37 results on '"Tastet O"'
Search Results
2. IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease
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Romain Bouziat, Cezary Ciszewski, Joseph A. Murray, Chaitan Khosla, Thomas Lejeune, Eric V. Marietta, Jean-Christophe Grenier, Olivier Tastet, Brad A. Palanski, Vania Yotova, Luis B. Barreiro, Irina E. Horwath, Matthew A. Zurenski, Bana Jabri, Ian Lawrence, Jordan D. Ernest, Jordan Voisine, Sangman M. Kim, Kaushik Panigrahi, Mohamed B.F. Hawash, Valérie Abadie, Valentina Discepolo, Anne Dumaine, Abadie, V., Kim, S. M., Lejeune, T., Palanski, B. A., Ernest, J. D., Tastet, O., Voisine, J., Discepolo, V., Marietta, E. V., Hawash, M. B. F., Ciszewski, C., Bouziat, R., Panigrahi, K., Horwath, I., Zurenski, M. A., Lawrence, I., Dumaine, A., Yotova, V., Grenier, J. -C., Murray, J. A., Khosla, C., Barreiro, L. B., and Jabri, B. more...
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CD4-Positive T-Lymphocytes ,Male ,Glutens ,Tissue transglutaminase ,Mice, Transgenic ,Human leukocyte antigen ,Biology ,Coeliac disease ,Article ,Interferon-gamma ,Mice ,HLA-DQ Antigens ,medicine ,Cytotoxic T cell ,Humans ,Animals ,Villous atrophy ,Interleukin-15 ,Lamina propria ,Multidisciplinary ,Innate immune system ,Animal ,Microfilament Proteins ,HLA-DQ Antigen ,nutritional and metabolic diseases ,medicine.disease ,digestive system diseases ,Celiac Disease ,medicine.anatomical_structure ,CD4-Positive T-Lymphocyte ,Interleukin 15 ,Immunology ,biology.protein ,Female ,Gluten ,Human - Abstract
Coeliac disease is a complex, polygenic inflammatory enteropathy caused by exposure to dietary gluten that occurs in a subset of genetically susceptible individuals who express either the HLA-DQ8 or HLA-DQ2 haplotypes1,2. The need to develop non-dietary treatments is now widely recognized3, but no pathophysiologically relevant gluten- and HLA-dependent preclinical model exists. Furthermore, although studies in humans have led to major advances in our understanding of the pathogenesis of coeliac disease4, the respective roles of disease-predisposing HLA molecules, and of adaptive and innate immunity in the development of tissue damage, have not been directly demonstrated. Here we describe a mouse model that reproduces the overexpression of interleukin-15 (IL-15) in the gut epithelium and lamina propria that is characteristic of active coeliac disease, expresses the predisposing HLA-DQ8 molecule, and develops villous atrophy after ingestion of gluten. Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease. In addition, CD4+ T cells and HLA-DQ8 have a crucial role in the licensing of cytotoxic T cells to mediate intestinal epithelial cell lysis. We also demonstrate a role for the cytokine interferon-γ (IFNγ) and the enzyme transglutaminase 2 (TG2) in tissue destruction. By reflecting the complex interaction between gluten, genetics and IL-15-driven tissue inflammation, this mouse model provides the opportunity to both increase our understanding of coeliac disease, and develop new therapeutic strategies. An HLA- and gluten-dependent mouse model of coeliac disease with villous atrophy provides evidence for the cooperative role of IL-15 and gluten-specific CD4+ T cells in licensing the full activation of cytotoxic T cells that are necessary for inducing epithelial damage. more...
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- 2020
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3. Prediction of incident atrial fibrillation using deep learning, clinical models, and polygenic scores.
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Jabbour G, Nolin-Lapalme A, Tastet O, Corbin D, Jordà P, Sowa A, Delfrate J, Busseuil D, Hussin JG, Dubé MP, Tardif JC, Rivard L, Macle L, Cadrin-Tourigny J, Khairy P, Avram R, and Tadros R
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- Humans, Male, Female, Middle Aged, Aged, Risk Assessment methods, Multifactorial Inheritance genetics, ROC Curve, Incidence, Atrial Fibrillation genetics, Atrial Fibrillation diagnosis, Deep Learning, Electrocardiography
- Abstract
Background and Aims: Deep learning applied to electrocardiograms (ECG-AI) is an emerging approach for predicting atrial fibrillation or flutter (AF). This study introduces an ECG-AI model developed and tested at a tertiary cardiac centre, comparing its performance with clinical models and AF polygenic score (PGS)., Methods: Electrocardiograms in sinus rhythm from the Montreal Heart Institute were analysed, excluding those from patients with pre-existing AF. The primary outcome was incident AF at 5 years. An ECG-AI model was developed by splitting patients into non-overlapping data sets: 70% for training, 10% for validation, and 20% for testing. The performance of ECG-AI, clinical models, and PGS was assessed in the test data set. The ECG-AI model was externally validated in the Medical Information Mart for Intensive Care-IV (MIMIC-IV) hospital data set., Results: A total of 669 782 ECGs from 145 323 patients were included. Mean age was 61 ± 15 years, and 58% were male. The primary outcome was observed in 15% of patients, and the ECG-AI model showed an area under the receiver operating characteristic (AUC-ROC) curve of .78. In time-to-event analysis including the first ECG, ECG-AI inference of high risk identified 26% of the population with a 4.3-fold increased risk of incident AF (95% confidence interval: 4.02-4.57). In a subgroup analysis of 2301 patients, ECG-AI outperformed CHARGE-AF (AUC-ROC = .62) and PGS (AUC-ROC = .59). Adding PGS and CHARGE-AF to ECG-AI improved goodness of fit (likelihood ratio test P < .001), with minimal changes to the AUC-ROC (.76-.77). In the external validation cohort (mean age 59 ± 18 years, 47% male, median follow-up 1.1 year), ECG-AI model performance remained consistent (AUC-ROC = .77)., Conclusions: ECG-AI provides an accurate tool to predict new-onset AF in a tertiary cardiac centre, surpassing clinical and PGS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.) more...
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- 2024
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4. Revolutionising Acute Cardiac Care With Artificial Intelligence: Opportunities and Challenges.
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Doolub G, Khurshid S, Theriault-Lauzier P, Nolin Lapalme A, Tastet O, So D, Labrecque Langlais E, Cobin D, and Avram R
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- Humans, Cardiovascular Diseases therapy, Cardiovascular Diseases diagnosis, Algorithms, Artificial Intelligence
- Abstract
This article reviews the application of artificial intelligence (AI) in acute cardiac care, highlighting its potential to transform patient outcomes in the face of the global burden of cardiovascular diseases. It explores how AI algorithms can rapidly and accurately process data for the prediction and diagnosis of acute cardiac conditions. The review examines AI's impact on patient health across various diagnostic tools such as echocardiography, electrocardiography, coronary angiography, cardiac computed tomography, and magnetic resonance imaging, discusses the regulatory landscape for AI in health care, and categorises AI algorithms by their risk levels. Furthermore, it addresses the challenges of data quality, generalisability, bias, transparency, and regulatory considerations, underscoring the necessity for inclusive data and robust validation processes. The review concludes with future perspectives on integrating AI into clinical workflows and the ongoing need for research, regulation, and innovation to harness AI's full potential in improving acute cardiac care., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) more...
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- 2024
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5. Maximising Large Language Model Utility in Cardiovascular Care: A Practical Guide.
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Nolin-Lapalme A, Theriault-Lauzier P, Corbin D, Tastet O, Sharma A, Hussin JG, Kadoury S, Jiang R, Krahn AD, Gallo R, and Avram R
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- Humans, Natural Language Processing, Artificial Intelligence, Cardiology, Cardiovascular Diseases therapy
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Large language models (LLMs) have emerged as powerful tools in artificial intelligence, demonstrating remarkable capabilities in natural language processing and generation. In this article, we explore the potential applications of LLMs in enhancing cardiovascular care and research. We discuss how LLMs can be used to simplify complex medical information, improve patient-physician communication, and automate tasks such as summarising medical articles and extracting key information. In addition, we highlight the role of LLMs in categorising and analysing unstructured data, such as medical notes and test results, which could revolutionise data handling and interpretation in cardiovascular research. However, we also emphasise the limitations and challenges associated with LLMs, including potential biases, reasoning opacity, and the need for rigourous validation in medical contexts. This review provides a practical guide for cardiovascular professionals to understand and harness the power of LLMs while navigating their limitations. We conclude by discussing the future directions and implications of LLMs in transforming cardiovascular care and research., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) more...
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- 2024
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6. A Responsible Framework for Applying Artificial Intelligence on Medical Images and Signals at the Point of Care: The PACS-AI Platform.
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Theriault-Lauzier P, Cobin D, Tastet O, Langlais EL, Taji B, Kang G, Chong AY, So D, Tang A, Gichoya JW, Chandar S, Déziel PL, Hussin JG, Kadoury S, and Avram R
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- Humans, Point-of-Care Systems, Artificial Intelligence ethics, Radiology Information Systems
- Abstract
The potential of artificial intelligence (AI) in medicine lies in its ability to enhance clinicians' capacity to analyse medical images, thereby improving diagnostic precision and accuracy and thus enhancing current tests. However, the integration of AI within health care is fraught with difficulties. Heterogeneity among health care system applications, reliance on proprietary closed-source software, and rising cybersecurity threats pose significant challenges. Moreover, before their deployment in clinical settings, AI models must demonstrate their effectiveness across a wide range of scenarios and must be validated by prospective studies, but doing so requires testing in an environment mirroring the clinical workflow, which is difficult to achieve without dedicated software. Finally, the use of AI techniques in health care raises significant legal and ethical issues, such as the protection of patient privacy, the prevention of bias, and the monitoring of the device's safety and effectiveness for regulatory compliance. This review describes challenges to AI integration in health care and provides guidelines on how to move forward. We describe an open-source solution that we developed that integrates AI models into the Picture Archives Communication System (PACS), called PACS-AI. This approach aims to increase the evaluation of AI models by facilitating their integration and validation with existing medical imaging databases. PACS-AI may overcome many current barriers to AI deployment and offer a pathway toward responsible, fair, and effective deployment of AI models in health care. In addition, we propose a list of criteria and guidelines that AI researchers should adopt when publishing a medical AI model to enhance standardisation and reproducibility., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) more...
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- 2024
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7. Advancing Fairness in Cardiac Care: Strategies for Mitigating Bias in Artificial Intelligence Models Within Cardiology.
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Nolin-Lapalme A, Corbin D, Tastet O, Avram R, and Hussin JG
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- Humans, Bias, Reproducibility of Results, Artificial Intelligence, Cardiology
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In the dynamic field of medical artificial intelligence (AI), cardiology stands out as a key area for its technological advancements and clinical application. In this review we explore the complex issue of data bias, specifically addressing those encountered during the development and implementation of AI tools in cardiology. We dissect the origins and effects of these biases, which challenge their reliability and widespread applicability in health care. Using a case study, we highlight the complexities involved in addressing these biases from a clinical viewpoint. The goal of this review is to equip researchers and clinicians with the practical knowledge needed to identify, understand, and mitigate these biases, advocating for the creation of AI solutions that are not just technologically sound, but also fair and effective for all patients., (Copyright © 2024. Published by Elsevier Inc.) more...
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- 2024
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8. Specific plasma biomarker signatures associated with patients undergoing surgery for back pain.
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Coquelet P, Da Cal S, El Hage G, Tastet O, Balthazard R, Chaumont H, Yuh SJ, Shedid D, and Arbour N
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- Humans, Male, Female, Middle Aged, Adult, Aged, Back Pain blood, Back Pain surgery, Prospective Studies, Neurofilament Proteins blood, Biomarkers blood, Intervertebral Disc Degeneration surgery, Intervertebral Disc Degeneration blood
- Abstract
Background Context: Intervertebral disc degeneration (IDD) affects numerous people worldwide. The role of inflammation is increasingly recognized but remains incompletely resolved. Peripheral molecules could access neovascularized degenerated discs and contribute to the ongoing pathology., Purpose: To assess a large array of plasma molecules in patients with IDD to identify biomarkers associated with specific spinal pathologies and prognostic biomarkers for the surgery outcome., Design: Prospective observational study combining clinical data and plasma measures., Patient Sample: Plasma samples were collected just before surgery. Extensive clinical data (age, sex, smoking status, Modic score, glomerular filtration rate, etc.) were extracted from clinical files from 83 patients with IDD undergoing spine surgery., Outcome Measures: Recovery 2 months postsurgery as assessed by the treating neurosurgeon., Methods: Over 40 biological molecules were measured in patients' plasma using multiplex assays. Statistical analyses were performed to identify associations between biological and clinical characteristics (age, sex, Body Mass Index (BMI), smoking status, herniated disc, radiculopathy, myelopathy, stenosis, MODIC score, etc.) and plasma levels of biological molecules., Results: Plasma levels of Neurofilament Light chain (NfL) were significantly elevated in patients with myelopathy and spinal stenosis compared to herniated disc. Plasma levels of C- reactive protein (CRP), Neurofilament Light chain (NfL), and Serum Amyloid A (SAA) were negatively associated, while CCL22 levels were positively associated with an efficient recovery 2 months postsurgery., Conclusions: Our results show that CRP and CCL22 plasma levels combined with the age of the IDD patient can predict the 2-month postsurgery recovery (Area Under the Curve [AUC]=0.883). Moreover, NfL could become a valuable monitoring tool for patients with spinal cord injuries., Competing Interests: Declaration of competing interest One or more of the authors declare financial or professional relationships on ICMJE-TSJ disclosure forms., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) more...
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- 2025
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9. Insulin restores retinal ganglion cell functional connectivity and promotes visual recovery in glaucoma.
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El Hajji S, Shiga Y, Belforte N, Solorio YC, Tastet O, D'Onofrio P, Dotigny F, Prat A, Arbour N, Fortune B, and Di Polo A
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- Animals, Humans, Mice, Disease Models, Animal, Dendrites metabolism, Dendrites drug effects, Synapses metabolism, Synapses drug effects, Calcium metabolism, Retinal Ganglion Cells metabolism, Retinal Ganglion Cells drug effects, Glaucoma drug therapy, Glaucoma metabolism, Glaucoma pathology, Insulin metabolism, Insulin pharmacology
- Abstract
Dendrite pathology and synaptic loss result in neural circuit dysfunction, a common feature of neurodegenerative diseases. There is a lack of strategies that target dendritic and synaptic regeneration to promote neurorecovery. We show that daily human recombinant insulin eye drops stimulate retinal ganglion cell (RGC) dendrite and synapse regeneration during ocular hypertension, a risk factor to develop glaucoma. We demonstrate that the ribosomal protein p70S6 kinase (S6K) is essential for insulin-dependent dendritic regrowth. Furthermore, S6K phosphorylation of the stress-activated protein kinase-interacting protein 1 (SIN1), a link between the mammalian target of rapamycin complexes 1 and 2 (mTORC1/2), is required for insulin-induced dendritic regeneration. Using two-photon microscopy live retinal imaging, we show that insulin rescues single-RGC light-evoked calcium (Ca
2+ ) dynamics. We further demonstrate that insulin enhances neuronal survival and retina-brain connectivity leading to improved optomotor reflex-elicited behaviors. Our data support that insulin is a compelling pro-regenerative strategy with potential clinical implications for the treatment and management of glaucoma. more...- Published
- 2024
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10. Evaluation of stenoses using AI video models applied to coronary angiography.
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Labrecque Langlais É, Corbin D, Tastet O, Hayek A, Doolub G, Mrad S, Tardif JC, Tanguay JF, Marquis-Gravel G, Tison GH, Kadoury S, Le W, Gallo R, Lesage F, and Avram R
- Abstract
The coronary angiogram is the gold standard for evaluating the severity of coronary artery disease stenoses. Presently, the assessment is conducted visually by cardiologists, a method that lacks standardization. This study introduces DeepCoro, a ground-breaking AI-driven pipeline that integrates advanced vessel tracking and a video-based Swin3D model that was trained and validated on a dataset comprised of 182,418 coronary angiography videos spanning 5 years. DeepCoro achieved a notable precision of 71.89% in identifying coronary artery segments and demonstrated a mean absolute error of 20.15% (95% CI: 19.88-20.40) and a classification AUROC of 0.8294 (95% CI: 0.8215-0.8373) in stenosis percentage prediction compared to traditional cardiologist assessments. When compared to two expert interventional cardiologists, DeepCoro achieved lower variability than the clinical reports (19.09%; 95% CI: 18.55-19.58 vs 21.00%; 95% CI: 20.20-21.76, respectively). In addition, DeepCoro can be fine-tuned to a different modality type. When fine-tuned on quantitative coronary angiography assessments, DeepCoro attained an even lower mean absolute error of 7.75% (95% CI: 7.37-8.07), underscoring the reduced variability inherent to this method. This study establishes DeepCoro as an innovative video-based, adaptable tool in coronary artery disease analysis, significantly enhancing the precision and reliability of stenosis assessment., (© 2024. The Author(s).) more...
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- 2024
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11. Validation Study of Two Artificial Intelligence-Based Preplanning Methods for Transcatheter Aortic Valve Replacement Procedures.
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Corbin D, Santaló-Corcoy M, Tastet O, Lopes P, Schrot J, Modine T, Asgar A, Lesage F, and Ben Ali W
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- 2024
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12. Enhanced detection of antigen-specific T cells by a multiplexed AIM assay.
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Lemieux A, Sannier G, Nicolas A, Nayrac M, Delgado GG, Cloutier R, Brassard N, Laporte M, Duchesne M, Sreng Flores AM, Finzi A, Tastet O, Dubé M, and Kaufmann DE
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- Tumor Necrosis Factor Receptor Superfamily, Member 9, Antigens metabolism, Cytomegalovirus, CD8-Positive T-Lymphocytes, CD4-Positive T-Lymphocytes
- Abstract
Broadly applicable methods to identify and characterize antigen-specific CD4
+ and CD8+ T cells are key to immunology research, including studies of vaccine responses and immunity to infectious diseases. We developed a multiplexed activation-induced marker (AIM) assay that presents several advantages compared to single pairs of AIMs. The simultaneous measurement of four AIMs (CD69, 4-1BB, OX40, and CD40L) creates six AIM pairs that define CD4+ T cell populations with partial and variable overlap. When combined in an AND/OR Boolean gating strategy for analysis, this approach enhances CD4+ T cell detection compared to any single AIM pair, while CD8+ T cells are dominated by CD69/4-1BB co-expression. Supervised and unsupervised clustering analyses show differential expression of the AIMs in defined T helper lineages and that multiplexing mitigates phenotypic biases. Paired and unpaired comparisons of responses to infections (HIV and cytomegalovirus [CMV]) and vaccination (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) validate the robustness and versatility of the method., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) more...- Published
- 2024
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13. ALCAM on human oligodendrocytes mediates CD4 T cell adhesion.
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Jamann H, Desu HL, Cui QL, Halaweh A, Tastet O, Klement W, Zandee S, Pernin F, Mamane VH, Ouédraogo O, Daigneault A, Sidibé H, Millette F, Peelen E, Dhaeze T, Hoornaert C, Rébillard RM, Thai K, Grasmuck C, Vande Velde C, Prat A, Arbour N, Stratton JA, Antel J, and Larochelle C more...
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- Humans, Mice, Animals, CD4-Positive T-Lymphocytes metabolism, Activated-Leukocyte Cell Adhesion Molecule metabolism, Cell Adhesion, Oligodendroglia metabolism, Multiple Sclerosis, Encephalomyelitis, Autoimmune, Experimental
- Abstract
Multiple sclerosis is a chronic neuroinflammatory disorder characterized by demyelination, oligodendrocyte damage/loss and neuroaxonal injury in the context of immune cell infiltration in the CNS. No neuroprotective therapy is available to promote the survival of oligodendrocytes and protect their myelin processes in immune-mediated demyelinating diseases. Pro-inflammatory CD4 Th17 cells can interact with oligodendrocytes in multiple sclerosis and its animal model, causing injury to myelinating processes and cell death through direct contact. However, the molecular mechanisms underlying the close contact and subsequent detrimental interaction of Th17 cells with oligodendrocytes remain unclear. In this study we used single cell RNA sequencing, flow cytometry and immunofluorescence studies on CNS tissue from multiple sclerosis subjects, its animal model and controls to characterize the expression of cell adhesion molecules by mature oligodendrocytes. We found that a significant proportion of human and murine mature oligodendrocytes express melanoma cell adhesion molecule (MCAM) and activated leukocyte cell adhesion molecule (ALCAM) in multiple sclerosis, in experimental autoimmune encephalomyelitis and in controls, although their regulation differs between human and mouse. We observed that exposure to pro-inflammatory cytokines or to human activated T cells are associated with a marked downregulation of the expression of MCAM but not of ALCAM at the surface of human primary oligodendrocytes. Furthermore, we used in vitro live imaging, immunofluorescence and flow cytometry to determine the contribution of these molecules to Th17-polarized cell adhesion and cytotoxicity towards human oligodendrocytes. Silencing and blocking ALCAM but not MCAM limited prolonged interactions between human primary oligodendrocytes and Th17-polarized cells, resulting in decreased adhesion of Th17-polarized cells to oligodendrocytes and conferring significant protection of oligodendrocytic processes. In conclusion, we showed that human oligodendrocytes express MCAM and ALCAM, which are differently modulated by inflammation and T cell contact. We found that ALCAM is a ligand for Th17-polarized cells, contributing to their capacity to adhere and induce damage to human oligodendrocytes, and therefore could represent a relevant target for neuroprotection in multiple sclerosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...
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- 2024
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14. TAVI-PREP: A Deep Learning-Based Tool for Automated Measurements Extraction in TAVI Planning.
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Santaló-Corcoy M, Corbin D, Tastet O, Lesage F, Modine T, Asgar A, and Ben Ali W
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Background: Transcatheter aortic valve implantation (TAVI) is a less invasive alternative to open-heart surgery for treating severe aortic stenosis. Despite its benefits, the risk of procedural complications necessitates careful preoperative planning., Methods: This study proposes a fully automated deep learning-based method, TAVI-PREP, for pre-TAVI planning, focusing on measurements extracted from computed tomography (CT) scans. The algorithm was trained on the public MM-WHS dataset and a small subset of private data. It uses MeshDeformNet for 3D surface mesh generation and a 3D Residual U-Net for landmark detection. TAVI-PREP is designed to extract 22 different measurements from the aortic valvular complex. A total of 200 CT-scans were analyzed, and automatic measurements were compared to the ones made manually by an expert cardiologist. A second cardiologist analyzed 115 scans to evaluate inter-operator variability., Results: High Pearson correlation coefficients between the expert and the algorithm were obtained for most parameters (0.90-0.97), except for left and right coronary height (0.8 and 0.72, respectively). Similarly, the mean absolute relative error was within 5% for most measurements, except for left and right coronary height (11.6% and 16.5%, respectively). A greater consensus was observed among experts than when compared to the automatic approach, with TAVI-PREP showing no discernable bias towards either the lower or higher ends of the measurement spectrum., Conclusions: TAVI-PREP provides reliable and time-efficient measurements of the aortic valvular complex that could aid clinicians in the preprocedural planning of TAVI procedures. more...
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- 2023
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15. Spontaneous HIV expression during suppressive ART is associated with the magnitude and function of HIV-specific CD4 + and CD8 + T cells.
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Dubé M, Tastet O, Dufour C, Sannier G, Brassard N, Delgado GG, Pagliuzza A, Richard C, Nayrac M, Routy JP, Prat A, Estes JD, Fromentin R, Chomont N, and Kaufmann DE
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- Humans, In Situ Hybridization, Fluorescence, Phenotype, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Proviruses
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Spontaneous transcription and translation of HIV can persist during suppressive antiretroviral therapy (ART). The quantity, phenotype, and biological relevance of this spontaneously "active" reservoir remain unclear. Using multiplexed single-cell RNAflow-fluorescence in situ hybridization (FISH), we detect active HIV transcription in 14/18 people with HIV on suppressive ART, with a median of 28/million CD4
+ T cells. While these cells predominantly exhibit abortive transcription, p24-expressing cells are evident in 39% of participants. Phenotypically diverse, active reservoirs are enriched in central memory T cells and CCR6- and activation-marker-expressing cells. The magnitude of the active reservoir positively correlates with total HIV-specific CD4+ and CD8+ T cell responses and with multiple HIV-specific T cell clusters identified by unsupervised analysis. These associations are particularly strong with p24-expressing active reservoir cells. Single-cell vDNA sequencing shows that active reservoirs are largely dominated by defective proviruses. Our data suggest that these reservoirs maintain HIV-specific CD4+ and CD8+ T responses during suppressive ART., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) more...- Published
- 2023
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16. Classification of T lymphocyte motility behaviors using a machine learning approach.
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Carpentier Solorio Y, Lemaître F, Jabbour B, Tastet O, Arbour N, and Bou Assi E
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- Humans, Algorithms, Astrocytes, Machine Learning, CD8-Positive T-Lymphocytes, Brain
- Abstract
T lymphocytes migrate into organs and interact with local cells to perform their functions. How human T lymphocytes communicate with organ-specific cells and participate in pathobiological processes remains unresolved. Brain infiltration of T lymphocytes is associated with multiple neurological disorders. Thus, to characterize the behavior of human T lymphocytes reaching the human brain, we performed time-lapse microscopy on human CD8+ T lymphocytes co-cultured with either primary human astrocytes or neurons. Using traditional manual and visual assessment of microscopy data, we identified distinct CD8+ T lymphocyte motility behaviors. However, such characterization is time and labor-intensive. In this work, we trained and validated a machine-learning model for the automated classification of behaviors of CD8+ T lymphocytes interacting with astrocytes and neurons. A balanced random forest was trained for the binary classification of established classes of cell behaviors (synapse vs. kinapse) as well as visually identified behaviors (scanning, dancing, and poking). Feature selection was performed during 3-fold cross-validation using the minimum redundancy maximum relevance algorithm. Results show promising performances when tested on a held-out dataset of CD8+ T lymphocytes interacting with astrocytes with a new experimenter and a held-out independent dataset of CD8+ T lymphocytes interacting with neurons. When tested on the independent CD8+ T cell-neuron dataset, the final model achieved a binary classification accuracy of 0.82 and a 3-class accuracy of 0.79. This novel automated classification approach could significantly reduce the time required to label cell motility behaviors while facilitating the identification of interactions of T lymphocytes with multiple cell types., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Carpentier Solorio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.) more...
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- 2023
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17. Probing pathways by which rhynchophylline modifies sleep using spatial transcriptomics.
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Ballester Roig MN, Leduc T, Dufort-Gervais J, Maghmoul Y, Tastet O, and Mongrain V
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- Humans, Female, Rats, Mice, Animals, Oxindoles, Sleep, Indole Alkaloids pharmacology, Indole Alkaloids metabolism, Transcriptome
- Abstract
Background: Rhynchophylline (RHY) is an alkaloid component of Uncaria, which are plants extensively used in traditional Asian medicines. Uncaria treatments increase sleep time and quality in humans, and RHY induces sleep in rats. However, like many traditional natural treatments, the mechanisms of action of RHY and Uncaria remain evasive. Moreover, it is unknown whether RHY modifies key brain oscillations during sleep. We thus aimed at defining the effects of RHY on sleep architecture and oscillations throughout a 24-h cycle, as well as identifying the underlying molecular mechanisms. Mice received systemic RHY injections at two times of the day (beginning and end of the light period), and vigilance states were studied by electrocorticographic recordings., Results: RHY enhanced slow wave sleep (SWS) after both injections, suppressed paradoxical sleep (PS) in the light but enhanced PS in the dark period. Furthermore, RHY modified brain oscillations during both wakefulness and SWS (including delta activity dynamics) in a time-dependent manner. Interestingly, most effects were larger in females. A brain spatial transcriptomic analysis showed that RHY modifies the expression of genes linked to cell movement, apoptosis/necrosis, and transcription/translation in a brain region-independent manner, and changes those linked to sleep regulation (e.g., Hcrt, Pmch) in a brain region-specific manner (e.g., in the hypothalamus)., Conclusions: The findings provide support to the sleep-inducing effect of RHY, expose the relevance to shape wake/sleep oscillations, and highlight its effects on the transcriptome with a high spatial resolution. The exposed molecular mechanisms underlying the effect of a natural compound should benefit sleep- and brain-related medicine., (© 2023. The Author(s).) more...
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- 2023
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18. MCAM+ brain endothelial cells contribute to neuroinflammation by recruiting pathogenic CD4+ T lymphocytes.
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Charabati M, Zandee S, Fournier AP, Tastet O, Thai K, Zaminpeyma R, Lécuyer MA, Bourbonnière L, Larouche S, Klement W, Grasmuck C, Tea F, Zierfuss B, Filali-Mouhim A, Moumdjian R, Bouthillier A, Cayrol R, Peelen E, Arbour N, Larochelle C, and Prat A more...
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- Humans, Blood-Brain Barrier pathology, Brain pathology, CD146 Antigen metabolism, CD4-Positive T-Lymphocytes metabolism, Endothelial Cells metabolism, Endothelium metabolism, Endothelium pathology, Neuroinflammatory Diseases, Encephalomyelitis, Autoimmune, Experimental pathology, Multiple Sclerosis pathology
- Abstract
The trafficking of autoreactive leucocytes across the blood-brain barrier endothelium is a hallmark of multiple sclerosis pathogenesis. Although the blood-brain barrier endothelium represents one of the main CNS borders to interact with the infiltrating leucocytes, its exact contribution to neuroinflammation remains understudied. Here, we show that Mcam identifies inflammatory brain endothelial cells with pro-migratory transcriptomic signature during experimental autoimmune encephalomyelitis. In addition, MCAM was preferentially upregulated on blood-brain barrier endothelial cells in multiple sclerosis lesions in situ and at experimental autoimmune encephalomyelitis disease onset by molecular MRI. In vitro and in vivo, we demonstrate that MCAM on blood-brain barrier endothelial cells contributes to experimental autoimmune encephalomyelitis development by promoting the cellular trafficking of TH1 and TH17 lymphocytes across the blood-brain barrier. Last, we showcase ST14 as an immune ligand to brain endothelial MCAM, enriched on CD4+ T lymphocytes that cross the blood-brain barrier in vitro, in vivo and in multiple sclerosis lesions as detected by flow cytometry on rapid autopsy derived brain tissue from multiple sclerosis patients. Collectively, our findings reveal that MCAM is at the centre of a pathological pathway used by brain endothelial cells to recruit pathogenic CD4+ T lymphocyte from circulation early during neuroinflammation. The therapeutic targeting of this mechanism is a promising avenue to treat multiple sclerosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.) more...
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- 2023
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19. A third SARS-CoV-2 mRNA vaccine dose in people receiving hemodialysis overcomes B cell defects but elicits a skewed CD4 + T cell profile.
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Sannier G, Nicolas A, Dubé M, Marchitto L, Nayrac M, Tastet O, Chatterjee D, Tauzin A, Lima-Barbosa R, Laporte M, Cloutier R, Sreng Flores AM, Boutin M, Gong SY, Benlarbi M, Ding S, Bourassa C, Gendron-Lepage G, Medjahed H, Goyette G, Brassard N, Delgado GG, Niessl J, Gokool L, Morrisseau C, Arlotto P, Rios N, Tremblay C, Martel-Laferrière V, Prat A, Bélair J, Beaubien-Souligny W, Goupil R, Nadeau-Fredette AC, Lamarche C, Finzi A, Suri RS, and Kaufmann DE more...
- Subjects
- Humans, SARS-CoV-2 genetics, CD4-Positive T-Lymphocytes, mRNA Vaccines, COVID-19 Vaccines, COVID-19 prevention & control
- Abstract
Cellular immune defects associated with suboptimal responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination in people receiving hemodialysis (HD) are poorly understood. We longitudinally analyze antibody, B cell, CD4
+ , and CD8+ T cell vaccine responses in 27 HD patients and 26 low-risk control individuals (CIs). The first two doses elicit weaker B cell and CD8+ T cell responses in HD than in CI, while CD4+ T cell responses are quantitatively similar. In HD, a third dose robustly boosts B cell responses, leads to convergent CD8+ T cell responses, and enhances comparatively more T helper (TH ) immunity. Unsupervised clustering of single-cell features reveals phenotypic and functional shifts over time and between cohorts. The third dose attenuates some features of TH cells in HD (tumor necrosis factor alpha [TNFα]/interleukin [IL]-2 skewing), while others (CCR6, CXCR6, programmed cell death protein 1 [PD-1], and HLA-DR overexpression) persist. Therefore, a third vaccine dose is critical to achieving robust multifaceted immunity in hemodialysis patients, although some distinct TH characteristics endure., Competing Interests: Declaration of interests C.T. serves as a consultant for Merck, Gilead, GSK, AstraZeneca, and Medicago., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.) more...- Published
- 2023
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20. Single-Cell Transcriptomics Identifies Brain Endothelium Inflammatory Networks in Experimental Autoimmune Encephalomyelitis.
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Fournier AP, Tastet O, Charabati M, Hoornaert C, Bourbonnière L, Klement W, Larouche S, Tea F, Wang YC, Larochelle C, Arbour N, Ragoussis J, Zandee S, and Prat A
- Subjects
- Humans, Animals, Mice, Transcriptome, Brain, Endothelium, Encephalomyelitis, Autoimmune, Experimental genetics, Neurodegenerative Diseases, Encephalitis, Multiple Sclerosis genetics
- Abstract
Background and Objectives: Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease characterized by infiltration of immune cells in multifocal areas of the CNS. The specific molecular processes allowing autoreactive immune cells to enter the CNS compartment through the blood-brain barrier remain elusive., Methods: Using endothelial cell (EC) enrichment and single-cell RNA sequencing, we characterized the cells implicated in the neuroinflammatory processes in experimental autoimmune encephalomyelitis, an animal model of MS. Validations on human MS brain sections of the most differentially expressed genes in venous ECs were performed using immunohistochemistry and confocal microscopy., Results: We found an upregulation of genes associated with antigen presentation and interferon in most populations of CNS-resident cells, including ECs. Interestingly, instead of transcriptionally distinct profiles, a continuous gradient of gene expression separated the arteriovenous zonation of the brain vasculature. However, differential gene expression analysis presented more transcriptomic alterations on the venous side of the axis, suggesting a prominent role of venous ECs in neuroinflammation. Furthermore, analysis of ligand-receptor interactions identified important potential molecular communications between venous ECs and infiltrated immune populations. To confirm the relevance of our observation in the context of human disease, we validated the protein expression of the most upregulated genes ( Ackr1 and Lcn2 ) in MS lesions., Discussion: In this study, we provide a landscape of the cellular heterogeneity associated with neuroinflammation. We also present important molecular insights for further exploration of specific cell processes that promote infiltration of immune cells inside the brain of experimental autoimmune encephalomyelitis mice., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.) more...
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- 2022
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21. Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function.
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Brunet-Ratnasingham E, Morou A, Dubé M, Niessl J, Baxter AE, Tastet O, Brassard N, Ortega-Delgado G, Charlebois R, Freeman GJ, Tremblay C, Routy JP, and Kaufmann DE
- Subjects
- CD4-Positive T-Lymphocytes, Cytokines metabolism, Humans, Immune Checkpoint Inhibitors, In Situ Hybridization, Fluorescence, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor metabolism, RNA therapeutic use, Receptors, Chemokine metabolism, Receptors, Chemokine therapeutic use, Receptors, Immunologic metabolism, Transcription Factors metabolism, B7-H1 Antigen metabolism, HIV Infections
- Abstract
Background: Immune checkpoint blockade (ICB) partially reverses the dysfunctional state of antigen-specific T cell in chronic infections. However, its impact on the diverse subsets of CD4+ T cells in humans is largely unknown., Methods: We examined immune checkpoint (IC) expression and function in HIV-specific CD4+ T cells of viremic individuals (≥5000 vRNA cp/ml, n = 17) prior to ART and persons with spontaneous (n = 11) or therapy-induced (n = 16) viral suppression (<40 cp/ml). We investigated IC patterns associated with exhaustion-related transcription factors and chemokine receptors using activation-induced marker assays. We determined effector functions representative of T
FH , TH 1, and TH 17/TH 22 using RNA flow cytometric fluorescence in situ hybridization (FISH). We compared increase in cytokine expression upon ICB across functions and patient status., Findings: Expression of dysfunction-related molecules, such as transcription factors and ICs PD-1, TIGIT, and CD200, followed a hierarchy associated with infection status and effector profile. In vitro responsiveness to PD-L1 blockade varied with defined functions rather than IC levels: frequencies of cells with TH 1- and TH 17/TH 22-, but not TFH -related functions, increased. Cells co-expressing TH 1 and TFH functions showed response to ICB, suggesting that the cell's state rather than function dictates responsiveness to PD-L1 blockade. Response to PD-L1 blockade was strongest in viremic participants and reduced after ART initiation., Interpretation: Our data highlight a polarization-specific regulation of IC expression and differing sensitivities of antigen-specific T helper subsets to PD-1-mediated inhibition. This heterogeneity may direct and constrain ICB efficacy in restoring CD4+ T cell function in HIV infection and other diseases., Funding: NIH, CIHR, CFI, FRQS., Competing Interests: Declaration of interests G.J.F. has patents/pending royalties on the PD-1/PD-L1 pathway from Roche, Merck M.S.D., Bristol-Myers-Squibb, Merck K.G.A., Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic, and Novartis. G.J.F. has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, Triursus, iTeos, and NextPoint. GJF has equity in Nextpoint, Triursus, and Xios. The anti-PD-L1 antibody BMS-936559 and the anti-TIGIT antibody BMS-g86207-Ab were given by Bristol-Myers Squibb. C.T. serves as a consultant and has received honoraria from Merck, Gilead, G.S.K., AstraZeneca and Medicago. None of aforementioned companies had implications in the design and interpretation of the experiments performed in this manuscript., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.) more...- Published
- 2022
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22. CLMP Promotes Leukocyte Migration Across Brain Barriers in Multiple Sclerosis.
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Fournier AP, Zandee S, Charabati M, Peelen E, Tastet O, Alvarez JI, Kebir H, Bourbonnière L, Larouche S, Lahav B, Klement W, Tea F, Bouthillier A, Moumdjian R, Cayrol R, Duquette P, Girard M, Larochelle C, Arbour N, and Prat A more...
- Subjects
- Humans, Brain metabolism, Coxsackie and Adenovirus Receptor-Like Membrane Protein metabolism, Endothelial Cells metabolism, Leukocytes metabolism, Leukocytes, Mononuclear, Tumor Necrosis Factor-alpha metabolism, Multiple Sclerosis
- Abstract
Background and Objectives: In multiple sclerosis (MS), peripheral immune cells use various cell trafficking molecules to infiltrate the CNS where they cause damage.The objective of this study was to investigate the involvement of coxsackie and adenovirus receptor-like membrane protein (CLMP) in the migration of immune cells into the CNS of patients with MS., Methods: Expression of CLMP was measured in primary cultures of human brain endothelial cells (HBECs) and human meningeal endothelial cells (HMECs), postmortem brain samples, and peripheral blood mononuclear cells (PBMCs) from patients with MS and controls by RNA sequencing, quantitative PCR, immunohistochemistry, and flow cytometry. In vitro migration assays using HBECs and HMECs were performed to evaluate the function of CLMP., Results: Using bulk RNA sequencing of primary cultures of human brain and meningeal endothelial cells (ECs), we have identified CLMP as a new potential cell trafficking molecule upregulated in inflammatory conditions. We first confirmed the upregulation of CLMP at the protein level on TNFα-activated and IFNγ-activated primary cultures of human brain and meningeal ECs. In autopsy brain specimens from patients with MS, we demonstrated an overexpression of endothelial CLMP in active MS lesions when compared with normal control brain tissue. Flow cytometry of human PBMCs demonstrated an increased frequency of CLMP
+ B lymphocytes and monocytes in patients with MS, when compared with that in healthy controls. The use of a blocking antibody against CLMP reduced the migration of immune cells across the human brain and meningeal ECs in vitro. Finally, we found CLMP+ immune cell infiltrates in the perivascular area of parenchymal lesions and in the meninges of patients with MS., Discussion: Collectively, our data demonstrate that CLMP is an adhesion molecule used by immune cells to access the CNS during neuroinflammatory disorders such as MS. CLMP could represent a target for a new treatment of neuroinflammatory conditions., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.) more...- Published
- 2022
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23. IL-27 shapes the immune properties of human astrocytes and their impact on encountered human T lymphocytes.
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Lemaître F, Farzam-Kia N, Carmena Moratalla A, Carpentier Solorio Y, Clenet ML, Tastet O, Cleret-Buhot A, Guimond JV, Haddad E, Duquette P, Girard JM, Prat A, Larochelle C, and Arbour N
- Subjects
- Astrocytes metabolism, B7-H1 Antigen metabolism, CD8-Positive T-Lymphocytes, Cytokines metabolism, Humans, Intercellular Adhesion Molecule-1 metabolism, Interleukins, Interleukin-27 metabolism, Multiple Sclerosis
- Abstract
Background: Interleukin-27 (IL-27) can trigger both pro- and anti-inflammatory responses. This cytokine is elevated in the central nervous system (CNS) of multiple sclerosis (MS) patients, but how it influences neuroinflammatory processes remains unclear. As astrocytes express the receptor for IL-27, we sought to determine how these glial cells respond to this cytokine and whether such exposure alters their interactions with infiltrating activated T lymphocytes. To determine whether inflammation shapes the impact of IL-27, we compared the effects of this cytokine in non-inflamed and inflamed conditions induced by an IL-1β exposure., Main Body: Transcriptomic analysis of IL-27-exposed human astrocytes showed an upregulation of multiple immune genes. Human astrocytes increased the secretion of chemokines (CXCL9, CXCL10, and CXCL11) and the surface expression of proteins (PD-L1, HLA-E, and ICAM-1) following IL-27 exposure. To assess whether exposure of astrocytes to IL-27 influences the profile of activated T lymphocytes infiltrating the CNS, we used an astrocyte/T lymphocyte co-culture model. Activated human CD4
+ or CD8+ T lymphocytes were co-cultured with astrocytes that have been either untreated or pre-exposed to IL‑27 or IL-1β. After 24 h, we analyzed T lymphocytes by flow cytometry for transcription factors and immune molecules. The contact with IL-27-exposed astrocytes increased the percentages of T-bet, Eomes, CD95, IL-18Rα, ICAM-1, and PD-L1 expressing CD4+ and CD8+ T lymphocytes and reduced the proportion of CXCR3-positive CD8+ T lymphocytes. Human CD8+ T lymphocytes co-cultured with human IL-27-treated astrocytes exhibited higher motility than when in contact with untreated astrocytes. These results suggested a preponderance of kinapse-like over synapse-like interactions between CD8+ T lymphocytes and IL-27-treated astrocytes. Finally, CD8+ T lymphocytes from MS patients showed higher motility in contact with IL-27-exposed astrocytes compared to healthy donors' cells., Conclusion: Our results establish that IL-27 alters the immune functions of human astrocytes and shapes the profile and motility of encountered T lymphocytes, especially CD8+ T lymphocytes from MS patients., (© 2022. The Author(s).) more...- Published
- 2022
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24. Temporal associations of B and T cell immunity with robust vaccine responsiveness in a 16-week interval BNT162b2 regimen.
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Nayrac M, Dubé M, Sannier G, Nicolas A, Marchitto L, Tastet O, Tauzin A, Brassard N, Lima-Barbosa R, Beaudoin-Bussières G, Vézina D, Gong SY, Benlarbi M, Gasser R, Laumaea A, Prévost J, Bourassa C, Gendron-Lepage G, Medjahed H, Goyette G, Ortega-Delgado GG, Laporte M, Niessl J, Gokool L, Morrisseau C, Arlotto P, Richard J, Bélair J, Prat A, Tremblay C, Martel-Laferrière V, Finzi A, and Kaufmann DE more...
- Subjects
- Antibodies, Viral, BNT162 Vaccine, Humans, Immunity, Humoral, RNA, Messenger, SARS-CoV-2, COVID-19, Viral Vaccines
- Abstract
Spacing of BNT162b2 mRNA doses beyond 3 weeks raises concerns about vaccine efficacy. We longitudinally analyze B cell, T cell, and humoral responses to two BNT162b2 mRNA doses administered 16 weeks apart in 53 SARS-CoV-2 naive and previously infected donors. This regimen elicits robust RBD-specific B cell responses whose kinetics differs between cohorts, the second dose leading to increased magnitude in naive participants only. While boosting does not increase magnitude of CD4
+ T cell responses further compared with the first dose, unsupervised clustering of single-cell features reveals phenotypic and functional shifts over time and between cohorts. Integrated analysis shows longitudinal immune component-specific associations, with early T helper responses post first dose correlating with B cell responses after the second dose, and memory T helper generated between doses correlating with CD8 T cell responses after boosting. Therefore, boosting elicits a robust cellular recall response after the 16-week interval, indicating functional immune memory., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.) more...- Published
- 2022
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25. Contact-Dependent Granzyme B-Mediated Cytotoxicity of Th17-Polarized Cells Toward Human Oligodendrocytes.
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Jamann H, Cui QL, Desu HL, Pernin F, Tastet O, Halaweh A, Farzam-Kia N, Mamane VH, Ouédraogo O, Cleret-Buhot A, Daigneault A, Balthazard R, Klement W, Lemaître F, Arbour N, Antel J, Stratton JA, and Larochelle C more...
- Subjects
- Granzymes metabolism, Humans, Interferon-gamma metabolism, Oligodendroglia, RNA, Messenger metabolism, Multiple Sclerosis metabolism, Th17 Cells metabolism
- Abstract
Multiple sclerosis (MS) is characterized by the loss of myelin and of myelin-producing oligodendrocytes (OLs) in the central nervous system (CNS). Pro-inflammatory CD4
+ Th17 cells are considered pathogenic in MS and are harmful to OLs. We investigated the mechanisms driving human CD4+ T cell-mediated OL cell death. Using fluorescent and brightfield in vitro live imaging, we found that compared to Th2-polarized cells, Th17-polarized cells show greater interactions with primary human OLs and human oligodendrocytic cell line MO3.13, displaying longer duration of contact, lower mean speed, and higher rate of vesicle-like structure formation at the sites of contact. Using single-cell RNA sequencing, we assessed the transcriptomic profile of primary human OLs and Th17-polarized cells in direct contact or separated by an insert. We showed that upon close interaction, OLs upregulate the expression of mRNA coding for chemokines and antioxidant/anti-apoptotic molecules, while Th17-polarized cells upregulate the expression of mRNA coding for chemokines and pro-inflammatory cytokines such as IL-17A, IFN-γ, and granzyme B. We found that secretion of CCL3, CXCL10, IFN-γ, TNFα, and granzyme B is induced upon direct contact in cocultures of human Th17-polarized cells with human OLs. In addition, we validated by flow cytometry and immunofluorescence that granzyme B levels are upregulated in Th17-polarized compared to Th2-polarized cells and are even higher in Th17-polarized cells upon direct contact with OLs or MO3.13 cells compared to Th17-polarized cells separated from OLs by an insert. Moreover, granzyme B is detected in OLs and MO3.13 cells following direct contact with Th17-polarized cells, suggesting the release of granzyme B from Th17-polarized cells into OLs/MO3.13 cells. To confirm granzyme B-mediated cytotoxicity toward OLs, we showed that recombinant human granzyme B can induce OLs and MO3.13 cell death. Furthermore, pretreatment of Th17-polarized cells with a reversible granzyme B blocker (Ac-IEPD-CHO) or a natural granzyme B blocker (serpina3N) improved survival of MO3.13 cells upon coculture with Th17 cells. In conclusion, we showed that human Th17-polarized cells form biologically significant contacts with human OLs and exert direct toxicity by releasing granzyme B., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jamann, Cui, Desu, Pernin, Tastet, Halaweh, Farzam-kia, Mamane, Ouédraogo, Cleret-Buhot, Daigneault, Balthazard, Klement, Lemaître, Arbour, Antel, Stratton and Larochelle.) more...- Published
- 2022
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26. DICAM promotes T H 17 lymphocyte trafficking across the blood-brain barrier during autoimmune neuroinflammation.
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Charabati M, Grasmuck C, Ghannam S, Bourbonnière L, Fournier AP, Lécuyer MA, Tastet O, Kebir H, Rébillard RM, Hoornaert C, Gowing E, Larouche S, Fortin O, Pittet C, Filali-Mouhim A, Lahav B, Moumdjian R, Bouthillier A, Girard M, Duquette P, Cayrol R, Peelen E, Quintana FJ, Antel JP, Flügel A, Larochelle C, Arbour N, Zandee S, and Prat A more...
- Subjects
- Animals, Blood-Brain Barrier metabolism, Cell Adhesion Molecules metabolism, Humans, Mice, Natalizumab metabolism, Natalizumab pharmacology, Natalizumab therapeutic use, Neuroinflammatory Diseases, T-Lymphocytes metabolism, Th17 Cells, Multiple Sclerosis drug therapy, Multiple Sclerosis metabolism, Multiple Sclerosis, Relapsing-Remitting
- Abstract
The migration of circulating leukocytes into the central nervous system (CNS) is a key driver of multiple sclerosis (MS) pathogenesis. The monoclonal antibody natalizumab proved that pharmaceutically obstructing this process is an effective therapeutic approach for treating relapsing-remitting MS (RRMS). Unfortunately, the clinical efficacy of natalizumab is somewhat offset by its incapacity to control the progressive forms of MS (PMS) and by life-threatening side effects in RRMS rising from the expression of its molecular target, very late antigen 4 (VLA4), on most immune cells and consequent impairment of CNS immunosurveillance. Here, we identified dual immunoglobulin domain containing cell adhesion molecule (DICAM) as a cell trafficking molecule preferentially expressed by T helper 17 (T
H 17)–polarized CD4+ T lymphocytes. We found that DICAM expression on circulating CD4+ T cells was increased in patients with active RRMS and PMS disease courses, and expression of DICAM ligands was increased on the blood-brain barrier endothelium upon inflammation and in MS lesions. Last, we demonstrated that pharmaceutically neutralizing DICAM reduced murine and human TH 17 cell trafficking across the blood-brain barrier in vitro and in vivo, and alleviated disease symptoms in four distinct murine autoimmune encephalomyelitis models, including relapsing-remitting and progressive disease models. Collectively, our data highlight DICAM as a candidate therapeutic target to impede the migration of disease-inducing leukocytes into the CNS in both RRMS and PMS and suggest that blocking DICAM with a monoclonal antibody may be a promising therapeutic approach. more...- Published
- 2022
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27. Temporal associations of B and T cell immunity with robust vaccine responsiveness in a 16-week interval BNT162b2 regimen.
- Author
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Nayrac M, Dubé M, Sannier G, Nicolas A, Marchitto L, Tastet O, Tauzin A, Brassard N, Beaudoin-Bussières G, Vézina D, Gong SY, Benlarbi M, Gasser R, Laumaea A, Bourassa C, Gendron-Lepage G, Medjahed H, Goyette G, Ortega-Delgado GG, Laporte M, Niessl J, Gokool L, Morrisseau C, Arlotto P, Richard J, Tremblay C, Martel-Laferrière V, Finzi A, and Kaufmann DE more...
- Abstract
Spacing of the BNT162b2 mRNA doses beyond 3 weeks raised concerns about vaccine efficacy. We longitudinally analyzed B cell, T cell and humoral responses to two BNT162b2 mRNA doses administered 16 weeks apart in 53 SARS-CoV-2 naïve and previously-infected donors. This regimen elicited robust RBD-specific B cell responses whose kinetics differed between cohorts, the second dose leading to increased magnitude in naïve participants only. While boosting did not increase magnitude of CD4
+ T cell responses further compared to the first dose, unsupervised clustering analyses of single-cell features revealed phenotypic and functional shifts over time and between cohorts. Integrated analysis showed longitudinal immune component-specific associations, with early Thelper responses post-first dose correlating with B cell responses after the second dose, and memory Thelper generated between doses correlating with CD8 T cell responses after boosting. Therefore, boosting elicits a robust cellular recall response after the 16-week interval, indicating functional immune memory. more...- Published
- 2021
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28. IL-17A reprograms intestinal epithelial cells to facilitate HIV-1 replication and outgrowth in CD4+ T cells.
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Wiche Salinas TR, Gosselin A, Raymond Marchand L, Moreira Gabriel E, Tastet O, Goulet JP, Zhang Y, Vlad D, Touil H, Routy JP, Bego MG, El-Far M, Chomont N, Landay AL, Cohen ÉA, Tremblay C, and Ancuta P more...
- Abstract
The crosstalk between intestinal epithelial cells (IECs) and Th17-polarized CD4
+ T cells is critical for mucosal homeostasis, with HIV-1 causing significant alterations in people living with HIV (PLWH) despite antiretroviral therapy (ART). In a model of IEC and T cell co-cultures, we investigated the effects of IL-17A, the Th17 hallmark cytokine, on IEC ability to promote de novo HIV infection and viral reservoir reactivation . Our results demonstrate that IL-17A acts in synergy with TNF to boost IEC production of CCL20, a Th17-attractant chemokine, and promote HIV trans -infection of CD4+ T cells and viral outgrowth from reservoir cells of ART-treated PLWH. Importantly, the Illumina RNA-sequencing revealed an IL-17A-mediated pro-inflammatory and pro-viral molecular signature, including a decreased expression of type I interferon (IFN-I)-induced HIV restriction factors. These findings point to the deleterious features of IL-17A and raise awareness for caution when designing therapies aimed at restoring the paucity of mucosal Th17 cells in ART-treated PLWH., Competing Interests: The authors declare no competing interests., (Crown Copyright © 2021.) more...- Published
- 2021
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29. Pro-inflammatory T helper 17 directly harms oligodendrocytes in neuroinflammation.
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Larochelle C, Wasser B, Jamann H, Löffel JT, Cui QL, Tastet O, Schillner M, Luchtman D, Birkenstock J, Stroh A, Antel J, Bittner S, and Zipp F
- Subjects
- Animals, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Encephalomyelitis, Autoimmune, Experimental metabolism, Encephalomyelitis, Autoimmune, Experimental pathology, Freund's Adjuvant, Inflammation, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Oligodendroglia metabolism, Pertussis Toxin toxicity, Encephalomyelitis, Autoimmune, Experimental chemically induced, Myelin-Oligodendrocyte Glycoprotein pharmacology, Oligodendroglia drug effects, Th17 Cells physiology
- Abstract
T helper (Th)17 cells are considered to contribute to inflammatory mechanisms in diseases such as multiple sclerosis (MS). However, the discussion persists regarding their true role in patients. Here, we visualized central nervous system (CNS) inflammatory processes in models of MS live in vivo and in MS brains and discovered that CNS-infiltrating Th17 cells form prolonged stable contact with oligodendrocytes. Strikingly, compared to Th2 cells, direct contact with Th17 worsened experimental demyelination, caused damage to human oligodendrocyte processes, and increased cell death. Importantly, we found that in comparison to Th2 cells, both human and murine Th17 cells express higher levels of the integrin CD29, which is linked to glutamate release pathways. Of note, contact of human Th17 cells with oligodendrocytes triggered release of glutamate, which induced cell stress and changes in biosynthesis of cholesterol and lipids, as revealed by single-cell RNA-sequencing analysis. Finally, exposure to glutamate decreased myelination, whereas blockade of CD29 preserved oligodendrocyte processes from Th17-mediated injury. Our data provide evidence for the direct and deleterious attack of Th17 cells on the myelin compartment and show the potential for therapeutic opportunities in MS., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.) more...
- Published
- 2021
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30. A single dose of the SARS-CoV-2 vaccine BNT162b2 elicits Fc-mediated antibody effector functions and T cell responses.
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Tauzin A, Nayrac M, Benlarbi M, Gong SY, Gasser R, Beaudoin-Bussières G, Brassard N, Laumaea A, Vézina D, Prévost J, Anand SP, Bourassa C, Gendron-Lepage G, Medjahed H, Goyette G, Niessl J, Tastet O, Gokool L, Morrisseau C, Arlotto P, Stamatatos L, McGuire AT, Larochelle C, Uchil P, Lu M, Mothes W, De Serres G, Moreira S, Roger M, Richard J, Martel-Laferrière V, Duerr R, Tremblay C, Kaufmann DE, and Finzi A more...
- Subjects
- Adult, Antibodies, Neutralizing immunology, Antibodies, Viral chemistry, BNT162 Vaccine, Betacoronavirus, COVID-19 prevention & control, Carrier Proteins, Female, Humans, Immunity, Immunoglobulin Fc Fragments, Male, Middle Aged, Vaccination, Vaccines, Synthetic immunology, Young Adult, mRNA Vaccines, Antibodies, Viral immunology, COVID-19 immunology, COVID-19 Vaccines administration & dosage, COVID-19 Vaccines immunology, SARS-CoV-2 immunology, T-Lymphocytes immunology
- Abstract
While the standard regimen of the BNT162b2 mRNA vaccine for SARS-CoV-2 includes two doses administered 3 weeks apart, some public health authorities are spacing these doses, raising concerns about efficacy. However, data indicate that a single dose can be up to 90% effective starting 14 days post-administration. To assess the mechanisms contributing to protection, we analyzed humoral and T cell responses three weeks after a single BNT162b2 dose. We observed weak neutralizing activity elicited in SARS-CoV-2 naive individuals but strong anti-receptor binding domain and spike antibodies with Fc-mediated effector functions and cellular CD4
+ T cell responses. In previously infected individuals, a single dose boosted all humoral and T cell responses, with strong correlations between T helper and antibody immunity. Our results highlight the potential role of Fc-mediated effector functions and T cell responses in vaccine efficacy. They also provide support for spacing doses to vaccinate more individuals in conditions of vaccine scarcity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.) more...- Published
- 2021
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31. Capturing T Lymphocytes' Dynamic Interactions With Human Neural Cells Using Time-Lapse Microscopy.
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Lemaître F, Carmena Moratalla A, Farzam-Kia N, Carpentier Solorio Y, Tastet O, Cleret-Buhot A, Guimond JV, Haddad E, and Arbour N
- Subjects
- Adult, Astrocytes drug effects, Astrocytes immunology, CD8-Positive T-Lymphocytes immunology, Cell Movement, Cells, Cultured, Coculture Techniques, Female, Histocompatibility Antigens Class I immunology, Humans, Inflammation immunology, Interleukin-1beta pharmacology, Male, Middle Aged, Neurons drug effects, Neurons immunology, Phenotype, Time Factors, Young Adult, Astrocytes physiology, CD8-Positive T-Lymphocytes physiology, Cell Communication drug effects, Microscopy, Video, Neurons metabolism, Time-Lapse Imaging
- Abstract
To fully perform their functions, T lymphocytes migrate within organs' parenchyma and interact with local cells. Infiltration of T lymphocytes within the central nervous system (CNS) is associated with numerous neurodegenerative disorders. Nevertheless, how these immune cells communicate and respond to neural cells remains unresolved. To investigate the behavior of T lymphocytes that reach the CNS, we have established an in vitro co-culture model and analyzed the spatiotemporal interactions between human activated CD8
+ T lymphocytes and primary human astrocytes and neurons using time-lapse microscopy. By combining multiple variables extracted from individual CD8+ T cell tracking, we show that CD8+ T lymphocytes adopt a more motile and exploratory behavior upon interacting with astrocytes than with neurons. Pretreatment of astrocytes or neurons with IL-1β to mimic in vivo inflammation significantly increases CD8+ T lymphocyte motility. Using visual interpretation and analysis of numerical variables extracted from CD8+ T cell tracking, we identified four distinct CD8+ T lymphocyte behaviors: scanning, dancing, poking and round. IL-1β-pretreatment significantly increases the proportion of scanning CD8+ T lymphocytes, which are characterized by active exploration, and reduces the proportion of round CD8+ T lymphocytes, which are less active. Blocking MHC class I on astrocytes significantly diminishes the proportion of poking CD8+ T lymphocytes, which exhibit synapse-like interactions. Lastly, our co-culture time-lapse model is easily adaptable and sufficiently sensitive and powerful to characterize and quantify spatiotemporal interactions between human T lymphocytes and primary human cells in different conditions while preserving viability of fragile cells such as neurons and astrocytes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lemaître, Carmena Moratalla, Farzam-kia, Carpentier Solorio, Tastet, Cleret-Buhot, Guimond, Haddad and Arbour.) more...- Published
- 2021
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32. Identification of SARS-CoV-2-specific immune alterations in acutely ill patients.
- Author
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Rébillard RM, Charabati M, Grasmuck C, Filali-Mouhim A, Tastet O, Brassard N, Daigneault A, Bourbonnière L, Anand SP, Balthazard R, Beaudoin-Bussières G, Gasser R, Benlarbi M, Moratalla AC, Solorio YC, Boutin M, Farzam-Kia N, Descôteaux-Dinelle J, Fournier AP, Gowing E, Laumaea A, Jamann H, Lahav B, Goyette G, Lemaître F, Mamane VH, Prévost J, Richard J, Thai K, Cailhier JF, Chomont N, Finzi A, Chassé M, Durand M, Arbour N, Kaufmann DE, Prat A, and Larochelle C more...
- Subjects
- Acute Disease, Adult, Aged, B-Lymphocyte Subsets immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, COVID-19 epidemiology, COVID-19 mortality, Case-Control Studies, Cohort Studies, Female, Hospitalization, Humans, Lymphocyte Activation, Male, Middle Aged, Models, Immunological, Monocytes immunology, Multivariate Analysis, Neutrophils immunology, Pandemics, Prognosis, Prospective Studies, Quebec epidemiology, Risk Factors, Severity of Illness Index, COVID-19 immunology, Leukocytes classification, Leukocytes immunology, SARS-CoV-2 immunology
- Abstract
Dysregulated immune profiles have been described in symptomatic patients infected with SARS-CoV-2. Whether the reported immune alterations are specific to SARS-CoV-2 infection or also triggered by other acute illnesses remains unclear. We performed flow cytometry analysis on fresh peripheral blood from a consecutive cohort of (a) patients hospitalized with acute SARS-CoV-2 infection, (b) patients of comparable age and sex hospitalized for another acute disease (SARS-CoV-2 negative), and (c) healthy controls. Using both data-driven and hypothesis-driven analyses, we found several dysregulations in immune cell subsets (e.g., decreased proportion of T cells) that were similarly associated with acute SARS-CoV-2 infection and non-COVID-19-related acute illnesses. In contrast, we identified specific differences in myeloid and lymphocyte subsets that were associated with SARS-CoV-2 status (e.g., elevated proportion of ICAM-1+ mature/activated neutrophils, ALCAM+ monocytes, and CD38+CD8+ T cells). A subset of SARS-CoV-2-specific immune alterations correlated with disease severity, disease outcome at 30 days, and mortality. Our data provide an understanding of the immune dysregulation specifically associated with SARS-CoV-2 infection among acute care hospitalized patients. Our study lays the foundation for the development of specific biomarkers to stratify SARS-CoV-2-positive patients at risk of unfavorable outcomes and to uncover candidate molecules to investigate from a therapeutic perspective. more...
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- 2021
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33. A single BNT162b2 mRNA dose elicits antibodies with Fc-mediated effector functions and boost pre-existing humoral and T cell responses.
- Author
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Tauzin A, Nayrac M, Benlarbi M, Gong SY, Gasser R, Beaudoin-Bussières G, Brassard N, Laumaea A, Vézina D, Prévost J, Anand SP, Bourassa C, Gendron-Lepage G, Medjahed H, Goyette G, Niessl J, Tastet O, Gokool L, Morrisseau C, Arlotto P, Stamatatos L, McGuire AT, Larochelle C, Uchil P, Lu M, Mothes W, Serres G, Moreira S, Roger M, Richard J, Martel-Laferrière V, Duerr R, Tremblay C, Kaufmann DE, and Finzi A more...
- Abstract
The standard dosing of the Pfizer/BioNTech BNT162b2 mRNA vaccine validated in clinical trials includes two doses administered three weeks apart. While the decision by some public health authorities to space the doses because of limiting supply has raised concerns about vaccine efficacy, data indicate that a single dose is up to 90% effective starting 14 days after its administration. We analyzed humoral and T cells responses three weeks after a single dose of this mRNA vaccine. Despite the proven efficacy of the vaccine at this time point, no neutralizing activity were elicited in SARS-CoV-2 naïve individuals. However, we detected strong anti-receptor binding domain (RBD) and Spike antibodies with Fc-mediated effector functions and cellular responses dominated by the CD4
+ T cell component. A single dose of this mRNA vaccine to individuals previously infected by SARS-CoV-2 boosted all humoral and T cell responses measured, with strong correlations between T helper and antibody immunity. Neutralizing responses were increased in both potency and breadth, with distinctive capacity to neutralize emerging variant strains. Our results highlight the importance of vaccinating uninfected and previously-infected individuals and shed new light into the potential role of Fc-mediated effector functions and T cell responses in vaccine efficacy. They also provide support to spacing the doses of two-vaccine regimens to vaccinate a larger pool of the population in the context of vaccine scarcity against SARS-CoV-2. more...- Published
- 2021
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34. The IL-27/IL-27R axis is altered in CD4 + and CD8 + T lymphocytes from multiple sclerosis patients.
- Author
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Clénet ML, Laurent C, Lemaitre F, Farzam-Kia N, Tastet O, Devergne O, Lahav B, Girard M, Duquette P, Prat A, Larochelle C, and Arbour N
- Abstract
Objectives: Pro- and anti-inflammatory properties have been attributed to interleukin-27 (IL-27). Nevertheless, the impact of this cytokine on chronic inflammatory diseases such as multiple sclerosis (MS) remains ill-defined. We investigated the biology of IL-27 and its specific receptor IL-27Rα in MS patients., Methods: Levels of IL-27 and its natural antagonist (IL-27-Rα) were measured by ELISA in biological fluids. CD4
+ and CD8+ T lymphocytes were isolated from untreated relapsing-remitting MS patients and healthy donors. Transcriptome-wide analysis compared T-cell subsets stimulated or not with IL-27. Expression of the IL-27Rα, key immune factors, STAT phosphorylation and cytokine production was assessed by flow cytometry., Results: We observed elevated levels of IL-27 in the serum and cerebrospinal fluid of MS patients compared with controls. Moreover, we show that specific IL-27-mediated effects on T lymphocytes are reduced in MS patients including the induction of PD-L1. IL-27-triggered STAT3 signalling pathway is enhanced in CD4+ and CD8+ T lymphocytes from MS patients. Elevated IL-27Rα levels in serum from MS patients are sufficient to impair the capacity of IL-27 to act on immune cells. We demonstrate that shedding of IL-27Rα by activated CD4+ T lymphocytes from MS patients contributes to the increased IL-27Rα peripheral levels and consequently can dampen the IL-27 responsiveness., Conclusion: Our work identifies several mechanisms that are altered in the IL-27/IL-27R axis in MS patients, especially in T lymphocytes. Our results underline the importance of characterising the biology of cytokines in human patients prior to design new therapeutics., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.) more...- Published
- 2021
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35. Interleukin-26, preferentially produced by T H 17 lymphocytes, regulates CNS barrier function.
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Broux B, Zandee S, Gowing E, Charabati M, Lécuyer MA, Tastet O, Hachehouche L, Bourbonnière L, Ouimet JP, Lemaitre F, Larouche S, Cayrol R, Bouthillier A, Moumdjian R, Lahav B, Poirier J, Duquette P, Arbour N, Peelen E, and Prat A more...
- Subjects
- Animals, Cells, Cultured, Encephalomyelitis, Autoimmune, Experimental drug therapy, Endothelium, Vascular metabolism, Fetus, Humans, Interleukins blood, Interleukins cerebrospinal fluid, Interleukins pharmacology, Mice, Multiple Sclerosis blood, Multiple Sclerosis cerebrospinal fluid, Blood-Brain Barrier metabolism, Encephalomyelitis, Autoimmune, Experimental metabolism, Interleukins metabolism, Multiple Sclerosis metabolism, Th17 Cells metabolism
- Abstract
Objective: To investigate the involvement of interleukin (IL)-26 in neuroinflammatory processes in multiple sclerosis (MS), in particular in blood-brain barrier (BBB) integrity., Methods: Expression of IL-26 was measured in serum, CSF, in vitro differentiated T helper (T
H ) cell subsets, and postmortem brain tissue of patients with MS and controls by ELISA, quantitative PCR, and immunohistochemistry. Primary human and mouse BBB endothelial cells (ECs) were treated with IL-26 in vitro and assessed for BBB integrity. RNA sequencing was performed on IL-26-treated human BBB ECs. Myelin oligodendrocyte glycoprotein35-55 experimental autoimmune encephalomyelitis (EAE) mice were injected IP with IL-26. BBB leakage and immune cell infiltration were assessed in the CNS of these mice using immunohistochemistry and flow cytometry., Results: IL-26 expression was induced in TH lymphocytes by TH 17-inducing cytokines and was upregulated in the blood and CSF of patients with MS. CD4+ IL-26+ T lymphocytes were found in perivascular infiltrates in MS brain lesions, and both receptor chains for IL-26 (IL-10R2 and IL-20R1) were detected on BBB ECs in vitro and in situ. In contrast to IL-17 and IL-22, IL-26 promoted integrity and reduced permeability of BBB ECs in vitro and in vivo. In EAE, IL-26 reduced disease severity and proinflammatory lymphocyte infiltration into the CNS, while increasing infiltration of Tregs., Conclusions: Our study demonstrates that although IL-26 is preferentially expressed by TH 17 lymphocytes, it promotes BBB integrity in vitro and in vivo and is protective in chronic EAE, highlighting the functional diversity of cytokines produced by TH 17 lymphocytes., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.) more...- Published
- 2020
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36. IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease.
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Abadie V, Kim SM, Lejeune T, Palanski BA, Ernest JD, Tastet O, Voisine J, Discepolo V, Marietta EV, Hawash MBF, Ciszewski C, Bouziat R, Panigrahi K, Horwath I, Zurenski MA, Lawrence I, Dumaine A, Yotova V, Grenier JC, Murray JA, Khosla C, Barreiro LB, and Jabri B more...
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, Female, HLA-DQ Antigens genetics, Humans, Interferon-gamma immunology, Interleukin-15 genetics, Male, Mice, Mice, Transgenic, Microfilament Proteins genetics, Microfilament Proteins metabolism, Celiac Disease immunology, Celiac Disease pathology, Glutens immunology, HLA-DQ Antigens immunology, Interleukin-15 immunology
- Abstract
Coeliac disease is a complex, polygenic inflammatory enteropathy caused by exposure to dietary gluten that occurs in a subset of genetically susceptible individuals who express either the HLA-DQ8 or HLA-DQ2 haplotypes
1,2 . The need to develop non-dietary treatments is now widely recognized3 , but no pathophysiologically relevant gluten- and HLA-dependent preclinical model exists. Furthermore, although studies in humans have led to major advances in our understanding of the pathogenesis of coeliac disease4 , the respective roles of disease-predisposing HLA molecules, and of adaptive and innate immunity in the development of tissue damage, have not been directly demonstrated. Here we describe a mouse model that reproduces the overexpression of interleukin-15 (IL-15) in the gut epithelium and lamina propria that is characteristic of active coeliac disease, expresses the predisposing HLA-DQ8 molecule, and develops villous atrophy after ingestion of gluten. Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease. In addition, CD4+ T cells and HLA-DQ8 have a crucial role in the licensing of cytotoxic T cells to mediate intestinal epithelial cell lysis. We also demonstrate a role for the cytokine interferon-γ (IFNγ) and the enzyme transglutaminase 2 (TG2) in tissue destruction. By reflecting the complex interaction between gluten, genetics and IL-15-driven tissue inflammation, this mouse model provides the opportunity to both increase our understanding of coeliac disease, and develop new therapeutic strategies. more...- Published
- 2020
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37. Identification of a γc Receptor Antagonist That Prevents Reprogramming of Human Tissue-resident Cytotoxic T Cells by IL15 and IL21.
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Ciszewski C, Discepolo V, Pacis A, Doerr N, Tastet O, Mayassi T, Maglio M, Basheer A, Al-Mawsawi LQ, Green PHR, Auricchio R, Troncone R, Waldmann TA, Azimi N, Tagaya Y, Barreiro LB, and Jabri B
- Subjects
- Case-Control Studies, Celiac Disease immunology, Cell Line, Cell Proliferation drug effects, Cellular Reprogramming drug effects, Duodenum pathology, Humans, Interleukin-15 genetics, Interleukins genetics, Primary Cell Culture, RNA, Messenger, Receptors, Interleukin-15 genetics, Signal Transduction drug effects, Transcription, Genetic drug effects, Benzodiazepines pharmacology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes physiology, Interleukin Receptor Common gamma Subunit antagonists & inhibitors, Interleukin-15 pharmacology, Interleukins pharmacology
- Abstract
Background & Aims: Gamma chain (γc) cytokines (interleukin [IL]2, IL4, IL7, IL9, IL15, and IL21) signal via a common γc receptor. IL2 regulates the immune response, whereas IL21 and IL15 contribute to development of autoimmune disorders, including celiac disease. We investigated whether BNZ-2, a peptide designed to inhibit IL15 and IL21, blocks these cytokines selectively and its effects on intraepithelial cytotoxic T cells., Methods: We obtained duodenal biopsies from 9 patients with potential celiac disease (positive results from tests for anti-TG2 but no villous atrophy), 30 patients with untreated celiac disease (with villous atrophy), and 5 patients with treated celiac disease (on a gluten-free diet), as well as 43 individuals without celiac disease (controls). We stimulated primary intestinal intraepithelial CD8
+ T-cell lines, or CD8+ T cells directly isolated from intestinal biopsies, with γc cytokines in presence or absence of BNZ-2. Cells were analyzed by immunoblots, flow cytometry, or RNA-sequencing analysis for phosphorylation of signaling molecules, gene expression profiles, proliferation, and levels of granzyme B., Results: Duodenal tissues from patients with untreated celiac disease had increased levels of messenger RNAs encoding IL15 receptor subunit alpha (IL15RA) and IL21 compared with tissues from patients with potential celiac disease and controls. Activation of intraepithelial cytotoxic T cells with IL15 or IL21 induced separate signaling pathways; incubation of the cells with IL15 and IL21 cooperatively increased their transcriptional activity, proliferation, and cytolytic properties. BNZ-2 specifically inhibited the effects of IL15 and IL21, but not of other γc cytokines., Conclusions: We found increased expression of IL15RA and IL21 in duodenal tissues from patients with untreated celiac disease compared with controls. IL15 and IL21 cooperatively activated intestinal intraepithelial cytotoxic T cells. In particular, they increased their transcriptional activity, proliferation, and cytolytic activity. The peptide BNZ-2 blocked these effects, but not those of other γc cytokines, including IL2. BNZ-2 might be used to prevent cytotoxic T-cell-mediated tissue damage in complex immune disorders exhibiting upregulation of IL15 and IL21., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.) more...- Published
- 2020
- Full Text
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