of the tSH2 modules in Syk and ZAP‐70 have been tuned differently, such that the autoinhibited conformation of the Syk tSH2 module is less stable. This feature of Syk likely contributes to its ability to more readily escape autoinhibition when compared to ZAP‐70, consistent with tighter control of downstream signaling pathways in T cells., PDB Code(s): 7SA7
- Published
- 2021
4. The importance of Ca 2+ microdomains for the adaptive immune response.
- Author
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Diercks BP
- Subjects
- Humans, Animals, Lymphocyte Activation immunology, Membrane Microdomains metabolism, Membrane Microdomains immunology, Adaptive Immunity, Calcium Signaling, T-Lymphocytes immunology, T-Lymphocytes metabolism, Calcium metabolism, Receptors, Antigen, T-Cell metabolism, Receptors, Antigen, T-Cell immunology
- Abstract
Calcium signaling stands out as the most widespread and universally used signaling system and is of utmost importance for immunity. Controlled elevations in cytosolic and organellar Ca
2+ concentrations in T cells control complex and essential effector functions including proliferation, differentiation, cytokine secretion, and cytotoxicity, among others. Additionally, disruptions in Ca2+ regulation in T cells contribute to diverse autoimmune, inflammatory, and immunodeficiency conditions. Among the initial intracellular signals, which occurring even before T cell receptor (TCR) stimulation are highly localized, spatially and temporally restricted so-called Ca2+ microdomains, caused by adhesion to extracellular matrix proteins (ECM proteins). The Ca2+ microdomains present both before and within the initial seconds following TCR stimulation are likely to play a crucial role in fine-tuning the downstream activity of T cell activation and thus, shaping an adaptive immune response. In this review, the emphasis is on the recent advances of adhesion-dependent Ca2+ microdomains (ADCM) in the absence of TCR stimulation, initial Ca2+ microdomains evoked by TCR stimulation (TDCM), the downstream signaling processes as well as possible therapeutic targets for interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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5. Immune consequences of exercise in hypoxia: A narrative review.
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Burtscher J, Pasha Q, Chanana N, Millet GP, Burtscher M, and Strasser B
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- Humans, Immunity, Innate physiology, Altitude, Oxygen metabolism, Acclimatization physiology, Immune System physiology, Adaptation, Physiological, Exercise physiology, Hypoxia immunology, Adaptive Immunity
- Abstract
Immune outcomes are key mediators of many health benefits of exercise and are determined by exercise type, dose (frequency/duration, intensity), and individual characteristics. Similarly, reduced availability of ambient oxygen (hypoxia) modulates immune functions depending on the hypoxic dose and the individual capacity to respond to hypoxia. How combined exercise and hypoxia (e.g., high-altitude training) sculpts immune responses is not well understood, although such combinations are becoming increasingly popular. Therefore, in this paper, we summarize the impact on immune responses of exercise and of hypoxia, both independently and together, with a focus on specialized cells in the innate and adaptive immune system. We review the regulation of the immune system by tissue oxygen levels and the overlapping and distinct immune responses related to exercise and hypoxia, then we discuss how they may be modulated by nutritional strategies. Mitochondrial, antioxidant, and anti-inflammatory mechanisms underlie many of the adaptations that can lead to improved cellular metabolism, resilience, and overall immune functions by regulating the survival, differentiation, activation, and migration of immune cells. This review shows that exercise and hypoxia can impair or complement/synergize with each other while regulating immune system functions. Appropriate acclimatization, training, and nutritional strategies can be used to avoid risks and tap into the synergistic potentials of the poorly studied immune consequences of exercising in a hypoxic state., (Copyright © 2023. Production and hosting by Elsevier B.V.)
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- 2024
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6. The methods and advances of adaptive immune receptors repertoire sequencing
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Akihiko Yoshimura, Nongyue He, Wenjing Pan, Yujie Tang, Song Li, Hongmei Liu, Haijing Wu, Congli Tang, and Yan Deng
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Computer science ,T-Lymphocytes ,Population ,adaptive immune repertoire sequencing ,Medicine (miscellaneous) ,Computational biology ,Adaptive Immunity ,DNA sequencing ,Immune system ,Antigen ,Humans ,Receptors, Immunologic ,education ,Receptor ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,education.field_of_study ,B-Lymphocytes ,Repertoire ,high-throughput sequencing ,Computational Biology ,High-Throughput Nucleotide Sequencing ,bioinformatics ,Acquired immune system ,T or B cell receptors ,Experimental methods ,Single-Cell Analysis ,Research Paper - Abstract
The adaptive immune response is a powerful tool, capable of recognizing, binding to, and neutralizing a vast number of internal and external threats via T or B lymphatic receptors with widespread sets of antigen specificities. The emergence of high-throughput sequencing technology and bioinformatics provides opportunities for research in the fields of life sciences and medicine. The analysis and annotation for immune repertoire data can reveal biologically meaningful information, including immune prediction, target antigens, and effective evaluation. Continuous improvements of the immunological repertoire sequencing methods and analysis tools will help to minimize the experimental and calculation errors and realize the immunological information to meet the clinical requirements. That said, the clinical application of adaptive immune repertoire sequencing requires appropriate experimental methods and standard analytical tools. At the population cell level, we can acquire the overview of cell groups, but the information about a single cell is not obtained accurately. The information that is ignored may be crucial for understanding the heterogeneity of each cell, gene expression and drug response. The combination of high-throughput sequencing and single-cell technology allows us to obtain single-cell information with low-cost and high-throughput. In this review, we summarized the current methods and progress in this area.
- Published
- 2021
7. Altered expression of genes related to innate antifungal immunity in the absence of galectin-3
- Author
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André Moreira Pessoni, Patrícia Kellen Martins Oliveira Brito, Gustavo H. Goldman, Caroline Patini Rezende, Thiago Aparecido da Silva, and Fausto Almeida
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Microbiology (medical) ,Antifungal ,Antifungal Agents ,animal structures ,medicine.drug_class ,Galectin 3 ,Galectins ,Immunology ,Infectious and parasitic diseases ,RC109-216 ,Adaptive Immunity ,Biology ,Microbiology ,gene knockout ,Mice ,03 medical and health sciences ,Immunity ,galectin-3 ,Gene expression ,otorhinolaryngologic diseases ,medicine ,Animals ,Gene ,Gene knockout ,030304 developmental biology ,Galectin ,0303 health sciences ,Innate immune system ,030306 microbiology ,EXPRESSÃO GÊNICA ,Immunity, Innate ,Cell biology ,stomatognathic diseases ,Infectious Diseases ,Galectin-3 ,innate immune response ,gene expression ,Parasitology ,antifungal immunity ,Research Article ,Research Paper - Abstract
Galectin-3 (Gal-3) is the most studied member of the animal galectin family, which comprises β-galactoside-binding lectins and participates in several cellular events. Its expression in cells involved in innate and adaptive immunity is related to anti- and proinflammatory functions, signaling an important role in inflammatory, infectious, and tumorigenesis processes. Mice deficient in Gal-3 exhibit important phenotypes, but it is unclear whether these phenotypes reflect an impairment of the functions of this protein. Gal-3 plays an important role in modulating the immune response to different pathogenic microorganisms. However, the role of Gal-3 in immunity to infection is still poorly understood. Therefore, we investigated the effects of Gal-3 deletion on the expression of genes involved in the innate immune response in the lungs, spleens, and brains of Gal-3 KO mice. Gene profiling expression analysis suggested that Gal-3 deletion resulted in differentially modulated expression of the genes encoding beta-glucan, mannose and chitin-responsive pattern recognition receptors, signal transduction, inflammation, and phagocytosis. Our data thus suggest the importance of Gal-3 expression in the host innate immune system.
- Published
- 2021
8. A spontaneous multifunctional hydrogel vaccine amplifies the innate immune response to launch a powerful antitumor adaptive immune response
- Author
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Shunyao Zhu, Miaomiao Zhang, Songlin Gong, Changyang Gong, Tao He, Qinjie Wu, Xinchao Li, Xiuqi Liang, and Lu Li
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Ovalbumin ,T-Lymphocytes ,medicine.medical_treatment ,Medicine (miscellaneous) ,chemical and pharmacologic phenomena ,02 engineering and technology ,Adaptive Immunity ,Biology ,Cancer Vaccines ,Mannans ,Mice ,03 medical and health sciences ,Immune system ,Cancer immunotherapy ,Antigen ,Cell Line, Tumor ,Tumor Microenvironment ,medicine ,Animals ,Melanoma ,innate immunity ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Schiff Bases ,030304 developmental biology ,Inflammation ,Chitosan ,0303 health sciences ,Ncom Gel vaccine ,cancer immunotherapy ,Innate immune system ,Macrophages ,Hydrogels ,Dendritic Cells ,Immunotherapy ,021001 nanoscience & nanotechnology ,Acquired immune system ,Immunity, Innate ,adaptive immune response ,Tumor antigen ,Mice, Inbred C57BL ,spontaneous multifunctional hydrogel ,Humoral immunity ,Microscopy, Electron, Scanning ,Cancer research ,Female ,Rheology ,0210 nano-technology ,Research Paper - Abstract
Substantial progress has been made with cancer immunotherapeutic strategies in recent years, most of which mainly rely on enhancing the T cell response. However, sufficient tumor antigen information often cannot be presented to T cells, resulting in a failed effector T cell response. The innate immune system can effectively recognize tumor antigens and then initiate an adaptive immune response. Here, we developed a spontaneous multifunctional hydrogel (NOCC-CpG/OX-M, Ncom Gel) vaccine to amplify the innate immune response and harness innate immunity to launch and maintain a powerful adaptive immune response. Methods: Ncom Gel was formed by a Schiff base reaction between CpG-modified carboxymethyl chitosan (NOCC-CpG) and partially oxidized mannan (OX-M). The effects of the Ncom Gel vaccine on DCs and macrophages in vitro and antigen-specific humoral immunity and cellular immunity in vivo were studied. Furthermore, the antitumor immune response of the Ncom Gel vaccine and its effect on the tumor microenvironment were evaluated. Results: The Ncom Gel vaccine enhanced antigen presentation to T cells by facilitating DC uptake and maturation and inducing macrophages to a proinflammatory subtype, further leading to a T cell-mediated adaptive immune response. Moreover, the innate immune response could be amplified via the promotion of antigen-specific antibody production. The Ncom Gel vaccine reversed the tumor immune microenvironment to an inflamed phenotype and showed a significant antitumor response in a melanoma model. Conclusions: Our research implies the potential application of injectable hydrogels as a platform for tumor immunotherapy. The strategy also opens up a new avenue for multilayered cancer immunotherapy.
- Published
- 2021
9. The effect of repetitive exposure to intravenous anesthetic agents on the immunity in mice
- Author
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Liyun Piao, Seong-Hyop Kim, Eun-Hye Seo, Hyun-Jun Park, and Seung Hyun Lee
- Subjects
CD4-Positive T-Lymphocytes ,Male ,medicine.medical_specialty ,Midazolam ,medicine.medical_treatment ,Enzyme-Linked Immunosorbent Assay ,Adaptive Immunity ,Pharmacology ,Kidney ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Dexmedetomidine ,Mice, Inbred BALB C ,propofol ,Cluster of differentiation ,business.industry ,dexmedetomidine ,General Medicine ,Immunohistochemistry ,immunity ,Cytokine ,medicine.anatomical_structure ,Liver ,Anesthetic ,intravenous anesthetic agent ,030211 gastroenterology & hepatology ,Histopathology ,Propofol ,business ,Anesthetics, Intravenous ,Research Paper ,medicine.drug - Abstract
Introduction: This study was designed to assess the effect of repetitive exposure to intravenous anesthetic agents on the immunity in mice. Materials and Methods: The mice were divided into six groups: three intravenous anesthetic agents groups (dexmedetomidine, midazolam and propofol groups), and three corresponding control groups (CD, CM, and CP groups). The intravenous injections were administered once per day for 5 days. The immunity of mice was checked after the last intravenous injection. Histopathology and immunochemistry of liver and kidneys were evaluated. Cytokine levels in the blood was also checked. vs. evaluated with cytokine levels in the blood. Results: Cluster of differentiation (CD)4+ T cells were significantly less expressed in dexmedetomidine and propofol groups, compared with the corresponding control groups [34.08 ± 5.63% in the dexmedetomidine group vs. 59.74 ± 8.64% in the CD group, p < 0.05; 25.28 ± 7.28% in the propofol group vs. 61.12 ± 2.70% in the Cp group, p < 0.05]. Apoptosis of CD4+ T cells was increased significantly in dexmedetomidine and propofol groups, compared with the corresponding control groups. Histopathological findings of liver and kidneys did not show any specific differences of any of three intravenous anesthetic agents groups with their corresponding control groups, although immunohistochemical examination indicated significantly lower expression of Toll-like receptor-4 from liver and kidneys in dexmedetomidine and propofol groups. The cytokine levels were not different between the groups. Conclusion: Repetitive exposure to dexmedetomidine and propofol reduced the expression of CD4+ T cells but did not induce any significant liver or kidney injuries.
- Published
- 2020
10. Novel calreticulin-nanoparticle in combination with focused ultrasound induces immunogenic cell death in melanoma to enhance antitumor immunity
- Author
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Mohit Pratap Singh, P. Jack Hoopes, Jerry R. Malayer, Shitao Li, Sri Nandhini Sethuraman, Steven Fiering, Ashish Ranjan, Girish Patil, and Chandan Guha
- Subjects
0301 basic medicine ,Ultrasonic Therapy ,Population ,Melanoma, Experimental ,Clone (cell biology) ,Medicine (miscellaneous) ,CD47 Antigen ,Immunogenic Cell Death ,Adaptive Immunity ,CD8-Positive T-Lymphocytes ,B7-H1 Antigen ,calreticulin ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunity ,Tumor-Associated Macrophages ,melanoma ,Animals ,Humans ,Medicine ,education ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,education.field_of_study ,biology ,business.industry ,nanoparticle ,Melanoma ,Cell Membrane ,medicine.disease ,Combined Modality Therapy ,Xenograft Model Antitumor Assays ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,focused ultrasound ,Cytokines ,Nanoparticles ,Immunogenic cell death ,Lymph Nodes ,business ,Calreticulin ,Spleen ,CD8 ,Research Paper - Abstract
Rationale: Some studies have shown that the local activation of immunogenic cell death (ICD) by upregulating calreticulin (CRT) expression in solid tumors can improve antitumor effects. Although a promising approach, a key current challenge in ICD tumor therapy is the absence of a clinically translatable method for reproducibly inducing the CRT expression. Herein, we report a novel calreticulin-nanoparticle (CRT-NP) that enhances ICD and synergizes with focused ultrasound (FUS) to achieve local and systemic antitumor effects. Methods: Full-length clone DNA of calreticulin was encapsulated in NPs made from DOTAP and cholesterol. Three CRT-NP intratumoral injections of 20 µg each were given 2 days apart, and FUS heating (42-45°C, ~15min) was applied sequentially 24h after each injection to induce ICD. To investigate ICD specific immune effect, the splenocytes of mice vaccinated with CRT-NP (± FUS) treated B16F10 cells were evaluated ex-vivo for TRP-2 antigen specific immunity. Additionally, the long-term protection was evaluated by re-challenging with the melanoma cells in the flank regions of tumor bearing mice. Results: CRT-NP plus FUS (CFUS) upregulated CRT expression, expanded the population of melanoma TRP-2 specific functional CD4+ and CD8+ T cells and tumor-suppressing M1 phenotype, and increased PD-1 and PD-L1 marker expression in the T cells. Therapeutically, CFUS suppressed B16 melanoma growth by >85% vs. that seen in untreated controls, and >~50% vs. CRT-NP or FUS alone, and prevented tumor growth in distal untreated sites. Conclusions: CRT-NP amplifies the FUS and ICD therapeutic outcomes against melanoma, suggesting that the proposed combinatorial methodology may be clinically translatable.
- Published
- 2020
11. Adaptive post-COVID-19 immune response in female subjects of the Russian arctic region.
- Author
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Shchegoleva LS, Kabbani MS, Shashkova EY, Filippova OE, Popovskaya EV, Sergeeva TB, and Morozova OS
- Subjects
- Humans, Female, Russia epidemiology, Arctic Regions epidemiology, Adult, Young Adult, COVID-19 immunology, SARS-CoV-2 immunology, Adaptive Immunity immunology
- Abstract
The Arctic region's unfavorable living conditions adversely affect the spread of infectious diseases, including COVID-19, This, in turn, can also lead to increased morbidity and mortality rates in the area due to a number of factors such as climate, environment, and high prevalence rate of pre-existing health issues like diabetes, obesity, and respiratory infections. These circumstances adversely affect maintaining the level of working capability. The aim of this paper is to investigate the ratio of immunocompetent cells involved in the adaptive post-COVID-19 immune response. The research includes an immunological assessment of 29 women aged 20-40 years residing in Arkhangelsk, Russia, six months after recovering from COVID-19. The count of leukocytes in the peripheral blood and their differential were evaluated using standard methods to assess the immunological status. To delve deeper into the immunological landscape, phenotypes of lymphocytes (CD5+, CD8+, CD10+, and CD95+) were evaluated using an indirect immunoperoxidase reaction with monoclonal antibodies on dried drop lymphocyte preparations. After incubating blood with latex molecules, the activity and quantity of phagocytes were assessed using a light microscope. The neutrophil/lymphocyte ratio was found to be inverted in the female subjects under investigation. The high concentration of cytotoxic T-lymphocytes (CD8+) and lymphocytes with apoptotic receptors (CD95+) suggests a potential correlation with a concurrent reduction in the expression of the total T-cell marker (CD5+) across all cases. This association was further linked to a decrease in lymphoproliferative activity and a relative decline in phagocytic activity. These findings led us to posit that the total recovery time after COVID-19 might extend beyond six months, indicative of a prolonged impact on the body's protective capacity. Our observations prompt the hypothesis that cellular immunity plays a crucial role in determining the severity of COVID-19 infection. Specifically, individuals with initially robust phagocytic activity may be predisposed to experiencing a milder form of the infection. However, this assumption warrants further investigation and clarification in individuals with moderate and severe disease progression (Tab. 1, Ref. 17). Keywords: arctic, COVID-19, cytotoxic t-lymphocytes, apoptosis, lymphoproliferation, cellular immunity, phagocytic activity.
- Published
- 2024
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12. Single-cell sequencing reveals the evolution of immune molecules across multiple vertebrate species.
- Author
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Jiao A, Zhang C, Wang X, Sun L, Liu H, Su Y, Lei L, Li W, Ding R, Ding C, Dou M, Tian P, Sun C, Yang X, Zhang L, and Zhang B
- Subjects
- Animals, Humans, Mice, Macrophages, Swine, Zebrafish genetics, Adaptive Immunity genetics, Transcriptome, Immunity, Innate genetics
- Abstract
Introduction: Both innate and adaptive immune system undergo evolution from low to high vertebrates. Due to the limitation of conventional approaches in identifying broader spectrum of immune cells and molecules from various vertebrates, it remains unclear how immune molecules evolve among vertebrates., Objectives: Here, we utilized carry out comparative transcriptome analysis in various immune cells across seven vertebrate species., Methods: Single-cell RNA sequencing (scRNA-seq)., Results: We uncovered both conserved and species-specific profiling of gene expression in innate and adaptive immunity. Macrophages exhibited highly-diversified genes and developed sophisticated molecular signaling networks along with evolution, indicating effective and versatile functions in higher species. In contrast, B cells conservatively evolved with less differentially-expressed genes in analyzed species. Interestingly, T cells represented a dominant immune cell populations in all species and unique T cell populations were identified in zebrafish and pig. We also revealed compensatory TCR cascade components utilized by different species. Inter-species comparison of core gene programs demonstrated mouse species has the highest similarity in immune transcriptomes to human., Conclusions: Therefore, our comparative study reveals gene transcription characteristics across multiple vertebrate species during the evolution of immune system, providing insights for species-specific immunity as well as the translation of animal studies to human physiology and disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Production and hosting by Elsevier B.V.)
- Published
- 2024
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13. CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature
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Akul Singhania, Paige Dubelko, Rebecca Kuan, William D. Chronister, Kaylin Muskat, Jyotirmoy Das, Elizabeth J. Phillips, Simon A. Mallal, Grégory Seumois, Pandurangan Vijayanand, Alessandro Sette, Maria Lerm, Bjoern Peters, and Cecilia Lindestam Arlehamn
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Male ,Receptors, CCR6 ,Medicine (General) ,Research paper ,BCG ,tuberculosis ,T cell ,Adaptive immunity ,vaccine ,transcriptomics ,CCR6+ T cells ,Receptors, Antigen, T-Cell ,chemical and pharmacologic phenomena ,General Biochemistry, Genetics and Molecular Biology ,R5-920 ,Humans ,Longitudinal Studies ,RNA-Seq ,Gene Expression Profiling ,General Medicine ,DNA Methylation ,Th1 Cells ,Gene Expression Regulation ,BCG Vaccine ,Medicine ,Th17 Cells ,Radiologi och bildbehandling ,Radiology, Nuclear Medicine and Medical Imaging - Abstract
Background: The century-old Mycobacterium bovis Bacillus Calmette-Guerin (BCG) remains the only licensed vaccine against tuberculosis (TB). Despite this, there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity. Methods: We investigated immune responses in adult individuals pre and 8 months post BCG vaccination. We specifically determined changes in gene expression, cell subset composition, DNA methylome, and the TCR repertoire induced in PBMCs and CD4 memory T cells associated with antigen stimulation by either BCG or a Mycobacterium tuberculosis (Mtb)-derived peptide pool. Findings: Following BCG vaccination, we observed increased frequencies of CCR6+ CD4 T cells, which includes both Th1* (CXCR3+CCR6+) and Th17 subsets, and mucosal associated invariant T cells (MAITs). A large number of immune response genes and pathways were upregulated post BCG vaccination with similar patterns observed in both PBMCs and memory CD4 T cells, thus suggesting a substantial role for CD4 T cells in the cellular response to BCG. These upregulated genes and associated pathways were also reflected in the DNA methylome. We described both qualitative and quantitative changes in the BCG-specific TCR repertoire post vaccination, and importantly found evidence for similar TCR repertoires across different subjects. Interpretation: The immune signatures defined herein can be used to track and further characterize immune responses induced by BCG, and can serve as reference for benchmarking novel vaccination strategies. (C) 2021 The Author(s). Published by Elsevier B.V. Funding Agencies|NIH, USAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U19 AI118626, S10 RR027366, S10 OD016262]
- Published
- 2021
14. SARS-CoV-2 elicits robust adaptive immune responses regardless of disease severity
- Author
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Ida Monrad, Marie H. Pahus, Rune Hartmann, Ole Schmeltz Søgaard, Martin Tolstrup, Jesper Damsgaard Gunst, Christian Erikstrup, Giacomo S. Frattari, Rikke Olesen, Mariane H. Schleimann, Line K. Vibholm, Stine S F Nielsen, Lars Østergaard, Andreas Holleufer, and Jesper F Højen
- Subjects
Male ,0301 basic medicine ,Medicine (General) ,Denmark ,Adaptive Immunity ,CD8-Positive T-Lymphocytes ,Antibodies, Viral ,medicine.disease_cause ,Severity of Illness Index ,Neutralization ,Serology ,0302 clinical medicine ,Medicine ,Coronavirus ,biology ,CD8 T-cell ,General Medicine ,Middle Aged ,Acquired immune system ,Adaptive ,Asymptomatic ,Virus ,030220 oncology & carcinogenesis ,Spike Glycoprotein, Coronavirus ,Female ,Angiotensin-Converting Enzyme 2 ,Antibody ,Research Paper ,Adult ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Young Adult ,03 medical and health sciences ,R5-920 ,Immune system ,Blocking antibody ,Animals ,Humans ,Immune response ,Aged ,Severe ,business.industry ,SARS-CoV-2 ,COVID-19 ,Antibodies, Neutralizing ,030104 developmental biology ,Immunology ,biology.protein ,Corona ,CD8+ T-cell ,business - Abstract
Background: The SARS-CoV-2 pandemic currently prevails worldwide. To understand the immunological signature of SARS-CoV-2 infections and aid the search and evaluation of new treatment modalities and vaccines, comprehensive characterization of adaptive immune responses towards SARS-CoV-2 is needed.Methods: We included 203 recovered SARS-CoV-2 infected patients in Denmark between April 3rd and July 9th 2020, at least 14 days after COVID-19 symptom recovery. The participants had experienced a range of disease severities from asymptomatic to severe. We collected plasma, serum and PBMC's for analysis of SARS-CoV-2 specific antibody response by Meso Scale analysis including other coronavirus strains, ACE2 competition, IgA ELISA, pseudovirus neutralization capacity, and dextramer flow cytometry analysis of CD8+ T cells. The immunological outcomes were compared amongst severity groups within the cohort, and 10 pre-pandemic SARS-CoV-2 negative controls.Findings: We report broad serological profiles within the cohort, detecting antibody binding to other human coronaviruses. 202(>99%) participants had SARS-CoV-2 specific antibodies, with SARS-CoV-2 neutralization and spike-ACE2 receptor interaction blocking observed in 193(95%) individuals. A significant positive correlation (r=0.7804) between spike-ACE2 blocking antibody titers and neutralization potency was observed. Further, SARS-CoV-2 specific CD8+ T-cell responses were clear and quantifiable in 95 of 106(90%) HLA-A2+ individuals.Interpretation: The viral surface spike protein was identified as the dominant target for both neutralizing antibodies and CD8+ T-cell responses. Overall, the majority of patients had robust adaptive immune responses, regardless of their disease severity.Funding: This study was supported by the Danish Ministry for Research and Education (grant# 0238-00001B) and The Danish Innovation Fund (grant# 0208-00018B)
- Published
- 2021
15. Directs effects of granulocyte-macrophage colony stimulating factor (GM-CSF) on adaptive immunogenesis
- Author
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Galina V. Seledtsova, Ekaterina M. Morozova, Natalja D. Gazatova, Victor I. Seledtsov, M. E. Meniailo, and V. V. Malashchenko
- Subjects
Lipopolysaccharides ,T-Lymphocytes ,030231 tropical medicine ,Immunology ,Adaptive Immunity ,Biology ,Lymphocyte Activation ,Monocytes ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Immunology and Allergy ,Monocytes macrophages ,030212 general & internal medicine ,Cells, Cultured ,Pharmacology ,Macrophages ,Direct effects ,Granulocyte-Macrophage Colony-Stimulating Factor ,Colony-stimulating factor ,Phenotype ,Granulocyte macrophage colony-stimulating factor ,Cytokines ,Research Paper ,medicine.drug - Abstract
Background: We studied direct effects of human granulocyte-macrophage colony stimulating factor (GM-CSF) on phenotypical characteristics and cytokine-production of non-activated and activated human monocytes/macrophages (Mc/Mphs) and T cells. Methods: Purified Mc/Mphs were activated by bacterial lipopolysaccharide (LPS, 1 μg/ml) for 24 h, while T cells were activated by particles conjugated and antibodies (Abs) against human CD2, CD3, and CD28 for 48 h. Results: GM-CSF treatment (0.01–10 ng/ml) was shown to reduce percentages of CD197 (CCR7)-positive cells in non-activated Mph cultures, without affecting significantly CD14(+) (LPS co-receptor), CD16(+) (FcγRIII, low-affinity Fc-receptor), CD119(+) (interferon-gamma receptor 1), and CD124(+) (IL4 receptor α-subunit) cells. In addition, GM-CSF reduced relative numbers of CD197(+) cells, as well as CD14(+), CD16(+), and CD119(+) cells in activated Mph cultures without affecting CD124(+) cell distribution. GM-CSF at the highest dose of 10 ng/ml enhanced TNF-α and IL-6 (but not IL-1β and IL-10) production in activated Mc/Mphs. In activated T cell cultures, GM-CSF at 0.1–1.0 ng/ml augmented CD38(+) cell numbers in naïve СD45RA(+)/СD197(+) and central memory СD45RA(−)/СD197(+) cell subsets, with no effect on effector СD45RA(−)/СD197(−) and terminally differentiated effector СD45RA(+)/СD197(−) cells. GM-CSF at a low dose (0.01 ng/ml) down-regulated INF-γ production, while at a high dosage (10.0 ng/ml) up-regulated IL-2 and IL-4 production. Conclusion: In general, the results suggest that GM-CSF is able to facilitate the implication of both Mph and T cells in the adaptive immunogenesis.
- Published
- 2019
16. Alteration of Adaptive Immunity in a Colorectal Peritoneal Carcinomatosis Model
- Author
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Hongming Miao, Xia Kang, Wei Xiang, Rongchen Shi, Lili Zhang, Jinping Wang, and Fengtian He
- Subjects
0301 basic medicine ,Colorectal cancer ,business.industry ,peritoneal carcinomatosis ,Intraperitoneal inoculation ,colorectal cancer ,Spleen ,adaptive immunity ,medicine.disease ,Acquired immune system ,Colorectal cancer cell line ,Peritoneal carcinomatosis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,business ,Visceral fat ,CD8 ,Research Paper - Abstract
Colorectal cancer (CRC) usually gives rise to transcoelomic spread and ultimately causes peritoneal carcinomatosis (PC). However, mechanism studies, especially the immunological basis of colorectal PC, are rarely revealed due to lack of a suitable PC model. Here we selected a mouse colorectal cancer cell line MC-38 for intraperitoneal inoculation in the C57BL/6 mice to mimic the development of colorectal PC. We demonstrated that the injected CRC cells preferentially and rapidly migrated and colonized in the visceral fat tissues, but not in other visceral organs. With flow cytometric analysis, we found the proportions of spleen T cells and B cells were not affected by PC progression, while the ratios of blood CD4+ and CD8+ T cells were largely influenced. Especially, the quantity or activity of CD4+ and CD8+ T cells in visceral fats were intimately regulated by PC development. Taken together, we successfully constructed a colorectal PC model in immune-competent mice and revealed the alteration of adaptive immunity in PC development. Our study might potentiate the research and therapy strategies of colorectal PC.
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- 2019
17. RIP3 promotes colitis-associated colorectal cancer by controlling tumor cell proliferation and CXCL1-induced immune suppression
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Hai-Jiao Yang, Jian Cui, Zhu-Chun Li, Juan Tang, Ming Zheng, Zhen-Yu Liu, Yi-Ming Li, Zhi-Nan Chen, Jian-Li Jiang, Xin-Yu Fan, Jing-Min Yu, and Jian-Chao Wang
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0301 basic medicine ,Myeloid ,Carcinogenesis ,Colon ,MAP Kinase Signaling System ,Chemokine CXCL1 ,T-Lymphocytes ,Necroptosis ,T cell ,IBD ,Gene Expression ,necroptosis ,Medicine (miscellaneous) ,Apoptosis ,colorectal cancer ,Adaptive Immunity ,medicine.disease_cause ,Gene Knockout Techniques ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Animals ,Medicine ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Cell Proliferation ,ulcerative colitis ,Anthracenes ,Tumor microenvironment ,business.industry ,Epithelial Cells ,Colitis ,Mice, Inbred C57BL ,CXCL1 ,030104 developmental biology ,medicine.anatomical_structure ,Tumor progression ,Receptor-Interacting Protein Serine-Threonine Kinases ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Cancer research ,Colorectal Neoplasms ,business ,Signal Transduction ,Research Paper ,RIP3 - Abstract
Rationale: Necroptosis is a programmed form of non-apoptotic cell death that requires receptor-interacting protein 3 (RIP3). RIP3 has been shown to be relevant in multiple tumor types and has differential impact on tumor progression. We investigated whether RIP3 is involved in the progression of colitis-associated cancer (CAC) in mice. Methods: Tissues from colorectal cancer patients were examined for RIP3 expression. CAC was induced using azoxymethane (AOM) injection followed by dextran sodium sulfate (DSS) treatment in RIP3-deficient or wild-type mice. Colon tissues were collected and analyzed by Western blotting and gene expression profile analyses. Immune cell infiltration and CXCL1 expression were examined by flow cytometry and Real-time PCR, respectively. Results: RIP3 expression was upregulated in mouse CAC and human colon cancer. RIP3-deficient mice showed significantly attenuated colitis-associated tumorigenesis. Bone marrow transplantation experiments suggested that RIP3's function in hematopoietic cells primarily contributes to the phenotype. RIP3 supported epithelial proliferation and tumor growth via JNK signaling but had no effect on apoptosis. RIP3 deletion increased T cell accumulation and reduced infiltration by immunosuppressive subsets of myeloid cells during acute colitis and CAC. The immune-suppressive tumor microenvironment was dependent on RIP3-induced expression of the chemokine attractant CXCL1, and administration of recombinant CXCL1 during CAC restored tumorigenesis in Rip3-/- mice. Conclusion: Our results reveal an unexpected function of RIP3 in enhancing the proliferation of premalignant intestinal epithelial cells (IECs) and promoting myeloid cell-induced adaptive immune suppression. These two distinct mechanisms of RIP3-induced JNK and CXCL1 signalling contribute to CAC progression.
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- 2019
18. Correlation Between Stem and Progenitor Cells Number and Immune Response in Patients After Allogeneic Kidney Transplant
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Maciej Kotowski, Karolina Kędzierska-Kapuza, Marek Ostrowski, K. Tejchman, Edyta Paczkowska, Anna Sobuś, Jerzy Sieńko, Ewa Pilichowska, and Jarosław Piątek
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Adult ,Male ,T-Lymphocytes ,medicine.medical_treatment ,CD34 ,Adaptive Immunity ,CD38 ,T-Lymphocytes, Regulatory ,Young Adult ,Immune system ,Humans ,Medicine ,Renal Insufficiency, Chronic ,Progenitor cell ,Kidney transplantation ,Aged ,Original Paper ,B-Lymphocytes ,Transplantation ,business.industry ,Stem Cells ,Immunosuppression ,General Medicine ,Middle Aged ,medicine.disease ,Kidney Transplantation ,Haematopoiesis ,Immunology ,Female ,Stem cell ,business - Abstract
BACKGROUND Stem and progenitor cells are of great interest in all medical procedures involving tissue regeneration. There is a consensus that the use of stem cells after solid organ transplantation may play a role in tissue repair and in immunosuppression. The aim of this study was to determine possible relations between stem cell count and the immune response in a group of patients after kidney transplantation. MATERIAL AND METHODS The study was conducted on a group of 100 patients who underwent kidney transplantation. The following phenotypic markers of the studied cell subpopulations were adopted: Treg cells (CD3+CD4+CD25high), circulating hematopoietic cells (CD34+CD133+CD45+CD38-), and non-hematopoietic cells (Lin-CXCR4+CD133-CD45-). Cell subpopulations were assessed using LSRII flow cytometer (BD Biosciences, San Jose, CA, USA). RESULTS Positive correlation was observed between non-hematopoietic stem cells percentage and recipient's platelets count (P=0.04). Moreover, a higher percentage of non-hematopoietic cells was accompanied by lower numbers of B lymphocytes (P=0.03) and Treg cells (P=0.02). CONCLUSIONS Our study revealed significant associations between the intensity of ongoing immune response processes and tissue damage, and the release of stem and progenitor cells into circulation. These findings suggest their role in the stimulation of protective processes in terms of graft regeneration.
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- 2018
19. Identification of an immune checkpoint gene signature that accurately predicts prognosis and immunotherapy response in endometrial carcinoma
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Jiayan Chen, Xin Zhang, Chun-Li Dong, Xiuying Xie, Xiaocui Gao, and Shao-Wen Li
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Aging ,Epithelial-Mesenchymal Transition ,DNA Repair ,medicine.medical_treatment ,immune checkpoint genes ,BTLA ,endometrial carcinoma ,Biology ,Gene mutation ,Adaptive Immunity ,Antigens, Neoplasm ,Databases, Genetic ,Carcinoma ,medicine ,Humans ,Survival analysis ,Disease Resistance ,TNFRSF18 ,Gene Expression Profiling ,biomarkers ,Cell Biology ,Immunotherapy ,Gene signature ,medicine.disease ,Immune Checkpoint Proteins ,Prognosis ,Survival Analysis ,Immune checkpoint ,Endometrial Neoplasms ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Mutation ,Cancer research ,Female ,immunotherapy ,Research Paper - Abstract
In this study, we performed a bioinformatics analysis to identify immune checkpoint genes (ICGs) associated with prognosis and the immunotherapeutic response in endometrial carcinoma (EC) patients. We classified 47 ICGs into high, medium, and low expression groups by performing RNA-sequencing data analysis of EC patient samples from The Cancer Genome Atlas (n = 521) and GSE77688 (n = 88) datasets. Univariate Cox regression analysis showed that seven ICGs (VTCN1, TNFRSF18, TNFRSF14, TNFRSF4, CD40LG, TMIGD2, and BTLA) were associated with prognosis in EC patients. Spearman correlation analysis showed that prognosis-related ICGs correlated positively with immunotherapy response factors, including tumor mutation burden (TMB), mismatch repair gene mutations, neoantigens, clinical stages, and adaptive immune resistance pathway genes. We identified a prognostic gene signature of four ICGs (IDO1, CD274, CTLA4, and TNFRSF14) that accurately predicted survival outcomes of EC patients. TIMER database and Kaplan-Meier survival analysis showed that OS among EC patients with low TNFRSF14 expression was significantly shorter than among those with high TNFRSF14 expression. In vitro experiments showed that TNFRSF14 silencing increased the migration and invasiveness of EC cells by promoting epithelial-mesenchymal transition (EMT). Collectively, these findings reveal an immune checkpoint gene signature that accurately predicts survival outcomes and immunotherapeutic responses in EC patients.
- Published
- 2021
20. Network- and systems-based re-engineering of dendritic cells with non-coding RNAs for cancer immunotherapy
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Lai, Xin, Dreyer, Florian S., Cantone, Martina, Eberhardt, Martin, Gerer, Kerstin F., Jaitly, Tanushree, Uebe, Steffen, Lischer, Christopher, Ekici, Arif, Wittmann, Jürgen, Jäck, Hans-Martin, Schaft, Niels, Dörrie, Jan, and Vera, Julio
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RNA, Untranslated ,dendritic cell ,network biology ,systems biology ,chemical and pharmacologic phenomena ,Dendritic Cells ,Adaptive Immunity ,Cancer Vaccines ,I-kappa B Kinase ,MicroRNAs ,Neoplasms ,Cytokines ,Humans ,therapeutic vaccination in cancer ,Immunotherapy ,ddc:610 ,Cells, Cultured ,Research Paper ,Signal Transduction - Abstract
Dendritic cells (DCs) are professional antigen-presenting cells that induce and regulate adaptive immunity by presenting antigens to T cells. Due to their coordinative role in adaptive immune responses, DCs have been used as cell-based therapeutic vaccination against cancer. The capacity of DCs to induce a therapeutic immune response can be enhanced by re-wiring of cellular signalling pathways with microRNAs (miRNAs). Methods: Since the activation and maturation of DCs is controlled by an interconnected signalling network, we deploy an approach that combines RNA sequencing data and systems biology methods to delineate miRNA-based strategies that enhance DC-elicited immune responses. Results: Through RNA sequencing of IKKβ-matured DCs that are currently being tested in a clinical trial on therapeutic anti-cancer vaccination, we identified 44 differentially expressed miRNAs. According to a network analysis, most of these miRNAs regulate targets that are linked to immune pathways, such as cytokine and interleukin signalling. We employed a network topology-oriented scoring model to rank the miRNAs, analysed their impact on immunogenic potency of DCs, and identified dozens of promising miRNA candidates, with miR-15a and miR-16 as the top ones. The results of our analysis are presented in a database that constitutes a tool to identify DC-relevant miRNA-gene interactions with therapeutic potential (https://www.synmirapy.net/dc-optimization). Conclusions: Our approach enables the systematic analysis and identification of functional miRNA-gene interactions that can be experimentally tested for improving DC immunogenic potency.
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- 2021
21. B and T Lymphocyte Densities Remain Stable With Age in Human Cortex
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Marion S. Buckwalter, Claudia K. Suemoto, Roberta Diehl Rodriguez, Edward D. Plowey, Kacey Berry, Daniela Souza Farias-Itao, Lea T. Grinberg, and Julie A. Schneider
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0301 basic medicine ,Adult ,Male ,Aging ,T-Lymphocytes ,brain ,1.1 Normal biological development and functioning ,Inflammation ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Cell Count ,Pilot Projects ,Biology ,Adaptive Immunity ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Clinical Research ,Underpinning research ,Cortex (anatomy) ,medicine ,80 and over ,Humans ,human ,Aged ,Aged, 80 and over ,Cerebral Cortex ,Glial activation ,Original Paper ,B-Lymphocytes ,General Neuroscience ,Inflammatory and immune system ,Neurosciences ,T lymphocyte ,adaptive immunity ,Middle Aged ,Acquired immune system ,Brain Disorders ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,Neurological ,Female ,Neurology (clinical) ,medicine.symptom ,immune ,030217 neurology & neurosurgery ,Function (biology) ,RC321-571 - Abstract
One hallmark of human aging is increased brain inflammation represented by glial activation. With age, there is also diminished function of the adaptive immune system, and modest decreases in circulating B- and T-lymphocytes. Lymphocytes traffic through the human brain and reside there in small numbers, but it is unknown how this changes with age. Thus we investigated whether B- and T-lymphocyte numbers change with age in the normal human brain. We examined 16 human subjects in a pilot study and then 40 human subjects from a single brain bank, ranging in age from 44–96 years old, using rigorous criteria for defining neuropathological changes due to age alone. We immunostained post-mortem cortical tissue for B- and T-lymphocytes using antibodies to CD20 and CD3, respectively. We quantified cell density and made a qualitative assessment of cell location in cortical brain sections, and reviewed prior studies. We report that density and location of both B- and T-lymphocytes do not change with age in the normal human cortex. Solitary B-lymphocytes were found equally in intravascular, perivascular, and parenchymal locations, while T-lymphocytes appeared primarily in perivascular clusters. Thus, any change in number or location of lymphocytes in an aging brain may indicate disease rather than normal aging.
- Published
- 2021
22. Editorial: Adaptive immunity in atherosclerosis.
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Slütter, Bram and Ley, Klaus
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AUTOIMMUNE diseases ,ATHEROSCLEROSIS ,REGULATORY T cells ,IMMUNITY ,T-cell exhaustion - Abstract
This document is an editorial published in the journal Frontiers in Immunology. It discusses the role of adaptive immunity in atherosclerosis, a condition that contributes to acute cardiovascular events. The editorial highlights the importance of chronic inflammation in atherosclerosis and the potential for new intervention strategies. It also explores the use of new immunological techniques to study the role of the adaptive immune system in the development, progression, and regression of atherosclerosis. The document includes summaries of several research papers that investigate different aspects of adaptive immunity in atherosclerosis, including T cell and B cell responses. Overall, the editorial provides an overview of the latest findings in this field and serves as a valuable resource for researchers interested in studying adaptive immunity in atherosclerosis. [Extracted from the article]
- Published
- 2024
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23. Investigating the immune mechanism of natural products in the treatment of lung cancer.
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Lian Yang, Yukun Chen, Kaile Liu, Yuanyuan Chen, Yu Zhang, Zhanxia Zhang, and Hegen Li
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NATURAL products ,LUNG cancer ,T cell differentiation ,CELL death ,CANCER treatment ,KILLER cells ,T cells - Abstract
With the deepening of people's understanding of lung cancer, the research of lung cancer immunotherapy has gradually become the focus of attention. As we all know, the treatment of many diseases relies on the rich sources, complex and varied compositions and wide range of unique biological properties of natural products. Studies have shown that natural products can exert anticancer effects by inducing tumor cell death, inhibiting tumor cell proliferation, and enhancing tumor cell autophagy. More notably, natural products can adjust and strengthen the body's immune response, which includes enhancing the function of NK cells and promoting the differentiation and proliferation of T lymphocytes. In addition, these natural products may enhance their anticancer effects by affecting inhibitory factors in the immune system, hormone levels, enzymes involved in biotransformation, and modulating other factors in the tumor microenvironment. The importance of natural products in lung cancer immunotherapy should not be underestimated. However, the specific links and correlations between natural products and lung cancer immunity are not clear enough, and further studies are urgently needed to clarify the relationship between the two. In this paper, we will focus on the correlation between natural products and lung cancer immune responses, with a view to providing new research perspectives for immunotherapy of lung cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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24. New chimeric TLR7/NOD2 agonist is a potent adjuvant to induce mucosal immune responses
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Laura Papagno, Stéphane Paul, Nicolas Rochereau, Alice Gutjahr, Eric Perouzel, Victor Appay, Bernard Verrier, Thierry Lioux, Fabienne Vernejoul, Fabienne Jospin, Blandine Chanut, Gestionnaire, Hal Sorbonne Université, Laboratoire de Biologie Tissulaire et d'ingénierie Thérapeutique UMR 5305 (LBTI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Groupe Immunité des Muqueuses et Agents Pathogènes (GIMAP), Université Jean Monnet - Saint-Étienne (UJM), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CIC Saint Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne), InvivoGen Europe, Kumamoto University, Université Jean Monnet [Saint-Étienne] (UJM), Centre d'Immunologie et de Maladies Infectieuses (CIMI), and Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne)
- Subjects
0301 basic medicine ,Research paper ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Nod2 Signaling Adaptor Protein ,lcsh:Medicine ,Pharmacology ,Adaptive Immunity ,CD8-Positive T-Lymphocytes ,Mice ,0302 clinical medicine ,HIV vaccine ,Receptor ,TLR7 ,AIDS Vaccines ,lcsh:R5-920 ,biology ,Chemistry ,Pattern recognition receptor ,virus diseases ,General Medicine ,3. Good health ,[SDV] Life Sciences [q-bio] ,030220 oncology & carcinogenesis ,Female ,lcsh:Medicine (General) ,Adjuvant ,Agonist ,medicine.drug_class ,Antigen presentation ,General Biochemistry, Genetics and Molecular Biology ,NOD2 ,Cell Line ,03 medical and health sciences ,Adjuvants, Immunologic ,MHC class I ,medicine ,Animals ,Humans ,Adjuvants ,Administration, Intranasal ,lcsh:R ,Immunity, Humoral ,030104 developmental biology ,Toll-Like Receptor 7 ,biology.protein ,Chimeric ,Vaccine ,HeLa Cells - Abstract
Background PRR (Pattern Recognition Receptor) agonists have been widely tested as potent vaccine adjuvants. TLR7 (Toll-Like Receptor 7) and NOD2 (nucleotide-binding oligomerization domain 2) are key innate receptors widely expressed at mucosal levels. Methods Here, we evaluated the immunostimulatory properties of a novel hybrid chemical compound designed to stimulate both TLR7 and NOD2 receptors. Finding The combined TLR7/NOD2 agonist showed increase efficacy than TLR7L or NOD2L agonists alone or combined in different in vitro models. Dual TLR7/NOD2 agonist efficiently stimulates TLR7 and NOD2, and promotes the maturation and reprogramming of human dendritic cells, as well as the secretion of pro-inflammatory or adaptive cytokines. This molecule also strongly induces autophagy in human cells which is a major intracellular degradation system that delivers cytoplasmic constituents to lysosomes in both MHC class I and II-restricted antigen presentation. In vivo, TLR7/NOD2L agonist is a potent adjuvant after intranasal administration with NP-p24 HIV vaccine, inducing high-quality humoral and adaptive responses both in systemic and mucosal compartments. Use of TLR7/NOD2L adjuvant improves very significantly the protection of mice against an intranasal challenge with a vaccinia virus expressing the p24. Interpretation Dual TLR7/NOD2L agonist is a very potent and versatile vaccine adjuvant and promote very efficiently both systemic and mucosal immunity. Funding This work was supported by Sidaction .
- Published
- 2020
25. Differences in C-type lectin receptors and their adaptor molecules in the peritoneal fluid of patients with endometriosis and gynecologic cancers
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Yong Sung Won, Dong Choon Park, Seung Geun Yeo, and Sang Hoon Kim
- Subjects
Adult ,Genital Neoplasms, Female ,Endometriosis ,Enzyme-Linked Immunosorbent Assay ,Adaptive Immunity ,Immunoglobulin secretion ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,C-type lectin ,Immunoglobulin ,medicine ,Ascitic Fluid ,Humans ,Lectins, C-Type ,Neoplasm Invasiveness ,Neoplasm Metastasis ,Gynecologic cancer ,Receptor ,B cell ,Galectin ,B-Lymphocytes ,030219 obstetrics & reproductive medicine ,business.industry ,Peritoneal fluid ,General Medicine ,Middle Aged ,medicine.disease ,Immunoglobulin A ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Immunoglobulin M ,Immunoglobulin G ,030220 oncology & carcinogenesis ,Cancer research ,Female ,C-type lectin receptors ,business ,Research Paper - Abstract
Endometriosis, although not malignant, has clinically demonstrated properties of invasiveness and metastasis. The pathogenesis of endometriosis, however, has not yet been elucidated. The immunological differences between endometriosis and malignant gynecologic tumors were analyzed by assessing C-type lectin receptors, which are associated with innate immunity, and immunoglobulin secretion, which is associated with B cell adaptive immunity, in the peritoneal fluid of these patients. Peritoneal fluid samples were obtained from 42 patients with benign masses (control group), 38 with endometriosis, and 43 with gynecologic (ovarian, uterine, and cervical) cancers. The levels of expression in these samples of mRNAs encoding the C-type lectin receptors Dectin-1, MR1, MR2, DC-SIGN, Syk, Card 9, Bcl 10, Malt 1, src, Dec 205, Galectin, Tim 3, Trem 1, and DAP 12, were measured by real-time reverse transcription polymerase chain reaction, and the concentrations of IgG, IgA and IgM were measured by enzyme-linked immunosorbent assays (ELISA). Findings in the three groups were compared. The level of galectin mRNA was significantly lower, and the levels of MR2 and DAP 12 mRNAs significantly higher, in the endometriosis than in the control group (p0.05). C-type lectin receptors and immunoglobulins act cooperatively and are closely associated in the pathogenesis of endometriosis. The decreased expression of galectin mRNA in the peritoneal fluid of the endometriosis group suggests that endometriosis and gynecologic cancers have similar immunologic characteristics.
- Published
- 2018
26. Innate immunity recovers earlier than acquired immunity during severe postoperative immunosuppression
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Clarissa von Haefen, Johannes Kurth, Gunnar Lachmann, Claudia Spies, and Fatima Yuerek
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0301 basic medicine ,Male ,Time Factors ,medicine.medical_treatment ,T cell ,Adaptive Immunity ,Monocytes ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Pancreatectomy ,Postoperative Complications ,Immunity ,Immune Tolerance ,Medicine ,Cytotoxic T cell ,Humans ,Lymphocyte Count ,Lymphocytes ,innate immunity ,monocytic function ,T cell function ,Aged ,Retrospective Studies ,Innate immune system ,business.industry ,Immunosuppression ,General Medicine ,Middle Aged ,Acquired immune system ,Immunity, Innate ,acquired immunity ,Esophagectomy ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Cytokines ,Female ,immune suppression ,business ,Research Paper - Abstract
Background: Postoperative immune suppression, particularly a loss of cell-mediated immunity, is commonly seen after surgery and is associated with worse outcome, i.e. delayed wound healing, infections, sepsis, multiple-organ failure and cancer recurrence. However, the recovery of immune cells focusing on differences between innate and acquired immunity during severe postoperative immunosuppression is not investigated. Methods: In this retrospective randomized controlled trial (RCT) subgroup analysis, 10 postoperatively immune suppressed patients after esophageal or pancreatic resection were analyzed. Innate and acquired immune cells, the expression of human leukocyte antigen-D related on monocytes (mHLA-DR), lipopolysaccharide (LPS)-induced monocytic TNF-α and IL-10 secretion ex vivo, Concanavalin A (Con A)-induced IFN-γ, TNF-α, IL-2, IL-4, IL-5 and IL-10 release were measured preoperatively (od) until day 5 after surgery (pod5). Recovery of immune cells was defined by a significant decrease respectively increase after a significant postoperative alteration. Statistical analyses were performed using nonparametric statistical procedures. Results: Postoperative alterations of innate immune cells recovered on pod2 (eosinophils), pod3 (neutrophils) and pod5 (mHLA-DR, monocytic TNF-α and IL-10 secretion), whereas alterations of acquired immune cells (lymphocytes, T cells, T helper cells, and cytotoxic T cells) did not recover until pod5. Peripheral blood T cells showed an impaired production of the T helper (Th) 1 cytokine IFN-γ upon Con A stimulation on pod1, while Th2 specific cytokine release did not change until pod5. Conclusions: Innate immunity recovered earlier than acquired immunity during severe postoperative immunosuppression. Furthermore, we found a more anti- than pro-inflammatory T cell function on the first day after surgery, while T cell counts decreased.
- Published
- 2018
27. CXCL14 Acts as a Specific Carrier of CpG DNA into Dendritic Cells and Activates Toll-like Receptor 9-mediated Adaptive Immunity
- Author
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Rena Takahashi, Naoto Naruse, Rina Iwase, Kohei Tsuji, Akira Shigenaga, Hideko Nuriya, Takahiko Hara, Akira Otaka, and Kosuke Tanegashima
- Subjects
0301 basic medicine ,Endosome ,CpG Oligodeoxynucleotide ,lcsh:Medicine ,chemical and pharmacologic phenomena ,Endosomes ,Adaptive Immunity ,General Biochemistry, Genetics and Molecular Biology ,TLR9 ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Animals ,CXCL14 ,lcsh:R5-920 ,CpG DNA ,Interleukin-12 Subunit p40 ,Chemistry ,lcsh:R ,hemic and immune systems ,Dendritic Cells ,General Medicine ,Acquired immune system ,Toll-Like Receptor 9 ,Immunosurveillance ,030104 developmental biology ,Gene Expression Regulation ,Oligodeoxyribonucleotides ,CpG site ,Cancer research ,lcsh:Medicine (General) ,Lysosomes ,Chemokines, CXC ,Research Paper ,030215 immunology - Abstract
CXCL14 is a primordial chemokine that plays multiple roles in tumor suppression, autoimmune arthritis, and obesity-associated insulin resistance. However, the underlying molecular mechanisms are unclear. Here, we show that CXCL14 transports various types of CpG oligodeoxynucleotide (ODN) into the endosomes and lysosomes of bone marrow-derived dendritic cells (DCs), thereby activating Toll-like receptor 9 (TLR9). A combination of CpG ODN (ODN2395) plus CXCL14 induced robust production of IL-12 p40 by wild-type, but not Tlr9-knockout, DCs. Consistent with this, ODN2395-mediated activation of DCs was significantly attenuated in Cxcl14-knockout mice. CXCL14 bound CpG ODN with high affinity at pH 7.5, but not at pH 6.0, thereby enabling efficient delivery of CpG ODN to TLR9 in the endosome/lysosome. Furthermore, the CXCL14-CpG ODN complex specifically bound to high affinity CXCL14 receptors on DCs. Thus, CXCL14 serves as a specific carrier of CpG DNA to sensitize TLR9-mediated immunosurveillance., Highlights • CXCL14 specifically binds CpG DNA with high affinity. • CXCL14/CpG DNA complex is efficiently transported into dendritic cells. • CXCL14/CpG DNA induces cytokine production via Toll-like receptor 9. We discovered that CXCL14 specifically binds CpG DNAs with high affinity and transports them into the endosomes and lysosomes of dendritic cells (DCs). Consequently, Toll-like receptor 9 (Tlr9) in DCs was activated, thereby leading to robust production of IL-12 p40 and IL-6. These activities of CXCL14 were not observed in Tlr9-deficient DCs. Moreover, CpG DNA (ODN2395)-mediated activation of DCs was significantly attenuated in Cxcl14-knockout mice. Therefore, CXCL14 plays an important role in the Tlr9-mediated immunosurveillance against pathogens and cancers. From the clinical point of view, CXCL14/CpG DNA could be useful as a new type of vaccine adjuvant.
- Published
- 2017
28. Introduction to the special issue Amphibian immunity: stress, disease and ecoimmunology.
- Author
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Assis VR, Robert J, and Titon SCM
- Subjects
- Animals, Amphibians, Climate Change, Host-Pathogen Interactions, Disease Resistance, Adaptive Immunity
- Abstract
Amphibian populations have been declining worldwide, with global climate changes and infectious diseases being among the primary causes of this scenario. Infectious diseases are among the primary drivers of amphibian declines, including ranavirosis and chytridiomycosis, which have gained more attention lately. While some amphibian populations are led to extinction, others are disease-resistant. Although the host's immune system plays a major role in disease resistance, little is known about the immune mechanisms underlying amphibian disease resistance and host-pathogen interactions. As ectotherms, amphibians are directly subjected to changes in temperature and rainfall, which modulate stress-related physiology, including immunity and pathogen physiology associated with diseases. In this sense, the contexts of stress, disease and ecoimmunology are essential for a better understanding of amphibian immunity. This issue brings details about the ontogeny of the amphibian immune system, including crucial aspects of innate and adaptive immunity and how ontogeny can influence amphibian disease resistance. In addition, the papers in the issue demonstrate an integrated view of the amphibian immune system associated with the influence of stress on immune-endocrine interactions. The collective body of research presented herein can provide valuable insights into the mechanisms underlying disease outcomes in natural populations, particularly in the context of changing environmental conditions. These findings may ultimately enhance our ability to forecast effective conservation strategies for amphibian populations. This article is part of the theme issue 'Amphibian immunity: stress, disease and ecoimmunology'.
- Published
- 2023
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29. Intratumoral depletion of regulatory T cells using CD25-targeted photodynamic therapy in a mouse melanoma model induces antitumoral immune responses
- Author
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Yun Soo Lee, Hi Eun Jung, Dong Sun Oh, Heegon Kim, Ji Eun Oh, Ji-Ho Park, and Heung Kyu Lee
- Subjects
0301 basic medicine ,Cytotoxicity, Immunologic ,Male ,medicine.medical_treatment ,Melanoma, Experimental ,chemical and pharmacologic phenomena ,Apoptosis ,Adaptive Immunity ,T-Lymphocytes, Regulatory ,Lymphocyte Depletion ,Immunophenotyping ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Cancer immunotherapy ,medicine ,Animals ,Humans ,IL-2 receptor ,CD25 ,Melanoma ,Cytolytic granule ,Tumor microenvironment ,business.industry ,Interleukin-2 Receptor alpha Subunit ,Immunotherapy ,Acquired immune system ,medicine.disease ,Xenograft Model Antitumor Assays ,Treg ,Disease Models, Animal ,030104 developmental biology ,Oncology ,photodynamic therapy ,Photochemotherapy ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,business ,Chlorin e6 ,Biomarkers ,Research Paper - Abstract
Tumor immunotherapy aims to overcome the immunosuppressive microenvironment within tumors, and various approaches have been developed. Tumor-associated T regulatory cells (Tregs) suppress the activation and expansion of tumor antigen-specific effector T cells, thus, providing a permissive environment for tumor growth. Therefore, optimal strategies need to be established to deplete tumor-infiltrated Tregs because systemic depletion of Tregs can result in reduced anti-tumor effector cells and autoimmunity. Here, to selectively deplete Tregs in tumors, we intratumorally injected anti-CD25 antibodies conjugated to Chlorin e6 (Ce6), a photosensitizer that absorbs light to generate reactive oxygen species. Local depletion of tumor-associated Tregs with photodynamic therapy (PDT) inhibited tumor growth, which was likely due to the altered tumor immune microenvironment that was characterized by increased infiltration of CD8+ effector T cells and the expression of IFN-γ and CD107a, which is a cytolytic granule exocytosis marker in tumor tissues. Furthermore, PDT-induced intratumoral Treg depletion did not influence adaptive immune responses in a murine influenza infection model. Thus, our results show that intratumoral Treg-targeted PDT could specifically modulate tumor microenvironments by depleting Tregs and could be used as a novel cancer immunotherapy technique.
- Published
- 2017
30. Global importation and population risk factors for measles in New Zealand: a case study for highly immunized populations
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Nigel P. French, David T. S. Hayman, Tim E. Carpenter, Jonathan C. Marshall, T. Kiedrzynski, and Mick G. Roberts
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Adult ,Male ,Adolescent ,Epidemiology ,Population ,Adaptive Immunity ,Measles ,Herd immunity ,Young Adult ,03 medical and health sciences ,Rubella vaccine ,0302 clinical medicine ,Risk Factors ,030225 pediatrics ,Environmental health ,medicine ,Humans ,030212 general & internal medicine ,Risk factor ,Child ,education ,Aged ,Aged, 80 and over ,education.field_of_study ,Vaccination ,Infant, Newborn ,Infant ,Middle Aged ,medicine.disease ,Original Papers ,Infectious Diseases ,Geography ,Child, Preschool ,Immunology ,Regression Analysis ,Pacific islanders ,Female ,Population Risk ,New Zealand ,medicine.drug - Abstract
SUMMARYAs endemic measles is eliminated through immunization, countries must determine the risk factors for the importation of measles into highly immunized populations to target control measures. Despite eliminating endemic measles, New Zealand suffers from outbreaks after introductions from abroad, enabling us to use it as a model for measles introduction risk. We used a generalized linear model to analyze risk factors for 1137 measles cases from 2007 to June 2014, provide estimates of national immunity levels, and model measles importation risk. People of European ethnicity made up the majority of measles cases. Age is a positive risk factor, particularly 0–2-year-olds and 5–17-year-old Europeans, along with increased wealth. Pacific islanders were also at greater risk, but due to 0–2-year-old cases. Despite recent high measles, mumps, and rubella vaccine immunization coverage, overall population immunity against measles remains ~90% and is lower in people born between 1982 and 2005. Greatest measles importation risk is during December, and countries predicted to be sources have historical connections and highest travel rates (Australia and UK), followed by Asian countries with high travel rates and higher measles incidences. Our results suggest measles importation due to travel is seeding measles outbreaks, and immunization levels are insufficient to continue to prevent outbreaks because of heterogeneous immunity in the population, leaving particular age groups at risk.
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- 2017
31. Immune Cell Repertoire and Their Mediators in Patients with Acute Myocardial Infarction or Stable Angina Pectoris
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Lin Zhou, Yuqin Shen, Yanli Song, Wenwen Yan, Fang Yang, Lin Che, Haoming Song, Lemin Wang, Jinfa Jiang, and Qianglin Duan
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0301 basic medicine ,CD4-Positive T-Lymphocytes ,Male ,030103 biophysics ,medicine.medical_specialty ,CD3 ,Cell ,adaptive immunity ,Myocardial Infarction ,Adaptive Immunity ,CD8-Positive T-Lymphocytes ,Peripheral blood mononuclear cell ,03 medical and health sciences ,Interferon-gamma ,0302 clinical medicine ,Immune system ,Cytology ,Internal medicine ,medicine ,Humans ,cardiovascular diseases ,Angina, Stable ,innate immunity ,Aged ,Innate immune system ,biology ,business.industry ,Interleukin-6 ,General Medicine ,Middle Aged ,Acquired immune system ,stable angina pectoris ,medicine.anatomical_structure ,Immunology ,biology.protein ,Cardiology ,gene expression ,Interleukin-2 ,Female ,Interleukin-4 ,business ,CD8 ,030215 immunology ,Research Paper - Abstract
Background: To evaluate the natural innate and adaptive immunity through gene expression and cytology levels in peripheral blood mononuclear cells in patients with acute myocardial infarction (AMI), stable angina pectoris (SAP) and controls. Methods: 210 patients with AMI, 210 with SAP, and 250 clinical controls were recruited. Whole human genome microarray analysis was performed in 20 randomly chosen subjects per group were examined to detect the expressions of complement markers, natural killer cells, T cells and B cells. The quantity of these cells and related cytokines as well as immunoglobulin levels were measured in all subjects. Results: In AMI group, the mRNA expressions of late complement component, markers of natural killer cells, CD3+, CD8+ T cells and B cells were down-regulated, while those of early complement component and CD4+T cells were up-regulated (p
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- 2017
32. The involvement of endoplasmic reticulum stress response in immune dysfunction of dendritic cells after severe thermal injury in mice
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Ning Dong, Yong-ming Yao, Yan Yu, Hua-Ping Liang, Yan-Bo Wang, Qing-Hong Zhang, and Xiao-Mei Zhu
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0301 basic medicine ,Male ,X-Box Binding Protein 1 ,Burn injury ,Time Factors ,dendritic cell ,T cell ,medicine.medical_treatment ,Apoptosis ,Adaptive Immunity ,Lymphocyte Activation ,Severity of Illness Index ,Sepsis ,Salubrinal ,sepsis ,03 medical and health sciences ,chemistry.chemical_compound ,immune dysfunction ,burns ,Immune system ,Pathology Section ,Medicine ,Animals ,Cells, Cultured ,Mice, Inbred BALB C ,030102 biochemistry & molecular biology ,business.industry ,Endoplasmic reticulum ,Thiourea ,Immunosuppression ,Dendritic cell ,Dendritic Cells ,Th1 Cells ,medicine.disease ,Endoplasmic Reticulum Stress ,Research Paper: Pathology ,Coculture Techniques ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Phenotype ,Oncology ,chemistry ,Cinnamates ,Immunology ,Cytokines ,RNA Interference ,business ,Spleen - Abstract
// Xiao-Mei Zhu 1,2 , Ning Dong 2 , Yan-Bo Wang 2 , Qing-Hong Zhang 2 , Yan Yu 2 , Yong-Ming Yao 2 and Hua-Ping Liang 1 1 State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, China 2 Department of Microbiology and Immunology, Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, China Correspondence to: Yong-Ming Yao, email: // Hua-Ping Liang, email: // Keywords : endoplasmic reticulum stress; dendritic cell; immune dysfunction; burns; sepsis; Pathology Section Received : April 18, 2016 Accepted : January 10, 2017 Published : January 19, 2017 Abstract Suppressed adaptive immune function is one of the major concerns responsible for the development of opportunistic infections and subsequent sepsis with high mortality in severe burns. Endoplasmic reticulum stress (ERS) is the endogenous self-protective mechanism, and it plays an important role in almost every process of living by regulating the balance between homeostasis and apoptosis. The current study investigated the involvement of ERS in the pathogenesis of dysfunction of dendritic cells (DCs) in burn mice. Our results show a significant ERS response in splenic DC after burn injury. Treatment with salubrinal (Sal, reported to protect cells against ERS-induced apoptosis.) decrease the apoptotic rate of DC induced by burns, and promote maturation and activation of DC, as well as the ability to promote T cell proliferation and polarization towards Th1 immunity (all P
- Published
- 2017
33. MicroRNAs as regulators of drug abuse and immunity
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Guoqiang Wang, Kai Zhang, and Xuxiu Jing
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0301 basic medicine ,Untranslated region ,adaptive immunity ,Immunology ,lcsh:Medicine ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunity ,microRNA ,Immunology and Allergy ,innate immunity ,drug abuse ,Regulation of gene expression ,Review Paper ,Innate immune system ,lcsh:R ,Translation (biology) ,Acquired immune system ,immunity ,Cell biology ,030104 developmental biology ,030215 immunology - Abstract
MicroRNAs (miRNAs) are 20-22 nucleotide non-coding RNAs that participate in gene regulation. They bind to 3’-untranslated regions of their mRNA targets, inhibiting the transcripts’ translation and/or destabilizing them. Chronic drug abuse induces changes of miRNAs expression in the brain, which is thought to contribute to addictive behaviors. Lots of miRNAs have been identified to play critical roles in the development of drug addiction. Moreover, miRNAs have been shown to play critical roles in a broad array of biologic processes, including regulation of the cell cycle, oncogenic transformation, immune cell regeneration and differentiation, and psychiatry disorders. We hypothesized that chronic drug abuse leads to aberrant expression of several miRNAs, and then aberrant miRNAs influence the innate and adaptive immunity, especially differentiation and function of T cells and B cells, through down-regulated miRNAs’ target gene expression. Characterization of miRNA actions is important and has high potential effect for the management of drug addiction and immunity diseases. miRNAs are potential biomarkers, and the modulation of their expression can be used for therapeutic purposes.
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- 2017
34. Mathematical modeling based on ordinary differential equations: A promising approach to vaccinology
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Rodrigo Weber dos Santos, Guilherme Côrtes Fernandes, C. R. B. Bonin, and Marcelo Lobosco
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0301 basic medicine ,Pharmacology ,Yellow Fever Vaccine ,Immunology ,Yellow fever vaccine ,Computational biology ,Adaptive Immunity ,Models, Theoretical ,Biology ,Acquired immune system ,Research Papers ,01 natural sciences ,Virology ,03 medical and health sciences ,030104 developmental biology ,Computational immunology ,Ordinary differential equation ,Yellow Fever ,0103 physical sciences ,medicine ,Animals ,Humans ,Immunology and Allergy ,010306 general physics ,medicine.drug - Abstract
New contributions that aim to accelerate the development or to improve the efficacy and safety of vaccines arise from many different areas of research and technology. One of these areas is computational science, which traditionally participates in the initial steps, such as the pre-screening of active substances that have the potential to become a vaccine antigen. In this work, we present another promising way to use computational science in vaccinology: mathematical and computational models of important cell and protein dynamics of the immune system. A system of Ordinary Differential Equations represents different immune system populations, such as B cells and T cells, antigen presenting cells and antibodies. In this way, it is possible to simulate, in silico, the immune response to vaccines under development or under study. Distinct scenarios can be simulated by varying parameters of the mathematical model. As a proof of concept, we developed a model of the immune response to vaccination against the yellow fever. Our simulations have shown consistent results when compared with experimental data available in the literature. The model is generic enough to represent the action of other diseases or vaccines in the human immune system, such as dengue and Zika virus.
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- 2016
35. Impact of a Heat Shock Protein Impurity on the Immunogenicity of Biotherapeutic Monoclonal Antibodies
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Rebecca J. Dearman, Shahid Uddin, Adrian Podmore, Stephen Bishop, Maryam Shah, Jeremy P. Derrick, Ian Kimber, Shraddha S. Rane, and Alain Pluen
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Pharmaceutical Science ,02 engineering and technology ,immunogenicity ,030226 pharmacology & pharmacy ,law.invention ,Mice ,0302 clinical medicine ,law ,Pharmacology (medical) ,Immunogenetic Phenomena ,Mice, Inbred BALB C ,biology ,Chemistry ,Immunogenicity ,aggregation ,Antibodies, Monoclonal ,adaptive immunity ,021001 nanoscience & nanotechnology ,Acquired immune system ,Recombinant Proteins ,Cell biology ,host cell impurity ,Recombinant DNA ,Molecular Medicine ,Female ,Antibody ,0210 nano-technology ,Research Paper ,Protein Binding ,Biotechnology ,medicine.drug_class ,Monoclonal antibody ,03 medical and health sciences ,Protein Aggregates ,Immune system ,Heat shock protein ,medicine ,Animals ,HSP70 Heat-Shock Proteins ,Pharmacology ,Organic Chemistry ,Hsp70 ,monoclonal antibody ,Antibody Formation ,biology.protein ,Stress, Mechanical ,Heat-Shock Response - Abstract
Purpose Anti-drug antibodies can impair the efficacy of therapeutic proteins and, in some circumstances, induce adverse health effects. Immunogenicity can be promoted by aggregation; here we examined the ability of recombinant mouse heat shock protein 70 (rmHSP70) - a common host cell impurity - to modulate the immune responses to aggregates of two therapeutic mAbs in mice. Methods Heat and shaking stress methods were used to generate aggregates in the sub-micron size range from two human mAbs, and immunogenicity assessed by intraperitoneal exposure in BALB/c mice. Results rmHSP70 was shown to bind preferentially to aggregates of both mAbs, but not to the native, monomeric proteins. Aggregates supplemented with 0.1% rmHSP70 induced significantly enhanced IgG2a antibody responses compared with aggregates alone but the effect was not observed for monomeric mAbs. Dendritic cells pulsed with mAb aggregate showed enhanced IFNγ production on co-culture with T cells in the presence of rmHSP70. Conclusion The results indicate a Th1-skewing of the immune response by aggregates and show that murine rmHSP70 selectively modulates the immune response to mAb aggregates, but not monomer. These data suggest that heat shock protein impurities can selectively accumulate by binding to mAb aggregates and thus influence immunogenic responses to therapeutic proteins. Electronic supplementary material The online version of this article (10.1007/s11095-019-2586-7) contains supplementary material, which is available to authorized users.
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- 2019
36. Thymopentin ameliorates dextran sulfate sodium-induced colitis by triggering the production of IL-22 in both innate and adaptive lymphocytes
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Chongxiu Yue, Fei Quan, Di Qin, Lutz Birnbaumer, Kun Hao, Yue Wang, Yuan Lu, Xiaoxuan Liu, Yong Yang, Xianjing Li, Hongbao Yang, Zixuan Zhang, Qiuhua Cao, Yanting Lin, Xinghua Gao, and Yanling Zhan
- Subjects
0301 basic medicine ,Male ,lymphocytes ,DSS-INDUCED COLITIS ,medicine.medical_treatment ,Medicine (miscellaneous) ,Adaptive Immunity ,LYMPHOCYTES ,T-Lymphocytes, Regulatory ,Interleukin 22 ,purl.org/becyt/ford/1 [https] ,Feces ,Mice ,0302 clinical medicine ,RAR-related orphan receptor gamma ,IL-22 ,Intestinal Mucosa ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,DSS-induced colitis ,LINFOCITOS ,GUT MICROBIOTA ,TIMOPENTINA ,Dextran Sulfate ,Ulcerative colitis ,3. Good health ,Cytokine ,030220 oncology & carcinogenesis ,CIENCIAS NATURALES Y EXACTAS ,medicine.drug ,COLITIS ,Research Paper ,Colon ,thymopentin ,Peripheral blood mononuclear cell ,Ciencias Biológicas ,THYMOPENTIN ,03 medical and health sciences ,Immune system ,Biología Celular, Microbiología ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Thymopentin ,Colitis ,purl.org/becyt/ford/1.6 [https] ,gut microbiota ,business.industry ,Interleukins ,medicine.disease ,HCT116 Cells ,Immunity, Innate ,Gastrointestinal Microbiome ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,13. Climate action ,Immunology ,TRATAMIENTO MEDICO ,Colitis, Ulcerative ,business ,Spleen - Abstract
Fil: Cao, Qiuhua. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Cao, Qiuhua. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Gao, Xinghua. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Gao, Xinghua. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Lin, Yanting. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Lin, Yanting. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Yue, Chongxiu. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Yue, Chongxiu. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Wang, Yue. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Wang, Yue. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Quan, Fei. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Quan, Fei. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Zhang, Zixuan. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Zhang, Zixuan. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Liu, Xiaoxuan. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Liu, Xiaoxuan. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Lu, Yuan.China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Lu, Yuan. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Zhan, Yanling. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Zhan, Yanling. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Yang, Hongbao. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Yang, Hongbao. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Li, Xianjing. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Li, Xianjing. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Qin, Di. Nanjing sport institute. School of Sports and Health; China Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Laboratory of Neurobiology; Estados Unidos Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Hao, Kun. China Pharmaceutical University. Key Lab of Drug Metabolism & Pharmacokinetics; China Fil: Yang, Yong. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Yang, Yong. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Background: Ulcerative colitis (UC) is a chronic inflammatory gastrointestinal disease, notoriously challenging to treat. Previous studies have found a positive correlation between thymic atrophy and colitis severity. It was, therefore, worthwhile to investigate the effect of thymopentin (TP5), a synthetic pentapeptide corresponding to the active domain of the thymopoietin, on colitis. Methods: Dextran sulfate sodium (DSS)-induced colitis mice were treated with TP5 by subcutaneous injection. Body weight, colon length, colon weight, immune organ index, disease activity index (DAI) score, and the peripheral blood profile were examined. The immune cells of the spleen and colon were analyzed by flow cytometry. Histology was performed on isolated colon tissues for cytokine analysis. Bacterial DNA was extracted from mouse colonic feces to assess the intestinal microbiota. Intestinal lamina propria mononuclear cells (LPMCs), HCT116, CT26, and splenocytes were cultured and treated with TP5. Results: TP5 treatment increased the body weight and colon length, decreased the DAI score, and restored colon architecture of colitic mice. TP5 also decreased the infiltration of immune cells and expression levels of pro-inflammatory cytokines such as IL-6. Importantly, the damaged thymus and compromised lymphocytes in peripheral blood were significantly restored by TP5. Also, the production of IL-22, both in innate and adaptive lymphoid cells, was triggered by TP5. Given the critical role of IL-22 in mucosal host defense, we tested the effect of TP5 on mucus barrier and gut microbiota and found that the number of goblet cells and the level of Mucin-2 expression were restored, and the composition of the gut microbiome was normalized after TP5 treatment. The critical role of IL-22 in the protective effect of TP5 on colitis was further confirmed by administering the anti-IL-22 antibody (αIL-22), which completely abolished the effect of TP5. Furthermore, TP5 significantly increased the expression level of retinoic acid receptor-related orphan receptor γ (RORγt), a transcription factor for IL-22. Consistent with this, RORγt inhibitor abrogated the upregulation of IL-22 induced by TP5. Conclusion: TP5 exerts a protective effect on DSS-induced colitis by triggering the production of IL-22 in both innate and adaptive lymphocytes. This study delineates TP5 as an immunomodulator that may be a potential drug for the treatment of UC.
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- 2019
37. Simultaneous blocking of CD47 and PD-L1 increases innate and adaptive cancer immune responses and cytokine release
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Lee Jia, Vladimir L. Katanaev, Bifei Li, Yunlong Cheng, Ruizhi Xie, Shu Lian, Yuying Ye, Xiaodong Xie, Yusheng Lu, and Shuhui Li
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Cytotoxicity, Immunologic ,0301 basic medicine ,B7-H1 Antigen/metabolism ,Research paper ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,animal diseases ,Cytotoxicity ,CD47 Antigen ,chemical and pharmacologic phenomena ,Adaptive Immunity ,B7-H1 Antigen ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunologic ,Neoplasms ,PD-L1 ,medicine ,Humans ,Innate ,T-Lymphocytes/immunology/metabolism ,ddc:612 ,Innate immune system ,biology ,business.industry ,CD47 Antigen/metabolism ,Cytokines/metabolism ,Immunity ,General Medicine ,Immunotherapy ,biochemical phenomena, metabolism, and nutrition ,Acquired immune system ,Immunohistochemistry ,Immunity, Innate ,Neoplasms/immunology/metabolism/pathology ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Cancer research ,Cytokines ,bacteria ,business ,Biomarkers - Abstract
Background Treatment multiple tumors by immune therapy can be achieved by mobilizing both innate and adaptive immunity. The programmed death ligand 1 (PD-L1; or CD274, B7-H1) is a critical “don't find me” signal to the adaptive immune system. Equally CD47 is a critical “don't eat me” signal to the innate immune system and a regulator of the adaptive immune response. Method Both of CD47 and PD-L1 are overexpressed on the surface of cancer cells to enable to escape immune-surveillance. We designed EpCAM (epithelial cell adhesion molecule)-targeted cationic liposome (LPP-P4-Ep) containing si-CD47 and si-PD-L1 could target high-EpCAM cancer cells and knockdown both CD47 and PD-L1 proteins. Findings Efficient silencing of CD47 and PD-L1 versus single gene silencing in vivo by systemic administration of LPP-P4-Ep could significantly inhibited the growth of solid tumors in subcutaneous and reduced lung metastasis in lung metastasis model. Target delivery of the complexes LPP-P4-Ep increased anti-tumor T cell and NK cell response, and release various cytokines including IFN-γ and IL-6 in vivo and in vitro. Interpretation This multi-nanoparticles showed significantly high-EpCAM tumor targeting and lower toxicity, and enhanced immune therapeutic efficacy. Our data indicated that dual-blockade tumor cell-specific innate and adaptive checkpoints represents an improved strategy for tumor immunotherapy. Fund This research supported by the Ministry of Science and Technology of the People's Republic of China (grant number 2015CB931804); the National Natural Science Foundation of China (NSFC, grant numbers 81703555, U1505225 and 81773063), and the China Postdoctoral Science Foundation (grant number 2017 M620268).
- Published
- 2019
38. Adaptive immunity and IL‐17A are not involved in the progression of chronic kidney disease after 5/6 nephrectomy in mice
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Stefanie Klinge, Marlies Bode, Hans-Willi Mittrücker, Reza Kabiri, Alva Rosendahl, Heimo Ehmke, Ulrich Wenzel, and Anna Cai
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0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Inflammation ,Adaptive Immunity ,Nephrectomy ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,medicine ,Animals ,Renal Insufficiency, Chronic ,Pharmacology ,Mice, Knockout ,Kidney ,business.industry ,Interleukin-17 ,Glomerulosclerosis ,Acquired immune system ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Mice, Inbred DBA ,Albuminuria ,Themed Section: Research Papers ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Kidney disease - Abstract
BACKGROUND AND PURPOSE: The adaptive immune response and IL‐17A contribute to renal damage in several experimental models of renal injury. EXPERIMENTAL APPROACH: To evaluate the role of the adaptive immune response, 5/6 nephrectomy was performed in wildtype DBA/1J mice and in recombination‐activating gene‐1 (RAG‐1) deficient mice that lack B and T‐cells. To assess the role of IL‐17A, we carried out 5/6 nephrectomy in IL‐17A deficient mice. Flow cytometric analysis, immunohistochemistry and RT‐PCR were used. KEY RESULTS: Infiltration of CD3(+) T‐cells in the remnant kidney was increased after 5/6 nephrectomy in wildtype mice, along with a robust induction of IL‐17A production in CD4(+) T and γδ T‐cells. After 5/6 nephrectomy, wildtype mice developed albuminuria in the nephrotic range over 10 weeks. This was accompanied by severe glomerular sclerosis and tubulointerstitial injury, and as well as renal mRNA expression of markers of inflammation and fibrosis (the chemokine CCL2, plasminogen activator inhibitor‐1; PAI‐1 and neutrophil gelatinase‐associated lipocalin; NGAL). Unexpectedly, RAG‐1 deficient mice and IL‐17A deficient mice developed renal injury, similar to that in wildtype mice. No differences were found for albuminuria, glomerular sclerosis, tubulointerstitial injury and mRNA expression of CCL2, PAI‐1 and NGAL. Mortality did not differ between the three groups. CONCLUSIONS AND IMPLICATIONS: Numbers of CD3(+) T‐cells and IL‐17A(+) lymphocytes infiltrating the kidney were increased after 5/6 nephrectomy. In contrast to other experimental models of renal injury, genetic deficiency of the adaptive immune system or of IL‐17A did not attenuate induction or progression of chronic kidney disease after 5/6 nephrectomy. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc
- Published
- 2018
39. Global Properties of Cytokine-Enhanced HIV-1 Dynamics Model with Adaptive Immunity and Distributed Delays.
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Dahy, Elsayed, Elaiw, Ahmed M., Raezah, Aeshah A., Zidan, Hamdy Z., and Abdellatif, Abd Elsattar A.
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HIGHLY active antiretroviral therapy ,HOPFIELD networks ,CYTOTOXIC T cells ,HIV ,GLOBAL asymptotic stability ,ADAPTIVE control systems ,BASIC reproduction number - Abstract
In this paper, we study a model that enhances our understanding of cytokine-influenced HIV-1 infection. The impact of adaptive immune response (cytotoxic T lymphocytes (CTLs) and antibodies) and time delay on HIV-1 infection is included. The model takes into account two types of distributional delays, (i) the delay in the HIV-1 infection of CD4
+ T cells and (ii) the maturation delay of new virions. We first investigated the fundamental characteristics of the system, then found the system's equilibria. We derived five threshold parameters, ℜ i , i = 0, 1,..., 4, which completely determine the existence and stability of the equilibria. The Lyapunov method was used to prove the global asymptotic stability for all equilibria. We illustrate the theoretical results by performing numerical simulations. We also performed a sensitivity analysis on the basic reproduction number ℜ 0 and identified the most-sensitive parameters. We found that pyroptosis contributes to the number ℜ 0 , and then, neglecting it will make ℜ 0 underevaluated. Necrosulfonamide and highly active antiretroviral drug therapy (HAART) can be effective in preventing pyroptosis and at reducing viral replication. Further, it was also found that increasing time delays can effectively decrease ℜ 0 and, then, inhibit HIV-1 replication. Furthermore, it is shown that both CTLs and antibody immune responses have no effect on ℜ 0 , while this can result in less HIV-1 infection. [ABSTRACT FROM AUTHOR]- Published
- 2023
- Full Text
- View/download PDF
40. Effect of Calcineurin Inhibitors and Mammalian Target of Rapamycin Inhibitors on the Course of COVID-19 in Kidney Transplant Recipients
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Sena Ulu, Ozkan Gungor, Nuri Baris Hasbal, Ebru Gok Oguz, and Didem Turgut
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Graft Rejection ,medicine.medical_treatment ,Calcineurin Inhibitors ,Adaptive Immunity ,Pathogenesis ,Immunocompromised Host ,Immune system ,Postoperative Complications ,Immunity ,medicine ,Humans ,Protein Kinase Inhibitors ,Kidney transplantation ,Transplantation ,Review Paper ,business.industry ,Calcineurin ,TOR Serine-Threonine Kinases ,COVID-19 ,Immunosuppression ,General Medicine ,medicine.disease ,Kidney Transplantation ,Immunity, Innate ,Cytokine release syndrome ,Oxidative Stress ,Immunology ,Cytokine storm ,business ,Cytokine Release Syndrome ,Immunosuppressive Agents - Abstract
Coronavirus disease 19 (COVID-19) has been an ongoing pandemic since December 2019. Unfortunately, kidney transplant recipients are a high-risk group during the disease course, and scientific data are still limited in this patient group. Beyond the dosage of immunosuppressive drugs, pharmacological immunosuppression may also alter the infection response in the COVID-19 course. The effects of immunosuppressive agents on the development and process of infection should not be decided only by determining how potent they are and how much they suppress the immune system; it is also thought that the direct effect of the virus, increased oxidative stress, and cytokine storm play a role in the pathogenesis of COVID-19 disease. There are data about immunosuppressive drugs like calcineurin inhibitors (CNI) or mammalian target of rapamycin inhibitors (mTORi) therapy related to their beneficial effects during any infection course. Limited data suggest that the use of CNI or mTORi may have beneficial effects on the process. In this hypothetical review, the probable impacts of CNI and mTORi on the pathogenesis of the COVID-19 were investigated.
- Published
- 2021
41. Immunoinformatics approach to understand molecular interaction between multi-epitopic regions of SARS-CoV-2 spike-protein with TLR4/MD-2 complex
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Garima Sharma, Ashish Ranjan Sharma, Chiranjib Chakraborty, Sang-Soo Lee, Manojit Bhattacharya, and Bidyut Mallick
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0301 basic medicine ,Microbiology (medical) ,Models, Molecular ,Antigenicity ,Protein Conformation ,030106 microbiology ,Lymphocyte Antigen 96 ,Epitopes, T-Lymphocyte ,Computational biology ,Plasma protein binding ,Biology ,Spike protein ,Adaptive Immunity ,medicine.disease_cause ,Microbiology ,Epitope ,03 medical and health sciences ,Epitopes ,Protein structure ,Immune system ,Antigen ,Genetics ,medicine ,Humans ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Coronavirus ,SARS-CoV-2 ,TLR4/MD-2 complex ,COVID-19 ,Computational Biology ,Acquired immune system ,Molecular Docking Simulation ,Toll-Like Receptor 4 ,030104 developmental biology ,Infectious Diseases ,Spike Glycoprotein, Coronavirus ,Epitopes, B-Lymphocyte ,Hydrophobic and Hydrophilic Interactions ,Research Paper ,Protein Binding - Abstract
Background The coronavirus (CoV) spike (S) protein is critical for receptor binding, membrane fusion and internalization of the virus into the human cells. We have tried to search the epitopic component of the S-protein that might be served as crucial targets for the vaccine development and also tried to understand the molecular mechanism of epitopes and TLR4/MD-2 complex for adaptive immunity. Material and methods Here we identified the antigenicity and the epitopic divergence of S-protein via immunoinformatics approach. The study was performed to identify the epitopes, composition of amino acids and its distribution in epitopic regions, composition of amino acid between the identified epitopes, secondary structure architecture of epitopes, physicochemical and biochemical parameters and molecular interaction between the identified epitope and TLR4/MD-2 complex. The SARS-CoV-2 can be possibly recognised by TLR4 of host immune cells that are responsible for the adaptive immune response. Results We identified four SARS-CoV-2 S-protein 9mer antigenic epitopes and observed that they bind with the TLR4/MD-2 complex by varied stable molecular bonding interactions. Molecular interaction between these characterized epitopes with TLR4/MD-2 complex might be indicated the binding affinity and downstream signalling of adaptive immune response. Different physicochemical and biochemical parameters such as O-glycosylation and N-glycosylation, Hydrophobicity, GRAVY were identified within epitopic regions of S-protein. These parameters help to understand the protein-protein interaction between epitopes and TLR4/MD-2 complex. The study also revealed different epitopic binding pockets of TLR4/MD-2 complex. Conclusions The identified epitopes impart suitable prospects for the development of novel peptide-based epitopic vaccine for the control of COVID-19 infection., Highlights • Identification and characterization of antigenic multi-epitopic region of SARS-CoV-2 Spike (S) protein. • Molecular interaction study of SARS-CoV-2 S-protein epitopes and human TLR4/MD-2 complex through molecular docking. • Binding with TLR4/MD-2 complex with four identified epitopes from SARS-CoV-2 S-protein might induce an immune response. • Identified epitopes (both B and T-cells) are promising candidates for epitope-based peptide-vaccine against COVID-19.
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- 2020
42. Role of the immune system in the peritoneal tumor spread of high grade serous ovarian cancer
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C. Grimm, Dietmar Pils, Reinhard Horvat, Katharina Auer, Samuel M. Meier, Klaus G. Schmetterer, Anna Bachmayr-Heyda, Christopher Gerner, Nyamdelger Sukhbaatar, and Stefanie Aust
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epithelial ovarian cancer ,0301 basic medicine ,Pathology ,Lymphocyte ,Cell Separation ,Adaptive Immunity ,T-Lymphocytes, Regulatory ,Monocytes ,0302 clinical medicine ,PD-1 ,Ascites ,Tumor Microenvironment ,Medicine ,Peritoneal Neoplasms ,Immunoassay ,Ovarian Neoplasms ,next generation sequencing ,B-Lymphocytes ,Immunohistochemistry ,humanities ,Treatment Outcome ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,medicine.symptom ,Research Paper ,medicine.medical_specialty ,Down-Regulation ,Inflammation ,03 medical and health sciences ,Immune system ,Antigens, Neoplasm ,Humans ,Metabolomics ,peritoneal tumor spread ,Innate immune system ,Sequence Analysis, RNA ,business.industry ,Macrophages ,flow cytometry ,Monocyte ,Cancer ,medicine.disease ,Immunity, Innate ,030104 developmental biology ,business - Abstract
// Katharina Auer 1 , Anna Bachmayr-Heyda 1 , Nyamdelger Sukhbaatar 1 , Stefanie Aust 1 , Klaus G. Schmetterer 2 , Samuel M. Meier 3 , Christopher Gerner 3 , Christoph Grimm 1 , Reinhard Horvat 4 , Dietmar Pils 1 1 Department of Obstetrics and Gynecology, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria 2 Department for Laboratory Medicine, Medical University of Vienna, Vienna, Austria 3 Department of Analytical Chemistry, University of Vienna, Vienna, Austria 4 Department of Pathology, Medical University of Vienna, Vienna, Austria Correspondence to: Dietmar Pils, email: dietmar.pils@univie.ac.at Keywords: epithelial ovarian cancer, peritoneal tumor spread, flow cytometry, PD-1, next generation sequencing Received: May 05, 2016 Accepted: July 14, 2016 Published: August 03, 2016 ABSTRACT The immune system plays a critical role in cancer progression and overall survival. Still, it is unclear if differences in the immune response are associated with different patterns of tumor spread apparent in high grade serous ovarian cancer patients and previously described by us. In this study we aimed to assess the role of the immune system in miliary (widespread, millet-sized lesions) and non-miliary (bigger, exophytically growing implants) tumor spread. To achieve this we comprehensively analyzed tumor tissues, blood, and ascites from 41 patients using immunofluorescence, flow cytometry, RNA sequencing, multiplexed immunoassays, and immunohistochemistry. Results showed that inflammation markers were systemically higher in miliary. In contrast, in non-miliary lymphocyte and monocyte/macrophage infiltration into the ascites was higher as well as the levels of PD-1 expression in tumor associated cytotoxic T-lymphocytes and PD-L1 expression in tumor cells. Furthermore, in ascites of miliary patients more epithelial tumor cells were present compared to non-miliary, possibly due to the active down-regulation of anti-tumor responses by B-cells and regulatory T-cells. Summarizing, adaptive immune responses prevailed in patients with non-miliary spread, whereas in patients with miliary spread a higher involvement of the innate immune system was apparent while adaptive responses were counteracted by immune suppressive cells and factors.
- Published
- 2016
43. Do human B-lymphocytes avoid aging until 60 years?
- Author
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Andrea Knight, Pavel Nemec, Pavla Všianská, Marketa Kolmanova, Renata Vytopilova, Marta Krejčí, Martin Piskacek, Lucie Válková, Marek Havelka, Sona Bretzova, and Lucie Rihova
- Subjects
0301 basic medicine ,Adult ,Male ,Aging ,Naive B cell ,Biology ,Adaptive Immunity ,Interleukin-7 Receptor alpha Subunit ,03 medical and health sciences ,0302 clinical medicine ,Research Paper: Gerotarget (Focus on Aging) ,IL7R ,Immunity ,medicine ,Humans ,Interleukin-7 receptor ,B cell ,B-Lymphocytes ,Gerotarget ,Gene Expression Profiling ,Middle Aged ,Acquired immune system ,GEP ,Immunity, Innate ,3. Good health ,naive B cells ,Gene expression profiling ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Immunology ,Female ,Stem cell ,Transcriptome ,030215 immunology - Abstract
Broad changes in human innate and adaptive immunity are associated with advanced age. The age-related alteration of gene expression was reported for both T and B lymphocytes. We analysed the genome-wide expression profiles (n=20) of naive and whole B cell populations from young and early aged healthy donors under 60 years. We revealed large homogeneity of all analysed genome-wide expression profiles but did not identified any significant gene deregulation between young (30-45 years) and early aged healthy donors (50-60 years). We argue that B cells avoid the aging program on molecular level until 60 years of age. Our results demonstrate the potential of hematopoietic stem cells to generate uncompromised lymphocytes in early elderly. These are very encouraging findings for the general health and the immunity maintenance would not need any intervention to naive B cells. Rather, a suitable immune stimulation in healthy body environment warrants further research into aging of older elderly.
- Published
- 2016
44. Dual B- and T-cell de-immunization of recombinant immunotoxin targeting mesothelin with high cytotoxic activity
- Author
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Dong Park, Ronit Mazor, Ira Pastan, Laiman Xiang, Jingli Zhang, Selamawit Addissie, Masanori Onda, and Raffit Hassan
- Subjects
Mesothelioma ,0301 basic medicine ,Lung Neoplasms ,pancreatic cancer ,Immunoglobulin Variable Region ,Epitopes, T-Lymphocyte ,immunogenicity ,Adaptive Immunity ,Protein Engineering ,Epitope ,Mice ,0302 clinical medicine ,Immunotoxin ,Medicine ,Cytotoxic T cell ,Molecular Targeted Therapy ,epitope ,biology ,Immunotoxins ,Immunogenicity ,Antibodies, Monoclonal ,T-Lymphocytes, Helper-Inducer ,Oncology ,Mesothelin ,030220 oncology & carcinogenesis ,Epitopes, B-Lymphocyte ,Female ,Immunotherapy ,Antigenicity ,Recombinant Fusion Proteins ,Bacterial Toxins ,rational design ,Exotoxins ,Mice, Nude ,GPI-Linked Proteins ,03 medical and health sciences ,Cell Line, Tumor ,Pancreatic cancer ,Animals ,Humans ,business.industry ,Mesothelioma, Malignant ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Mutation ,Immunology ,Cancer research ,biology.protein ,business ,Priority Research Paper - Abstract
// Ronit Mazor 1 , Masanori Onda 1 , Dong Park 1,3 , Selamawit Addissie 1 , Laiman Xiang 1,* , Jingli Zhang 2 , Raffit Hassan 2 and Ira Pastan 1 1 Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA 2 Thoracic and GI Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA 3 New Business Development Department, Medytox Inc., Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea * Retired Correspondence to: Ira Pastan, email: // Keywords : epitope, immunogenicity, rational design, mesothelioma, pancreatic cancer Received : March 22, 2016 Accepted : April 22, 2016 Published : May 04, 2016 Abstract Recombinant immunotoxins (RITs) are genetically engineered proteins being developed to treat cancer. They are composed of an Fv that targets a cancer antigen and a portion of a protein toxin. Their clinical success is limited by their immunogenicity. Our goal is to produce a new RIT that targets mesothelin and is non-immunogenic by combining mutations that decrease B- and T-cell epitopes. Starting with an immunotoxin that has B-cell epitopes suppressed, we added mutations step-wise that suppress T-cell epitopes. The final protein (LMB-T14) has greatly reduced antigenicity as assessed by binding to human anti-sera and a greatly decreased ability to activate helper T-cells evaluated in a T-cell activation assay. It is very cytotoxic to mesothelioma cells from patients , and to cancer cell lines. LMB-T14 produces complete remissions of a mesothelin expressing cancer (A431/H9) xenograft. The approach used here can be used to de-immunize other therapeutic foreign proteins.
- Published
- 2016
45. Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice
- Author
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Venugopal Reddy Venna, Rodney M. Ritzel, Kendra Maas, Joshua Crapser, Anita Patel, Anjali Chauhan, Rajkumar Verma, Edward C. Koellhoffer, Joerg Graf, Fudong Liu, Austin Ricker, and Louise D. McCullough
- Subjects
0301 basic medicine ,Aging ,middle cerebral artery occlusion ,Inflammation ,Adaptive Immunity ,Biology ,Permeability ,Brain Ischemia ,Sepsis ,Brain ischemia ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Gastric mucosa ,medicine ,Animals ,Risk factor ,Stroke ,Cell Biology ,Hypothermia ,medicine.disease ,Acquired immune system ,infection ,Immunity, Innate ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,inflammation ,Gastric Mucosa ,Bacterial Translocation ,030220 oncology & carcinogenesis ,Immunology ,medicine.symptom ,experimental stroke ,Research Paper - Abstract
Aging is an important risk factor for post-stroke infection, which accounts for a large proportion of stroke-associated mortality. Despite this, studies evaluating post-stroke infection rates in aged animal models are limited. In addition, few studies have assessed gut microbes as a potential source of infection following stroke. Therefore we investigated the effects of age and the role of bacterial translocation from the gut in post-stroke infection in young (8-12 weeks) and aged (18-20 months) C57Bl/6 male mice following transient middle cerebral artery occlusion (MCAO) or sham surgery. Gut permeability was examined and peripheral organs were assessed for the presence of gut-derived bacteria following stroke. Furthermore, sickness parameters and components of innate and adaptive immunity were examined. We found that while stroke induced gut permeability and bacterial translocation in both young and aged mice, only young mice were able to resolve infection. Bacterial species seeding peripheral organs also differed between young (Escherichia) and aged (Enterobacter) mice. Consequently, aged mice developed a septic response marked by persistent and exacerbated hypothermia, weight loss, and immune dysfunction compared to young mice following stroke.
- Published
- 2016
46. Immunoglobulin G-dependent enhancement of the infection with Coxsackievirus B4 in a murine system
- Author
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Didier Hober, Mehdi A. Benkahla, Leila Aguech-Oueslati, Hela Jaïdane, Firas Elmastour, Mahjoub Aouni, Famara Sane, and Jawhar Gharbi
- Subjects
0301 basic medicine ,Microbiology (medical) ,030106 microbiology ,Immunology ,Spleen ,Adaptive Immunity ,Microbiology ,Virus ,Immunoglobulin G ,03 medical and health sciences ,Immune system ,In vivo ,Enterovirus Infections ,medicine ,Splenocyte ,Humans ,Antibody-dependent enhancement ,biology ,Virology ,Titer ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,biology.protein ,Parasitology ,Research Paper - Abstract
It was demonstrated that specific IgG can enhance the infection with CV-B4, in vitro, in the human system. This enhancement could be involved in the pathophysiology of CV-B4 induced diseases. To investigate further the role of enhancing IgG in the infection with CV-B4 E2 in vivo, animal models are needed. Therefore, it was decided to assess whether inoculation of CV-B4 E2 to mice results in the appearance of IgG able to enhance the infection with this virus. Swiss albino mice were inoculated with CV-B4 E2 intraperitoneally. Serum samples were obtained from tail vein blood collected from day 0 to day 80 p.i. IgG were isolated by Protein G affinity chromatography. Seroneutralisation assays were carried out. In total murine spleen cells cultures inoculated with CV-B4 E2 mixed with various dilutions of serum or IgG samples, the enhancing activity was assayed through i) the antiviral activity titer of supernatants ii) the detection of intracellular viral RNA by RT-PCR iii) the level of infectious particles in supernatants. In most serum samples (76/105), neutralizing and enhancing activities were detected peaking between days 14 and 30 p.i and were higher in sera from mice inoculated with 2.10(6) TCID50 units than with lower doses. The enhancing activity was due to the IgG-enriched fraction of serum from CV-B4 E2 infected animals but not from control animals. These data show that IgG from immune mice can enhance the infection of splenocytes with CV-B4 E2 in vitro and open the way to explore whether such an enhancing activity can play a role in vivo.
- Published
- 2016
47. The Toll-like receptor 5 agonist entolimod suppresses hepatic metastases in a murine model of ocular melanoma via an NK cell-dependent mechanism
- Author
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Hans E. Grossniklaus, Craig M. Brackett, Vanessa M. Morales-Tirado, Edmund K. Waller, Qing Zhang, Wayne Harris, Lyudmila G. Burdelya, Matthew W. Wilson, Camille A Benjamin, Zezhong Li, Andrei V. Gudkov, and Hua Yang
- Subjects
Uveal Neoplasms ,0301 basic medicine ,Agonist ,medicine.drug_class ,medicine.medical_treatment ,Ocular Melanoma ,Melanoma, Experimental ,Antineoplastic Agents ,Adaptive Immunity ,entolimod ,Metastasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Cytotoxic T cell ,Melanoma ,TLR5 ,business.industry ,Liver Neoplasms ,Transcription Factor RelA ,Immunotherapy ,medicine.disease ,Acquired immune system ,Immunity, Innate ,3. Good health ,Killer Cells, Natural ,Mice, Inbred C57BL ,Disease Models, Animal ,Toll-Like Receptor 5 ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Hepatocytes ,Cancer research ,uveal melanoma ,Peptides ,business ,liver metastases ,Research Paper ,Entolimod - Abstract
Uveal melanoma (UM) is the most common primary cancer of the eye in adults and progresses to metastatic disease predominantly of the liver in ∼50% of patients. In these cases, life expectancy averages just 9 months due to the lack of effective treatment options. The Toll-like receptor 5 (TLR5) agonist entolimod (former name CBLB502) rapidly activates TLR5-NF-κB signaling in hepatocytes and suppresses growth of both TLR5-expressing and non-expressing tumors in the liver through mobilization and activation of innate and adaptive immune mechanisms. The goal of this study was to explore the potential of entolimod as an immunotherapeutic agent against hepatic metastasis of UM using the TLR5-positive B16LS9 mouse model of ocular melanoma. Mice were given seven subcutaneous injections of vehicle or entolimod given 72 h apart started one day before, on the same day or three days after intraocular injection of B16LS9 cells. All tested regimens of entolimod treatment resulted in significantly reduced B16LS9 metastasis to the liver. Entolimod induced mobilization of natural killer (NK) cells to the liver and stimulated their maturation, differentiation and activation. Antibody-mediated depletion of NK cells from mice abrogated entolimod's antimetastatic activity in the liver and eliminated the entolimod-elicited in vitro cytotoxic activity of hepatic lymphocytes against B16LS9 cells. These results provide pre-clinical evidence of entolimod's efficacy against hepatometastasis of UM and support its further development as an anticancer immunotherapeutic drug.
- Published
- 2015
48. Bioinformatic evidence of widespread priming in type I and II CRISPR-Cas systems
- Author
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Simon A. Jackson, Raymond H.J. Staals, Peter C. Fineran, Chris M. Brown, Thomas J. Nicholson, and Bradley I. Croft
- Subjects
Prophages ,Priming (immunology) ,Computational biology ,adaptation ,Genome, Viral ,Biology ,Microbiology ,03 medical and health sciences ,0302 clinical medicine ,Plasmid ,Microbiologie ,CRISPR ,CRISPR-Cas ,priming ,Molecular Biology ,Gene ,Prophage ,030304 developmental biology ,VLAG ,0303 health sciences ,primed ,Computational Biology ,Cell Biology ,Archaeal Viruses ,adaptive immunity ,Acquired immune system ,Adaptation, Physiological ,030220 oncology & carcinogenesis ,CRISPR Loci ,spacer acquisition ,CRISPR-Cas Systems ,Research Paper - Abstract
CRISPR-Cas systems provide bacteria and archaea with adaptive immunity against invading genetic elements, such as plasmids, bacteriophages and archaeal viruses. They consist of cas genes and CRISPR loci, which store genetic memories of previously encountered invaders as short sequences termed spacers. Spacers determine the specificity of CRISPR-Cas defence and immunity can be gained or updated by the addition of new spacers into CRISPR loci. There are two main routes to spacer acquisition, which are known as naïve and primed CRISPR adaptation. Naïve CRISPR adaptation involves the de novo formation of immunity, independent of pre-existing spacers. In contrast, primed CRISPR adaptation (priming) uses existing spacers to enhance the acquisition of new spacers. Priming typically results in spacer acquisition from locations near the site of target recognition by the existing (priming) spacer. Primed CRISPR adaptation has been observed in several type I CRISPR-Cas systems and it is potentially widespread. However, experimental evidence is unavailable for some subtypes, and for most systems, priming has only been shown in a small number of hosts. There is also no current evidence of priming by other CRISPR-Cas types. Here, we used a bioinformatic approach to search for evidence of priming in diverse CRISPR-Cas systems. By analysing the clustering of spacers acquired from phages, prophages and archaeal viruses, including strand and directional biases between subsequently acquired spacers, we demonstrate that two patterns of primed CRISPR adaptation dominate in type I systems. In addition, we find evidence of a priming-like pathway in type II CRISPR-Cas systems.
- Published
- 2018
49. The Vici syndrome protein EPG5 regulates intracellular nucleic acid trafficking linking autophagy to innate and adaptive immunity
- Author
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Valentina Folgiero, Heinz Jungbluth, Daniela T. Pilz, Franco Locatelli, Evangelos Axiotis, Chiara Farroni, Stefania Petrini, Valerio D’Alicandro, Carlo Dionisi-Vici, Ulrike Schara, E. Piano Mortari, Rita Carsetti, Diego Martinelli, Chiara Bocci, Paolo Romania, Valentina Marcellini, Rosalba Carrozzo, and Emanuele Bellacchio
- Subjects
0301 basic medicine ,Research Paper - Basic Science ,Medizin ,Vesicular Transport Proteins ,Autophagy-Related Proteins ,Endosomes ,Biology ,Adaptive Immunity ,Cataract ,Cell Line ,03 medical and health sciences ,TLR9 ,Immune system ,medicine ,memory B cells ,Autophagy ,Humans ,Vici syndrome ,Molecular Biology ,B-Lymphocytes ,Lysosome-Associated Membrane Glycoproteins ,Proteins ,Biological Transport ,Cell Biology ,DNA ,Acquired immune system ,medicine.disease ,Immunity, Innate ,Cell biology ,EPG5 ,030104 developmental biology ,Endosomal trafficking ,CpG site ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Toll-Like Receptor 9 ,epg5 ,tlr9 ,vici syndrome ,endosomal trafficking ,memory b cells ,Mutation ,Nucleic acid ,RNA ,Agenesis of Corpus Callosum ,Lysosomes ,Intracellular - Abstract
Vici syndrome is a human inherited multi-system disorder caused by recessive mutations in EPG5, encoding the EPG5 protein that mediates the fusion of autophagosomes with lysosomes. Immunodeficiency characterized by lack of memory B cells and increased susceptibility to infection is an integral part of the condition, but the role of EPG5 in the immune system remains unknown. Here we show that EPG5 is indispensable for the transport of the TLR9 ligand CpG to the late endosomal-lysosomal compartment, and for TLR9-initiated signaling, a step essential for the survival of human memory B cells and their ultimate differentiation into plasma cells. Moreover, the predicted structure of EPG5 includes a membrane remodeling domain and a karyopherin-like domain, thus explaining its function as a carrier between separate vesicular compartments. Our findings indicate that EPG5, by controlling nucleic acids intracellular trafficking, links macroautophagy/autophagy to innate and adaptive immunity.
- Published
- 2017
50. A correlation of measles specific antibodies and the number of plasmacytoid dendritic cells is observed after measles vaccination in 9 month old infants
- Author
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Lino Eduardo Cardiel-Marmolejo, Laura C. Bonifaz, Brenda Hernández-Pérez, Miguel L. García-León, Rosa María Wong-Chew, José Ignacio Santos-Preciado, and Bogart Espinosa-Torres
- Subjects
Adult ,Male ,T-Lymphocytes ,Measles Vaccine ,Immunology ,Population ,Cell Count ,Viral Plaque Assay ,Adaptive Immunity ,Biology ,Antibodies, Viral ,Measles ,Measles virus ,Immune system ,medicine ,Humans ,Immunology and Allergy ,education ,Mexico ,Pharmacology ,education.field_of_study ,Innate immune system ,Vaccination ,Age Factors ,Infant ,hemic and immune systems ,Dendritic Cells ,Acquired immune system ,biology.organism_classification ,medicine.disease ,Antibodies, Neutralizing ,Virology ,Immunity, Innate ,Immunity, Humoral ,Female ,Measles vaccine ,Research Paper - Abstract
Measles virus (MeV) represents one of the main causes of death among young children, particularly in developing countries. Upon infection, MeV controls both interferon induction (IFN) and the interferon signaling pathway which results in a severe host immunosuppression that can persists for up to 6 mo after infection. Despite the global biology of MeV infection is well studied, the role of the plasmacytoid dendritic cells (pDCs) during the host innate immune response after measles vaccination remains largely uncharacterized. Here we investigated the role of pDCs, the major producers of interferon in response to viral infections, in the development of adaptive immune response against MeV vaccine. We report that there is a strong correlation between pDCs population and the humoral immune response to Edmonston Zagreb (EZ) measles vaccination in 9-month-old mexican infants. Five infants were further evaluated after vaccination, showing a clear increase in pDCs at baseline, one week and 3 months after immunization. Three months postvaccination they showed increase in memory T-cells and pDCs populations, high induction of adaptive immunity and also observed a correlation between pDCs number and the humoral immune response. These findings suggest that the development and magnitude of the adaptive immune response following measles immunization is directly dependent on the number of pDCs of the innate immune response.
- Published
- 2015
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