56 results on '"Oliver J. Harrison"'
Search Results
2. A cost analysis of robotic vs. video-assisted thoracic surgery: The impact of the learning curve and the COVID-19 pandemic
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Oliver J. Harrison, Alessandro Maraschi, Tom Routledge, Savvas Lampridis, Corinne LeReun, and Andrea Bille
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lung cancer ,robot—assisted thoracic surgery ,video assisted thoracic surgery ,cost analyses ,COVID—19 ,learning curve ,Surgery ,RD1-811 - Abstract
IntroductionRobot-assisted thoracoscopic surgery (RATS) is an alternative to video-assessed thoracoscopic surgery (VATS) for the treatment of lung cancer but concern exists regarding the high associated costs. The COVID-19 pandemic added further financial pressure to healthcare systems. This study investigated the impact of the learning curve on the cost-effectiveness of RATS lung resection and the financial impact of the COVID-19 pandemic on a RATS program.MethodsPatients undergoing RATS lung resection between January 2017 and December 2020 were prospectively followed. A matched cohort of VATS cases were analyzed in parallel. The first 100 and most recent 100 RATS cases performed at our institution were compared to assess the learning curve. Cases performed before and after March 2020 were compared to assess the impact of the COVID-19 pandemic. A comprehensive cost analysis of multiple theatre and postoperative data points was performed using Stata statistics package (v14.2).Results365 RATS cases were included. Median cost per procedure was £7,167 and theatre cost accounted for 70%. Major contributing factors to overall cost were operative time and postoperative length of stay. Cost per case was £640 less after passing the learning curve (p
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- 2023
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3. Combined minimally invasive resection of thoracic neurogenic dumbbell tumors: A European case series
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Oliver J. Harrison, Adnan Bakir, Martin H. Chamberlain, Ali Nader‐Sepahi, and Khalid M. Amer
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minimally invasive surgery ,neurogenic thoracic tumors ,surgical oncology ,video‐assisted thoracoscopic surgery ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Paraspinal tumors are rare neoplasms arising from neurogenic elements of the posterior mediastinum and surgical resection can be challenging. Here, we demonstrate feasibility and outcomes from the first European case series of combined laminectomy and video‐assisted thoracoscopic surgery (VATS) resection of thoracic neurogenic dumbbell tumors. Methods A retrospective review of all combined thoracic dumbbell tumor resections performed at our institution between March 2015 to February 2019 was undertaken. Outcomes included operative time, blood loss, length of stay and recurrence rate. Statistical analysis was performed with SPSS statistics (v26). Values are given as mean ± standard deviation and median ± interquartile range. Results Seven patients were included in the case series and there were no major complications or mortality. Mean tumor size and operative time were 66 (± 35) mm and 171 (± 63) min, respectively. Median blood loss and length of stay were 40 (± 70) ml and four (± 3) days, respectively. One patient required conversion to thoracotomy to remove a tumor of 135 mm in maximal dimension. Histology in all seven cases confirmed schwannoma. There was no disease recurrence at a maximum follow‐up of 54 months. Conclusions Our experience demonstrates favorable operative times, minimal blood loss and short length of stay when dealing with relatively large tumors compared to previous reports. Thoracotomy may be required for tumors exceeding 90 mm and chest drain removal on the operative day can facilitate early mobility and discharge. We advocate a combined, minimally invasive laminectomy and VATS resection as the gold‐standard approach for thoracic neurogenic dumbbell tumors.
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- 2021
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4. Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-Protocadherins
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Oliver J. Harrison, Julia Brasch, Phinikoula S. Katsamba, Goran Ahlsen, Alex J. Noble, Hanbin Dan, Rosemary V. Sampogna, Clinton S. Potter, Bridget Carragher, Barry Honig, and Lawrence Shapiro
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Biology (General) ,QH301-705.5 - Abstract
Summary: Non-clustered δ1- and δ2-protocadherins, close relatives of clustered protocadherins, function in cell adhesion and motility and play essential roles in neural patterning. To understand the molecular interactions underlying these functions, we used solution biophysics to characterize binding of δ1- and δ2-protocadherins, determined crystal structures of ectodomain complexes from each family, and assessed ectodomain assembly in reconstituted intermembrane junctions by cryoelectron tomography (cryo-ET). Homophilic trans (cell–cell) interactions were preferred for all δ-protocadherins, with additional weaker heterophilic interactions observed exclusively within each subfamily. As expected, δ1- and δ2-protocadherin trans dimers formed through antiparallel EC1–EC4 interfaces, like clustered protocadherins. However, no ectodomain-mediated cis (same-cell) interactions were detectable in solution; consistent with this, cryo-ET of reconstituted junctions revealed dense assemblies lacking the characteristic order observed for clustered protocadherins. Our results define non-clustered protocadherin binding properties and their structural basis, providing a foundation for interpreting their functional roles in neural patterning. : Non-clustered δ-protocadherins are adhesion molecules linked to a number of neurological disorders. Harrison et al. apply biophysical and structural methods across the family to show preferential self-binding through a canonical interface and disordered assemblies of adhesive dimers between membranes that diverge from ordered assemblies of close relatives clustered protocadherins. Keywords: cell adhesion, non-clustered protocadherins, cadherin, X-ray crystallography, cryo-electron tomography, homophilic adhesion, neuronal cell adhesion
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- 2020
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5. Candidate plasma biomarkers for predicting ascending aortic aneurysm in bicuspid aortic valve disease
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Oliver J. Harrison, Felino Cagampang, Sunil K. Ohri, Christopher Torrens, Kareem Salhiyyah, Amit Modi, Narain Moorjani, Anthony D. Whetton, and Paul A. Townsend
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Bicuspid aortic valve ,Ascending aortic aneurysm ,Plasma biomarker ,Risk prediction ,Surgery ,RD1-811 ,Anesthesiology ,RD78.3-87.3 - Abstract
Abstract Background Bicuspid aortic valve (BAV) disease is the most common congenital cardiac abnormality affecting 1–2% of the population and is associated with a significantly increased risk of ascending aortic aneurysm. However, predicting which patients will develop aneurysms remains a challenge. This pilot study aimed to identify candidate plasma biomarkers for monitoring ascending aortic diameter and predicting risk of future aneurysm in BAV patients. Methods Plasma samples were collected pre-operatively from BAV patients undergoing aortic valve surgery. Maximum ascending aortic diameter was measured on pre-operative transoesophageal echocardiography. Maximum diameter ≥ 45 mm was classified as aneurysmal. Sequential Window Acquisition of all THeoretical Mass Spectra (SWATH-MS), an advanced mass spectrometry technique, was used to identify and quantify all proteins within the samples. Protein abundance and aortic diameter were correlated using logistic regression. Levene’s test was used to identify proteins demonstrating low abundance variability in the aneurysmal patients (consistent expression in disease), and high variability in the non-aneurysmal patients (differential expression between ‘at risk’ and not ‘at risk’ patients). Results Fifteen plasma samples were collected (seven non-aneurysmal and 8 aneurysmal BAV patients). The mean age of the patients was 55.5 years and the majority were female (10/15, 67%). Four proteins (haemoglobin subunits alpha, beta and delta and mannan-binding lectin serine protease) correlated significantly with maximal ascending aortic diameter (p
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- 2018
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6. Homophilic and Heterophilic Interactions of Type II Cadherins Identify Specificity Groups Underlying Cell-Adhesive Behavior
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Julia Brasch, Phinikoula S. Katsamba, Oliver J. Harrison, Göran Ahlsén, Regina B. Troyanovsky, Indrajyoti Indra, Anna Kaczynska, Benjamin Kaeser, Sergey Troyanovsky, Barry Honig, and Lawrence Shapiro
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Biology (General) ,QH301-705.5 - Abstract
Summary: Type II cadherins are cell-cell adhesion proteins critical for tissue patterning and neuronal targeting but whose molecular binding code remains poorly understood. Here, we delineate binding preferences for type II cadherin cell-adhesive regions, revealing extensive heterophilic interactions between specific pairs, in addition to homophilic interactions. Three distinct specificity groups emerge from our analysis with members that share highly similar heterophilic binding patterns and favor binding to one another. Structures of adhesive fragments from each specificity group confirm near-identical dimer topology conserved throughout the family, allowing interface residues whose conservation corresponds to specificity preferences to be identified. We show that targeted mutation of these residues converts binding preferences between specificity groups in biophysical and co-culture assays. Our results provide a detailed understanding of the type II cadherin interaction map and a basis for defining their role in tissue patterning and for the emerging importance of their heterophilic interactions in neural connectivity. : Type II cadherins are a family of vertebrate cell adhesion proteins expressed primarily in the CNS. Brasch et al. measure binding between adhesive fragments, revealing homophilic and extensive selective heterophilic binding with specificities that define groups of similar cadherins. Structures reveal common adhesive dimers, with residues governing cell-adhesive specificity. Keywords: cell adhesion, crystal structure, hemophilic specificity, heterophilic specificity, neural patterning, synaptic targeting, cadherin
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- 2018
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7. T-bet is a key modulator of IL-23-driven pathogenic CD4+ T cell responses in the intestine
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Thomas Krausgruber, Chris Schiering, Krista Adelmann, Oliver J. Harrison, Agnieszka Chomka, Claire Pearson, Philip P. Ahern, Matthew Shale, Mohamed Oukka, and Fiona Powrie
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Science - Abstract
How transcription factor T-bet and Th17 cells contribute to colitis remains incompletely understood. Here the authors identify T-bet as a negative regulator of IL-23R pathway activation and show that T-bet deficient T cells drive colitogenic Th17 responses dependent on the cytokines IL-17A and IL-22.
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- 2016
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8. Computational model of E-cadherin clustering under force
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Oliver J. Harrison, Yang Chen, Julia Brasch, and Tamara C. Bidone
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Cadherin ,Chemistry ,Biophysics ,Actomyosin ,Articles ,Adhesion ,Cadherins ,Mechanotransduction, Cellular ,Cell Adhesion ,Brownian dynamics ,Extracellular ,Cluster Analysis ,Mechanotransduction ,Cytoskeleton ,Cluster analysis ,Intracellular - Abstract
E-cadherins play a critical role in the formation of cell-cell adhesions for several physiological functions, including tissue development, repair, and homeostasis. The formation of clusters of E-cadherins involves extracellular adhesive (trans-) and lateral (cis-) associations between E-cadherin ectodomains and stabilization through intracellular binding to the actomyosin cytoskeleton. This binding provides force to the adhesion and is required for mechanotransduction. However, the exact role of cytoskeletal force on the clustering of E-cadherins is not well understood. To gain insights into this mechanism, we developed a computational model based on Brownian dynamics. In the model, E-cadherins transit between structural and functional states; they are able to bind and unbind other E-cadherins on the same and/or opposite cell(s) through trans- and cis-interactions while also creating dynamic links with the actomyosin cytoskeleton. Our results show that actomyosin force governs the fraction of E-cadherins in clusters and the size and number of clusters. For low forces (below 10 pN), a large number of small E-cadherin clusters form with less than five E-cadherins each. At higher forces, the probability of forming fewer but larger clusters increases. These findings support the idea that force reinforces cell-cell adhesions, which is consistent with differences in cluster size previously observed between apical and lateral junctions of epithelial tissues.
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- 2021
9. Combined minimally invasive resection of thoracic neurogenic dumbbell tumors: A European case series
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Ali Nader-Sepahi, Oliver J Harrison, Martin H. Chamberlain, Khalid Amer, and Adnan Bakir
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Pulmonary and Respiratory Medicine ,Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Schwannoma ,Mediastinal Neoplasms ,Resection ,surgical oncology ,Interquartile range ,Surgical oncology ,medicine ,Humans ,Minimally Invasive Surgical Procedures ,Thoracotomy ,video‐assisted thoracoscopic surgery ,RC254-282 ,minimally invasive surgery ,Aged ,Retrospective Studies ,business.industry ,Thoracic Surgery, Video-Assisted ,Laminectomy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,General Medicine ,Original Articles ,Middle Aged ,Thoracic Neoplasms ,medicine.disease ,Surgery ,neurogenic thoracic tumors ,Oncology ,Video-assisted thoracoscopic surgery ,Original Article ,Female ,Dumbbell ,business ,Neurilemmoma - Abstract
Background Paraspinal tumors are rare neoplasms arising from neurogenic elements of the posterior mediastinum and surgical resection can be challenging. Here, we demonstrate feasibility and outcomes from the first European case series of combined laminectomy and video‐assisted thoracoscopic surgery (VATS) resection of thoracic neurogenic dumbbell tumors. Methods A retrospective review of all combined thoracic dumbbell tumor resections performed at our institution between March 2015 to February 2019 was undertaken. Outcomes included operative time, blood loss, length of stay and recurrence rate. Statistical analysis was performed with SPSS statistics (v26). Values are given as mean ± standard deviation and median ± interquartile range. Results Seven patients were included in the case series and there were no major complications or mortality. Mean tumor size and operative time were 66 (± 35) mm and 171 (± 63) min, respectively. Median blood loss and length of stay were 40 (± 70) ml and four (± 3) days, respectively. One patient required conversion to thoracotomy to remove a tumor of 135 mm in maximal dimension. Histology in all seven cases confirmed schwannoma. There was no disease recurrence at a maximum follow‐up of 54 months. Conclusions Our experience demonstrates favorable operative times, minimal blood loss and short length of stay when dealing with relatively large tumors compared to previous reports. Thoracotomy may be required for tumors exceeding 90 mm and chest drain removal on the operative day can facilitate early mobility and discharge. We advocate a combined, minimally invasive laminectomy and VATS resection as the gold‐standard approach for thoracic neurogenic dumbbell tumors., Paraspinal tumors are rare and surgical resection can be challenging. Optimal surgical strategy is contentious. We demonstrate outcomes from the first European case series of combined microlaminectomy and video‐assisted thoracoscopic surgery. Our experience demonstrates favorable operative times, minimal blood loss and short length of stay when dealing with relatively large tumors compared to previous reports. Removing the chest drain on the operative day facilitates early discharge. We advocate a combined minimally invasive approach as the gold‐standard for paraspinal tumor resection.
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- 2021
10. sLRP1’in up retinol keeps the gut SAAfe
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Oliver J. Harrison and Jasmine Labuda
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Immunology ,Retinol ,Retinoic acid ,Biology ,LRP1 ,Cell biology ,chemistry.chemical_compound ,Infectious Diseases ,Immune system ,chemistry ,hemic and lymphatic diseases ,Myeloid cells ,Immunology and Allergy ,Receptor - Abstract
Retinol is shuttled to myeloid cells for conversion to retinoic acid, but the receptor facilitating uptake of SAA:retinol complexes on myeloid cells is unknown. In a recent issue of Science, Bang et al. (2021) use genetic and biochemical approaches to reveal this critical receptor to be LRP1 and show that this axis is essential for intestinal innate and adaptive immune responses.
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- 2021
11. Ambulatory chest drainage with advanced nurse practitioner-led follow-up facilitates early discharge after thoracic surgery
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Oliver J, Harrison, Maria Elena, Vilar Alvarez, Victoria, Snow, Alessandro, Tamburrini, Edwin, Woo, Lukacs, Veres, Martin H, Chamberlain, and Aiman, Alzetani
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To demonstrate the safety and feasibility of advanced nurse practitioner-led (ANP-led) outpatient follow-up after discharge with ambulatory chest drains for prolonged air leak and excessive fluid drainage.Patients discharged with ambulatory chest drains between January 2017 and December 2019 were retrospectively reviewed. Discharge criteria included air leak 200 ml/min or fluid drainage 100 ml/24 h on a digital drain. Patients were reviewed weekly in the clinic by ANPs, a highly skilled cohort of nurses with physician support available. Outcomes included length of stay, duration of air or fluid leak and complications.Two-hundred patients were included, amounting to 368 clinic episodes. The median age was 68 ± 13 years and 119 (60%) were male. 112 (56%) patients underwent anatomical lung resection (total anatomical lung resections during the study period = 917) equating to a discharge with ambulatory chest drain rate of 12.2% in this group. The median length of stay was 6 ± 3 days and 176 (88%) patients were discharged with air leak versus 24 (12%) with excessive fluid drainage. The median time to drain removal was 12 ± 11 days. Complications occurred in 16 patients (8%) and 12 (6%) required readmission. An estimated 2075 inpatient days were saved over the study period equating to an annual cost saving of £123,167 (US$149,032) per annum.Patients with air leak or excessive fluid drainage can safely be discharged with ambulatory chest drains, allowing them to return to their familiar home environment safely and quickly. ANP-led clinics are a robust and cost-effective follow-up strategy and are associated with a low complication rate.
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- 2022
12. Image-guided combined ablation and resection in thoracic surgery for the treatment of multiple pulmonary metastases: A preliminary case series
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Oliver J. Harrison, Aiman Alzetani, Sajiram Sarvananthan, Alessandro Tamburrini, and Charles Peebles
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Percutaneous ,wedge resection ,image-guided surgery ,Radiofrequency ablation ,medicine.medical_treatment ,iCART, image-guided combined ablation and resection in thoracic surgery ,law.invention ,law ,medicine ,iVATS, image-guided video-assisted thoracoscopic surgery ,pulmonary metastasis ,RFA, radiofrequency ablation ,business.industry ,Microwave ablation ,metastatectomy ,hybrid surgery ,pulmonary nodule ,Ablation ,medicine.disease ,Image-guided surgery ,GGO, ground-glass opacity ,pMWA, percutaneous microwave ablation ,Pneumothorax ,Thoracic: Lung Cancer: Evolving Technology ,microwave ablation ,Surgery ,Radiology ,business ,Lung cancer screening ,Wedge resection (lung) - Abstract
Objectives To demonstrate the feasibility and preliminary outcomes of a novel hybrid technique combining percutaneous microwave ablation and wire-assisted wedge resection for patients with multiple pulmonary metastases using intraoperative imaging. Methods We describe our technique and present a retrospective case series of 4 patients undergoing iCART at our institution between August 2018 and January 2020. Procedures were performed in a hybrid operating suite using the ARTIS Pheno cone beam computerized tomography scanner (Siemens Healthineers, Erlangen, German). Patient information included past history of malignancy as well as lesion size, depth, location, and histology result. Surgical complications and length of stay were also recorded. Results Five procedures were performed on 4 patients during the study period. One patient underwent bilateral procedures 4 weeks apart. All patients underwent at least 1 ablation and 1 wedge resection during the combined procedure. Patient ages ranged from 40 to 66 years and the majority (75%) were men. All had a past history of cancer. Lesions were treated in every lobe. Size and depth ranged from 6 to 24 mm and 21 to 33 mm, respectively, for ablated nodules and 5 to 27 mm and 0 to 22 mm, respectively, for the wedge resected nodules. Three procedures were completed uniportal and operative time ranged from 51 to 210 minutes. All cases sustained, Graphical abstract
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- 2021
13. Immunity to commensal skin fungi promotes psoriasiform skin inflammation
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Yaíma L. Lightfoot, Saeko Nakajima, Verena M. Link, Samira Tamoutounour, Oliver J. Harrison, Christopher K. E. Bleck, Mariana J. Kaplan, E. Merrill, Jonathan L. Linehan, Margery G. Smelkinson, Seong-Ji Han, Yasmine Belkaid, C. Hurabielle, Nicolas Bouladoux, Nickie L Seto, and Michail S. Lionakis
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Male ,0301 basic medicine ,T cell ,Inflammation ,Context (language use) ,Extracellular Traps ,Mice ,03 medical and health sciences ,Psoriatic skin ,0302 clinical medicine ,Immune system ,Immunity ,Psoriasis ,medicine ,Animals ,Humans ,Symbiosis ,Skin ,Multidisciplinary ,business.industry ,Arthrodermataceae ,Microbiota ,Neutrophil extracellular traps ,Biological Sciences ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Th17 Cells ,Female ,medicine.symptom ,business - Abstract
Under steady-state conditions, the immune system is poised to sense and respond to the microbiota. As such, immunity to the microbiota, including T cell responses, is expected to precede any inflammatory trigger. How this pool of preformed microbiota-specific T cells contributes to tissue pathologies remains unclear. Here, using an experimental model of psoriasis, we show that recall responses to commensal skin fungi can significantly aggravate tissue inflammation. Enhanced pathology caused by fungi preexposure depends on Th17 responses and neutrophil extracellular traps and recapitulates features of the transcriptional landscape of human lesional psoriatic skin. Together, our results propose that recall responses directed to skin fungi can directly promote skin inflammation and that exploration of tissue inflammation should be assessed in the context of recall responses to the microbiota.
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- 2020
14. Response to Comments on 'Aberrant type 1 immunity drives susceptibility to mucosal fungal infections'
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Heather D. Hickman, Chyi-Chia Richard Lee, Peter Olbrich, Jean K. Lim, Daniel Chauss, Vasileios Oikonomou, Daniel L. Barber, Philip M. Murphy, Monica M. Schmitt, Tilo Freiwald, Marc Swidergall, Stefania Pittaluga, Steven M. Holland, Daniel Martin, Luigi D. Notarangelo, Oliver J. Harrison, Scott G. Filler, Lindsey B. Rosen, Ian A. Myles, Wint Lwin, Sergio M. Pontejo, Behdad Afzali, Timothy J. Break, Niki M. Moutsopoulos, Vincent M. Bruno, Julie Alejo, Jigar V. Desai, Nicolas Bouladoux, Elise M. N. Ferré, Norma V. Solis, Mitsuru Matsumoto, David V. Serreze, Yasmine Belkaid, Andy Renteria, John P. Shannon, Nicolas Dutzan, Teresa Greenwell-Wild, Michail S. Lionakis, Drake W. Williams, Kevin W. Hoffman, Muthulekha Swamydas, and Mark S. Anderson
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Multidisciplinary ,Mucous Membrane ,Type 1 immunity ,Mycoses ,business.industry ,Immunology ,Autoantibody ,Medicine ,Humans ,business ,Immunity, Mucosal ,Article - Abstract
Puel and Casanova and Kisand et al . challenge our conclusions that interferonopathy and not IL-17/IL-22 autoantibodies promote candidiasis in autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy. We acknowledge that conclusive evidence for causation is difficult to obtain in complex human diseases. However, our studies clearly document interferonopathy driving mucosal candidiasis with intact IL-17/IL-22 responses in Aire -deficient mice, with strong corroborative evidence in patients.
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- 2021
15. Prenatal maternal infection promotes tissue-specific immunity and inflammation in offspring
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Verena M. Link, Rose-Marie Karlsson, Jigar V. Desai, Han-Yu Shih, Ai Ing Lim, Oliver J. Harrison, Michail S. Lionakis, Heather A. Cameron, Seong-Ji Han, Taryn McFadden, Taylor K. Farley, Apollo Stacy, Djalma S. Lima-Junior, and Yasmine Belkaid
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Offspring ,Yersinia pseudotuberculosis Infections ,Context (language use) ,Inflammation ,Biology ,Article ,Epigenesis, Genetic ,Fetal Development ,Epigenome ,Mice ,Immune system ,Pregnancy ,T-Lymphocyte Subsets ,Immunity ,medicine ,Animals ,Intestinal Mucosa ,Pregnancy Complications, Infectious ,Salmonella Infections, Animal ,Fetus ,Multidisciplinary ,Interleukin-6 ,Stem Cells ,Candidiasis ,Colitis ,medicine.disease ,Chromatin ,Gastrointestinal Microbiome ,Intestines ,Prenatal Exposure Delayed Effects ,Immunology ,Th17 Cells ,Female ,medicine.symptom - Abstract
Mom’s IL-6 rewires baby’s gut immunity Most infections that occur during pregnancy are mild and transient. However, whether such pathogen encounters can shape the long-term trajectory of the offspring’s immune system remains unclear. Lim et al . infected pregnant mice with the common food-borne pathogen Yersinia pseudotuberculosis (YopM) (see the Perspective by Amir and Zeng). Although the infection was maternally restricted and short-lived, the offspring harbored greater numbers of intestinal T helper 17 cells into adulthood. Interleukin-6 (IL-6) mediated this tissue-restricted effect by acting on fetal intestinal epithelium during development. Although offspring from mothers infected with YopM or injected with IL-6 showed enhanced resistance to oral infection with Salmonella Typhimurium, they also exhibited higher susceptibility toward enteric inflammatory disease. —STS
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- 2021
16. Maternal infection promotes offspring tissue-specific immune fitness
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Han-Yu Shih, Heather A. Cameron, Rose-Marie Karlsson, Ai Ing Lim, Yasmine Belkaid, Oliver J. Harrison, Taryn McFadden, Seong-Ji Han, Verena M. Link, Apollo Stacy, and Taylor K. Farley
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Fetus ,Pregnancy ,Immune system ,Offspring ,Immunity ,Immunology ,medicine ,Epigenetics ,Imprinting (psychology) ,Biology ,medicine.disease ,Maternal infection - Abstract
The mammalian immune system has evolved in the face of microbial exposure. How maternal infection experienced at distinct developmental stages shapes the offspring immune system remains poorly understood. Here we show that during pregnancy, maternally restricted infection can have permanent and tissue-specific impacts on offspring immunity. Mechanistically, maternal IL-6 produced in response to infection can specifically and directly impose epigenetic changes on fetal intestinal epithelial cells. Such imprinting is associated with long-lasting impacts on intestinal immune homeostasis, characterized by enhanced tonic immunity to the microbiota and heightened Th17 responses within the gut, but not at other barrier sites. Furthermore, the offspring from IL-6-exposed dams developed enhanced protective immunity to gastrointestinal infection. Together, this work demonstrates that maternal infection experienced during pregnancy can be coopted by the fetus to promote long-term tissue-specific fitness.Summary sentenceInfection-induced maternal IL-6 impacts offspring epithelial cells, resulting in heightened immunity to the microbiota and pathogens.
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- 2021
17. Aberrant type 1 immunity drives susceptibility to mucosal fungal infections
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Julie Alejo, Jigar V. Desai, Ian A. Myles, Niki M. Moutsopoulos, Peter Olbrich, Michail S. Lionakis, Vasileios Oikonomou, Philip M. Murphy, Norma V. Solis, Tilo Freiwald, Scott G. Filler, Heather D. Hickman, Steven M. Holland, Stefania Pittaluga, Sergio M. Pontejo, Teresa Greenwell-Wild, Marc Swidergall, Lindsey B. Rosen, Kevin W. Hoffman, Mark S. Anderson, Timothy J. Break, Vincent M. Bruno, Daniel Chauss, Wint Lwin, Muthulekha Swamydas, Behdad Afzali, Chyi-Chia Richard Lee, David V. Serreze, Daniel Martin, Oliver J. Harrison, Yasmine Belkaid, Jean K. Lim, Andy Renteria, John P. Shannon, Nicolas Dutzan, Monica M. Schmitt, Daniel L. Barber, Luigi D. Notarangelo, Drake W. Williams, Elise M. N. Ferré, Mitsuru Matsumoto, and Nicolas Bouladoux
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Male ,T-Lymphocytes ,medicine.disease_cause ,Autoimmunity ,Mice ,Interferon ,Candida albicans ,Receptors ,2.1 Biological and endogenous factors ,STAT1 ,Aetiology ,Immunologic Surveillance ,Inbred BALB C ,Mucosal ,Multidisciplinary ,Interleukin-17 ,Candidiasis ,Middle Aged ,STAT1 Transcription Factor ,Infectious Diseases ,Female ,Infection ,Genomics and Computational Biology Core ,medicine.drug ,Adult ,Adolescent ,General Science & Technology ,Biology ,Chronic Mucocutaneous ,Autoimmune Disease ,Article ,Interferon-gamma ,Young Adult ,Immune system ,Immunity ,medicine ,Animals ,Humans ,Aged ,Janus Kinases ,Animal ,Interleukins ,Inflammatory and immune system ,Mouth Mucosa ,Emerging Infectious Diseases ,Polyendocrinopathies ,Mucosal immunology ,Disease Models ,Immunology ,STAT protein ,biology.protein ,Janus kinase ,Autoimmune - Abstract
INTRODUCTION: Studies of monogenic diseases have uncovered the importance of immune pathways in human tissue-specific immunity and antimicrobial defense. In particular, human inborn errors of the interleukin-17 (IL-17) receptor signaling pathway and corroborating mouse studies have established the critical contribution of type 17 responses inmucosa-specific fungal surveillance. The yeast Candida albicans is the signature pathogen in autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), an inherited autoimmune disease caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. Fungal disease in APECED is limited to chronic mucocutaneous candidiasis (CMC) without dissemination, suggesting a central defect in barrier immunity. RATIONALE: AIRE deficiency impairs central immune tolerance, resulting in the generation of pathogenic autoreactive T cells and autoantibodies directed against many tissue-specific antigens and certain cytokines, including “type 17” cytokines. However, although a majority of APECED patients with CMC have type 17 cytokine–targeted autoantibodies, whether type 17 or other localmucosal immune responses are affected in AIRE deficiency has not been determined. Here, we broadly investigated oral mucosal immune responses both in a model of oropharyngeal candidiasis in Aire(−/−) mice and in a large cohort of APECED patients. RESULTS: Type 17 immune responses at the oralmucosa were unexpectedly intact in mice and humans with AIRE deficiency. To define alternative mechanisms of fungal susceptibility, we investigated Aire(−/−) mice, which exhibited oralmucosa-specific susceptibility to candidiasis without dissemination and controlled experimental challenges with viruses and bacteria normally, thereby phenocopying the infection predisposition observed in APECED patients. Notably, Aire(−/−) CD4(+) and CD8(+) T cells accumulated in increased numbers and displayed an activated and proliferative phenotype within the oral mucosa and were both necessary and sufficient to drive mucosal fungal infection in Aire deficiency. Enhanced production of interferon-γ (IFN-γ) by Aire(−/−) mucosal CD4(+) and CD8(+) T cells resulted in exacerbated IFN-γ/STAT1-mediated responses in the oral mucosa, which promoted IFN-γ–dependent epithelial barrier disruption and mucosal fungal susceptibility. Genetic and pharmacologic inhibition of IFN-γ or JAK-STAT signaling ameliorated mucosal fungal disease in Aire(−/−) mice. Aberrant type 1 responseswere also observed in the oral mucosa of APECED patients. CONCLUSION: We identify a T cell–dependent interferonopathy as a critical local mucosal mechanism underlying CMC in APECED. Although type 17 mucosal immunity is critical for host defense against barrier infection, mucosal type 17 responses were intact in patients with APECED and in a mouse model of the disease. These findings show that, in contrast to the known protective roles of T cells in antifungal host defense, aberrant type 1–associated T cell responses can be detrimental to antifungal mucosal immunity. They also support a paradigm by which exaggerated immunopathology may facilitate susceptibility to mucosal fungal infection by impairing the integrity of the epithelial barrier. Finally, they pave the way for investigating type 1 mucosal responses in other CMC-manifesting diseases and for the prevention and treatment of CMC in APECED patients using FDA-approved therapies that target IFN-γ or JAK-STAT signaling.
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- 2021
18. Tracheal leiomyoma mimicking asthma for over 20 years
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Oliver J. Harrison, Mark Jackson, Aiman Alzetani, and Emily C. Shaw
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Spirometry ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Incidence (epidemiology) ,Case Report ,Computed tomography ,Tracheal Leiomyoma ,respiratory system ,Airway obstruction ,medicine.disease ,Resection ,03 medical and health sciences ,0302 clinical medicine ,Leiomyoma ,030228 respiratory system ,030225 pediatrics ,medicine ,Surgery ,Radiology ,business ,Asthma - Abstract
Benign tracheal tumours have an incidence of 1 in 1,000,000, of which leiomyomas represent only 1%. We report a case of tracheal leiomyoma masquerading as asthma for over 20 years. A 48-year-old man presented aged 26 years with asthma symptoms unresponsive to treatments and an obstructive spirometry pattern. Symptoms were not particularly troubling but suddenly exacerbated 22 years later. Flow-volume studies were consistent with upper airway obstruction. Computed tomography chest revealed a 2.3 cm mass arising from the posterior aspect of the trachea 2 cm above the carina. Bronchoscopic resection was performed using a Nd:YAG laser. Histology confirmed leiomyoma. Follow-up after 6 weeks revealed complete resolution of symptoms with normal spirometry. Tracheal masses should be considered in any patient with atypical asthma. A flow-volume loop may provide a clue to diagnosis and bronchoscopic laser resection is a minimally invasive treatment option.
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- 2020
19. Poised for tissue repair
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Oliver J. Harrison
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Wound Healing ,Multidisciplinary ,integumentary system ,Microbiota ,biochemical phenomena, metabolism, and nutrition ,Biology ,Tissue repair ,CD8-Positive T-Lymphocytes ,Bioinformatics ,Immune system ,Immune System ,Staphylococcus epidermidis ,Humans ,Symbiosis ,Skin - Abstract
Skin microbes interact with the immune system to aid wound healing
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- 2020
20. Enteropathy-induced regulatory T cells inhibit intestinal CD4+ T cell responses against oral vaccines
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Elizabeth B. Norton, Amrita Bhattacharjee, Denise Morais da Fonseca, Yasmine Belkaid, Sean P. Spencer, Oliver J. Harrison, Abigail E. Overacre-Delgoffe, Justin T. Tometich, Ansen H.P. Burr, Timothy W. Hand, Jason A. Hall, Deyi Yang, Brydie R. Huckestein, and Jonathan L. Linehan
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Malabsorption ,business.industry ,T cell ,FOXP3 ,Inflammation ,medicine.disease ,Small intestine ,Vaccination ,medicine.anatomical_structure ,Immunity ,Immunology ,medicine ,Enteropathy ,medicine.symptom ,business - Abstract
SummaryEnvironmental Enteric Dysfunction (EED) is an intestinal disease caused by malnutrition and infection that leads to malabsorption and stunting. EED is also associated with a reduced efficacy of oral vaccines. We show in a microbiota and diet-dependent model of EED that oral vaccine-specific CD4+ T cell responses fail in the small intestine but responses in the draining lymph node were unaffected. Accordingly, the number of immunosuppressive RORγT+FOXP3+ Tregs in the small intestine inversely correlated with the response to oral vaccination. Depletion of RORγT+FOXP3+ Tregs indicated that they were necessary for EED-associated inhibition of the vaccine response. Additionally, RORγT+FOXP3+ Tregs are important to regulate EED-associated inflammation as their depletion significantly worsened stunting. We have shown that EED-associated intestinal inflammation leads to a localized intestinal blockade of CD4 T cell immunity. These results support a modular model for immunity where tissue responses can be regulated independently of systemic immunity to prevent autoinflammation.
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- 2020
21. Environmental enteric dysfunction induces regulatory T cells that inhibit local CD4+ T cell responses and impair oral vaccine efficacy
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Brydie R. Huckestein, Oliver J. Harrison, Deyi Yang, Ansen H.P. Burr, Justin T. Tometich, Jason A. Hall, Sean P. Spencer, Elizabeth B. Norton, Jonathan L. Linehan, Yasmine Belkaid, Amrita Bhattacharjee, Denise Morais da Fonseca, Abigail E. Overacre-Delgoffe, and Timothy W. Hand
- Subjects
Male ,Gastrointestinal Diseases ,Immunology ,Bacterial Toxins ,Administration, Oral ,Mice, Transgenic ,Biology ,medicine.disease_cause ,T-Lymphocytes, Regulatory ,Article ,Cell Line ,Mice ,RAR-related orphan receptor gamma ,Intestine, Small ,medicine ,Escherichia coli ,Immunology and Allergy ,Animals ,Toxin ,Escherichia coli Vaccines ,Vaccination ,FOXP3 ,Forkhead Transcription Factors ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,Vaccine efficacy ,Small intestine ,Mice, Inbred C57BL ,Chronic infection ,Disease Models, Animal ,Infectious Diseases ,medicine.anatomical_structure ,Drosophila ,Female ,Lymph ,Vaccine failure - Abstract
Summary Environmental enteric dysfunction (EED) is a gastrointestinal inflammatory disease caused by malnutrition and chronic infection. EED is associated with stunting in children and reduced efficacy of oral vaccines. To study the mechanisms of oral vaccine failure during EED, we developed a microbiota- and diet-dependent mouse EED model. Analysis of E. coli-labile toxin vaccine-specific CD4+ T cells in these mice revealed impaired CD4+ T cell responses in the small intestine and but not the lymph nodes. EED mice exhibited increased frequencies of small intestine-resident RORγT+FOXP3+ regulatory T (Treg) cells. Targeted deletion of RORγT from Treg cells restored small intestinal vaccine-specific CD4 T cell responses and vaccine-mediated protection upon challenge. However, ablation of RORγT+FOXP3+ Treg cells made mice more susceptible to EED-induced stunting. Our findings provide insight into the poor efficacy of oral vaccines in EED and highlight how RORγT+FOXP3+ Treg cells can regulate intestinal immunity while leaving systemic responses intact.
- Published
- 2020
22. Gut microbiome stability and dynamics in healthy donors and patients with non-gastrointestinal cancers
- Author
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Oliver J. Harrison, Lluis Quintana-Murci, Allyson L. Byrd, Darragh Duffy, Deepti R. Nagarkar, Jacob Bergstedt, Etienne Patin, Menghan Liu, Matthew L. Albert, Bruno Charbit, Kei E. Fujimura, Ira Mellman, Svetlana Lyalina, Genentech, Inc. [San Francisco], New York University School of Medicine, NYU System (NYU), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Institut Pasteur [Paris], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Benaroya Research Institute [Seattle] (BRI), Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), Immunologie Translationnelle - Translational Immunology lab, Insitro [San Francisco], This work benefited from support of the French government’s Invest in the Future program. This program is managed by the Agence Nationale de la Recherche, reference ANR-10-LABX-69-01., We thank all the donors for their participation in the study. We thank J. Segre and F. Tamburini for critical reading of the manuscript and helpful comments. We also thank J. Paulson and O. Mayba for expert statistical support., The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel, Andres Alcover, Hugues Aschard, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Ivo Gomperts-Boneca, Milena Hasan, Serge Hercberg, Olivier Lantz, Hugo Mouquet, Etienne Patin, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert, Mathilde Touvier, Marie-Noëlle Ungeheuer, Darragh Duffy, Matthew L. Albert, and Lluis Quintana-Murci., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Collège de France - Chaire Génomique humaine et évolution
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0301 basic medicine ,Adult ,Male ,Immunology ,Host factors ,Disease ,Technical Advances and Resources ,Infectious Disease and Host Defense ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Immunology and Allergy ,Humans ,Microbiome ,Bifidobacterium ,Aged ,biology ,Mucosal Immunology ,Middle Aged ,biology.organism_classification ,Biological sex ,Gut microbiome ,3. Good health ,Gastrointestinal Microbiome ,030104 developmental biology ,Community composition ,Cohort ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,030217 neurology & neurosurgery - Abstract
By characterizing gut microbiome composition across 946 healthy donors, Byrd et al. demonstrate strong influences of age and biological sex. Additionally, they define global shifts in the gut microbiome composition of patients with non-gastrointestinal tumors compared with healthy donors., As microbial therapeutics are increasingly being tested in diverse patient populations, it is essential to understand the host and environmental factors influencing the microbiome. Through analysis of 1,359 gut microbiome samples from 946 healthy donors of the Milieu Intérieur cohort, we detail how microbiome composition is associated with host factors, lifestyle parameters, and disease states. Using a genome-based taxonomy, we found biological sex was the strongest driver of community composition. Additionally, bacterial populations shift across decades of life (age 20–69), with Bacteroidota species consistently increased with age while Actinobacteriota species, including Bifidobacterium, decreased. Longitudinal sampling revealed that short-term stability exceeds interindividual differences. By accounting for these factors, we defined global shifts in the microbiomes of patients with non-gastrointestinal tumors compared with healthy donors. Together, these results demonstrated that the microbiome displays predictable variations as a function of sex, age, and disease state. These variations must be considered when designing microbiome-targeted therapies or interpreting differences thought to be linked to pathophysiology or therapeutic response., Graphical Abstract
- Published
- 2020
23. Stability and dynamics of the human gut microbiome and its association with systemic immune traits
- Author
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Lluis Quintana-Murci, Menghan Liu, Oliver J. Harrison, Jacob Bergstedt, Etienne Patin, Svetlana Lyalina, Matthew L. Albert, Deepti R. Nagarkar, Bruno Charbit, Darragh Duffy, Kei E. Fujimura, and Allyson L. Byrd
- Subjects
Genetics ,Immune system ,Human gut ,Community composition ,business.industry ,Personalized medicine ,Microbiome ,Prevotella species ,Biology ,business ,biology.organism_classification ,Genome ,Bifidobacterium - Abstract
SummaryAnalysis of 1,363 deeply sequenced gut microbiome samples from 946 healthy donors of the Milieu Intérieur cohort provides new opportunities to discover how the gut microbiome is associated with host factors and lifestyle parameters. Using a genome-based taxonomy to achieve higher resolution analysis, we found an enrichment of Prevotella species in males, and that bacterial profiles are dynamic across five decades of life (20-69), with Bacteroidota species consistently increased with age while Actinobacteriota species, including Bifidobacterium, decreased. Longitudinal sampling revealed short-term stability exceeds inter-individual differences; however, the degree of stability was variable between donors and influenced by their baseline community composition. We then integrated the microbiome results with systemic immunophenotypes to show that host/microbe associations discovered in animal models, such as T regulatory cells and short chain fatty acids, could be validated in human data. These results will enable personalized medicine approaches for microbial therapeutics and biomarkers.
- Published
- 2020
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24. Keratinocyte-intrinsic MHCII expression controls microbiota-induced Th1 cell responses
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Jonathan L. Linehan, Paula Juliana Pérez-Chaparro, Barbara Rehermann, Oliver J. Harrison, Ivan Vujkovic-Cvijin, Vanja Lazarevic, Michael G. Constantinides, Samira Tamoutounour, Julie Deckers, Seong-Ji Han, Nicolas Bouladoux, Stephan P. Rosshart, C. Hurabielle, Verena M. Link, and Yasmine Belkaid
- Subjects
Keratinocytes ,Staphylococcus aureus ,Lymphocyte ,T cell ,Antigen presentation ,Genes, MHC Class II ,Biology ,Interferon-gamma ,Mice ,Immune system ,Candida albicans ,medicine ,Staphylococcus epidermidis ,Skin immunity ,Animals ,Symbiosis ,MHC class II ,Antigen Presentation ,Multidisciplinary ,Host Microbial Interactions ,Microbiota ,Innate lymphoid cell ,Histocompatibility Antigens Class II ,Th1 Cells ,Biological Sciences ,Cell biology ,Specific Pathogen-Free Organisms ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Organ Specificity ,Radiation Chimera ,biology.protein ,Epidermis ,Keratinocyte - Abstract
The cross-talk between the microbiota and the immune system plays a fundamental role in the control of host physiology. However, the tissue-specific factors controlling this dialogue remain poorly understood. Here we demonstrate that T cell responses to commensal colonization are associated with the development of organized cellular clusters within the skin epithelium. These organized lymphocyte clusters are surrounded by keratinocytes expressing a discrete program associated with antigen presentation and antimicrobial defense. Notably, IL-22–mediated keratinocyte-intrinsic MHC class II expression was required for the selective accumulation of commensal-induced IFN-γ, but not IL-17A–producing CD4 + T cells within the skin. Taking these data together, this work uncovers an unexpected role for MHC class II expression by keratinocytes in the control of homeostatic type 1 responses to the microbiota. Our findings have important implications for the understanding of the tissue-specific rules governing the dialogue between a host and its microbiota.
- Published
- 2019
25. Pre-birth memory
- Author
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Ai Ing Lim, Yasmine Belkaid, and Oliver J. Harrison
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0301 basic medicine ,Pregnancy ,medicine.medical_specialty ,Fetus ,Obstetrics ,business.industry ,digestive, oral, and skin physiology ,Immunology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine ,Immunology and Allergy ,business ,030215 immunology - Abstract
The transition of the fetus from the womb to the external world represents an extraordinary challenge. The generation of memory T cells before birth may serve an important role in preparation for this fundamental transition.
- Published
- 2019
26. Neuropeptide CGRP limits group 2 innate lymphoid cell responses and constrains type 2 inflammation
- Author
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Yuefeng Huang, Yasmine Belkaid, David Artis, Fred P. Davis, Françoise Meylan, Oliver J. Harrison, Hiroyuki Nagashima, Yuka Kanno, Chen Yao, Kathleen M. Caron, John J. O'Shea, Joseph F. Urban, Han-Yu Shih, Yohei Mikami, and Tanel Mahlakõiv
- Subjects
0301 basic medicine ,Innate immune system ,Lymphocyte ,Immunology ,Innate lymphoid cell ,Interleukin ,Inflammation ,Calcitonin gene-related peptide ,Biology ,Article ,Interleukin 33 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Infectious Diseases ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,medicine ,Immunology and Allergy ,medicine.symptom ,Tissue homeostasis - Abstract
Innate lymphocytes maintain tissue homeostasis at mucosal barriers, with group 2 innate lymphoid cells (ILC2s) producing type 2 cytokines and controlling helminth infection. While the molecular understanding of ILC2 responses has advanced, the complexity of microenvironmental factors impacting ILC2s is becoming increasingly apparent. Herein, we used single-cell analysis to explore the diversity of gene expression among lung lymphocytes during helminth infection. Following infection, we identified a subset of ILC2s that preferentially expressed Il5-encoding interleukin (IL)-5, together with Calca-encoding calcitonin gene-related peptide (CGRP) and its cognate receptor components. CGRP in concert with IL-33 and neuromedin U (NMU) supported IL-5 but constrained IL-13 expression and ILC2 proliferation. Without CGRP signaling, ILC2 responses and worm expulsion were enhanced. Collectively, these data point to CGRP as a context-dependent negative regulatory factor that shapes innate lymphocyte responses to alarmins and neuropeptides during type 2 innate immune responses.
- Published
- 2019
27. Critical role of fatty acid metabolism in ILC2-mediated barrier protection during malnutrition and helminth infection
- Author
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Martin Pelletier, Christoph Wilhelm, Michelle Ploch, Yasmine Belkaid, Vanessa Schmitt, Thirumalai R. Ramalingam, Joseph F. Urban, Sean P. Spencer, Oliver J. Harrison, and Richard M. Siegel
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0301 basic medicine ,Immunology ,Helminthiasis ,Inflammation ,Context (language use) ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Immune system ,Immunity ,parasitic diseases ,medicine ,Immunology and Allergy ,Animals ,Lymphocytes ,Research Articles ,chemistry.chemical_classification ,Mice, Knockout ,Interleukin-13 ,Fatty acid metabolism ,Innate lymphoid cell ,Fatty Acids ,Malnutrition ,Brief Definitive Report ,Fatty acid ,Immunity, Innate ,030104 developmental biology ,chemistry ,Interleukin 13 ,medicine.symptom ,030215 immunology - Abstract
Belkaid et al. show that type 2 innate lymphoid cells rely predominately on fatty acid metabolism during helminth infection and malnutrition., Innate lymphoid cells (ILC) play an important role in many immune processes, including control of infections, inflammation, and tissue repair. To date, little is known about the metabolism of ILC and whether these cells can metabolically adapt in response to environmental signals. Here we show that type 2 innate lymphoid cells (ILC2), important mediators of barrier immunity, predominantly depend on fatty acid (FA) metabolism during helminth infection. Further, in situations where an essential nutrient, such as vitamin A, is limited, ILC2 sustain their function and selectively maintain interleukin 13 (IL-13) production via increased acquisition and utilization of FA. Together, these results reveal that ILC2 preferentially use FAs to maintain their function in the context of helminth infection or malnutrition and propose that enhanced FA usage and FA-dependent IL-13 production by ILC2 could represent a host adaptation to maintain barrier immunity under dietary restriction.
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- 2016
28. Commensal-specific T cell plasticity promotes rapid tissue adaptation to injury
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Rosalba Salcedo, Nicholas Collins, Chen Yao, Jonathan L. Linehan, Margery G. Smelkinson, Andrea Paun, Samira Tamoutounour, Shurjo K. Sen, Seong-Ji Han, Francois Van Laethem, John J. O'Shea, Michel Enamorado, Oliver J. Harrison, Yasmine Belkaid, Han-Yu Shih, Allyson L. Byrd, Nicolas Bouladoux, and C. Hurabielle
- Subjects
0301 basic medicine ,Male ,T cell plasticity ,Flexibility (anatomy) ,Transgene ,Cell Plasticity ,Context (language use) ,Mice, Transgenic ,GATA3 Transcription Factor ,Biology ,CD8-Positive T-Lymphocytes ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Candida albicans ,medicine ,Staphylococcus epidermidis ,Alarmins ,Animals ,Symbiosis ,Skin ,Multidisciplinary ,Microscopy, Confocal ,Effector ,Sequence Analysis, RNA ,Interleukins ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Microscopy, Fluorescence ,Th17 Cells ,Wounds and Injuries ,Female ,Adaptation ,030215 immunology - Abstract
Commensal-specific T cells are flexible Barrier tissues, like the skin, are sites where noninvasive commensal microbes constantly interact with resident T cells. These encounters can result in commensal-specific T cell responses that promote, for example, host defense and tissue repair. Harrison et al. show that subsets of skin-resident commensal-specific interleukin-17A–producing CD4 + and CD8 + T cells have a dual nature: They coexpress transcription factors that direct antagonistic antimicrobial (type 17) and antiparasite and pro–tissue repair (type 2) programs. When skin is damaged, epithelial cell alarmins license type 17 T cells to turn on type 2 cytokines. Thus, commensal-specific type 17 T cells can direct antimicrobial activity under homeostatic conditions but rapidly turn on tissue repair in the context of injury. Science , this issue p. eaat6280
- Published
- 2018
29. The mouse model of infection with Citrobacter rodentium
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Oliver J. Harrison, Nicolas Bouladoux, and Yasmine Belkaid
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0301 basic medicine ,Immunology ,Biology ,digestive system ,Article ,Microbiology ,Flow cytometry ,Pathogenesis ,03 medical and health sciences ,Mice ,Immune system ,Organ Culture Techniques ,medicine ,Citrobacter rodentium ,Escherichia coli ,Animals ,Humans ,Colitis ,Enteropathogenic Escherichia coli ,Intestinal Mucosa ,Pathogen ,Immunity, Mucosal ,Escherichia coli Infections ,medicine.diagnostic_test ,Enterobacteriaceae Infections ,medicine.disease ,Flow Cytometry ,Bacterial Load ,Disease Models, Animal ,030104 developmental biology ,Host-Pathogen Interactions ,Ex vivo - Abstract
Citrobacter rodentium is a murine mucosal pathogen used as a model to elucidate the molecular and cellular pathogenesis of infection with two clinically important human gastrointestinal pathogens, enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC). C. rodentium infection provides an excellent model to study different aspects of host-pathogen interaction in the gut, including intestinal inflammatory responses during bacteria-induced colitis, mucosal healing and epithelial repair, the induction of mucosal immune responses, and the role of the intestinal microbiota in mediating resistance to colonization by enteric pathogens. This unit provides detailed protocols for growing this bacterium, infecting mice by intragastric inoculation, measuring bacterial loads in feces and organs, and monitoring intestinal pathology induced by infection. Additional protocols describe steps needed to create frozen stocks, establish a growth curve, perform ex vivo organ cultures, isolate immune cells from the large intestine, and measure immune response by flow cytometry. © 2017 by John Wiley & Sons, Inc.
- Published
- 2017
30. Staphylococcus aureus and Staphylococcus epidermidis strain diversity underlying pediatric atopic dermatitis
- Author
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Sean Conlan, Julia A. Segre, Oliver J. Harrison, Sara K. B. Cassidy, Weng-Ian Ng, Clay Deming, Nisc Comparative Sequencing Program, Heidi H. Kong, Allyson L. Byrd, and Yasmine Belkaid
- Subjects
0301 basic medicine ,biology ,Case-control study ,General Medicine ,Atopic dermatitis ,Disease ,biology.organism_classification ,medicine.disease_cause ,medicine.disease ,Marker gene ,Microbiology ,03 medical and health sciences ,030104 developmental biology ,Immune system ,Staphylococcus epidermidis ,Staphylococcus aureus ,Metagenomics ,Immunology ,medicine - Abstract
The heterogeneous course, severity, and treatment responses among patients with atopic dermatitis (AD; eczema) highlight the complexity of this multifactorial disease. Prior studies have used traditional typing methods on cultivated isolates or sequenced a bacterial marker gene to study the skin microbial communities of AD patients. Shotgun metagenomic sequence analysis provides much greater resolution, elucidating multiple levels of microbial community assembly ranging from kingdom to species and strain-level diversification. We analyzed microbial temporal dynamics from a cohort of pediatric AD patients sampled throughout the disease course. Species-level investigation of AD flares showed greater Staphylococcus aureus predominance in patients with more severe disease and Staphylococcus epidermidis predominance in patients with less severe disease. At the strain level, metagenomic sequencing analyses demonstrated clonal S. aureus strains in more severe patients and heterogeneous S. epidermidis strain communities in all patients. To investigate strain-level biological effects of S. aureus, we topically colonized mice with human strains isolated from AD patients and controls. This cutaneous colonization model demonstrated S. aureus strain-specific differences in eliciting skin inflammation and immune signatures characteristic of AD patients. Specifically, S. aureus isolates from AD patients with more severe flares induced epidermal thickening and expansion of cutaneous T helper 2 (TH2) and TH17 cells. Integrating high-resolution sequencing, culturing, and animal models demonstrated how functional differences of staphylococcal strains may contribute to the complexity of AD disease.
- Published
- 2017
31. c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont
- Author
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Yi Ding, Yasmine Belkaid, Christy Au, Oliver J. Harrison, Maria Pokrovskii, Richard Bonneau, Carolina Galan, Ren Yi, Mo Xu, and Dan R. Littman
- Subjects
0301 basic medicine ,Male ,Cell ,Inflammation ,Bioengineering ,Biology ,Inflammatory bowel disease ,T-Lymphocytes, Regulatory ,Immune tolerance ,03 medical and health sciences ,Mice ,RAR-related orphan receptor gamma ,medicine ,Immune Tolerance ,Animals ,Homeostasis ,Multidisciplinary ,FOXP3 ,Forkhead Transcription Factors ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,biology.organism_classification ,medicine.disease ,Colitis ,3. Good health ,Interleukin-10 ,Intestines ,030104 developmental biology ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-maf ,Immunology ,Host-Pathogen Interactions ,Th17 Cells ,Female ,Helicobacter hepaticus ,medicine.symptom - Abstract
Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases. There is accumulating evidence that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease, often also colonize healthy individuals. These microorganisms, including the Helicobacter species, can induce pathogenic T cells and are collectively referred to as pathobionts. However, how such T cells are constrained in healthy individuals is not yet understood. Here we report that host tolerance to a potentially pathogenic bacterium, Helicobacter hepaticus, is mediated by the induction of RORγt+FOXP3+ regulatory T (iTreg) cells that selectively restrain pro-inflammatory T helper 17 (TH17) cells and whose function is dependent on the transcription factor c-MAF. Whereas colonization of wild-type mice by H. hepaticus promoted differentiation of RORγt-expressing microorganism-specific iTreg cells in the large intestine, in disease-susceptible IL-10-deficient mice, there was instead expansion of colitogenic TH17 cells. Inactivation of c-MAF in the Treg cell compartment impaired differentiation and function, including IL-10 production, of bacteria-specific iTreg cells, and resulted in the accumulation of H. hepaticus-specific inflammatory TH17 cells and spontaneous colitis. By contrast, RORγt inactivation in Treg cells had only a minor effect on the bacteria-specific Treg and TH17 cell balance, and did not result in inflammation. Our results suggest that pathobiont-dependent inflammatory bowel disease is driven by microbiota-reactive T cells that have escaped this c-MAF-dependent mechanism of iTreg-TH17 homeostasis.
- Published
- 2017
32. White Adipose Tissue Is a Reservoir for Memory T Cells and Promotes Protective Memory Responses to Infection
- Author
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Nicolas Bouladoux, Allyson L. Byrd, Nicholas Collins, Amiran Dzutsev, Yasmine Belkaid, Arielle Glatman Zaretsky, Igor E. Brodsky, Margery G. Smelkinson, Denise Morais da Fonseca, Oliver J. Harrison, James B. Bliska, Jason M. Brenchley, Jahangheer S. Shaik, Vinicius Andrade-Oliveira, Seong-Ji Han, and Samira Tamoutounour
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,Lymphocyte ,Transgene ,Adipose Tissue, White ,Immunology ,Adipose tissue ,Gene Expression ,Yersinia pseudotuberculosis Infections ,Mice, Transgenic ,White adipose tissue ,Biology ,CD8-Positive T-Lymphocytes ,03 medical and health sciences ,Interferon-gamma ,Mice ,Bacterial Proteins ,Genes, Reporter ,Gene expression ,medicine ,Immunology and Allergy ,Animals ,Pathogen ,Effector ,Tumor Necrosis Factor-alpha ,Interleukin-17 ,Lipid metabolism ,Lipid Metabolism ,Survival Analysis ,Cell biology ,Mice, Inbred C57BL ,Luminescent Proteins ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Yersinia pseudotuberculosis ,Tissue Transplantation ,Interleukin-5 ,Immunologic Memory ,Toxoplasma ,Toxoplasmosis - Abstract
White adipose tissue bridges body organs and plays a fundamental role in host metabolism. To what extent adipose tissue also contributes to immune surveillance and long-term protective defense remains largely unknown. Here, we have shown that at steady state, white adipose tissue contained abundant memory lymphocyte populations. After infection, white adipose tissue accumulated large numbers of pathogen-specific memory T cells, including tissue-resident cells. Memory T cells in white adipose tissue expressed a distinct metabolic profile, and white adipose tissue from previously infected mice was sufficient to protect uninfected mice from lethal pathogen challenge. Induction of recall responses within white adipose tissue was associated with the collapse of lipid metabolism in favor of antimicrobial responses. Our results suggest that white adipose tissue represents a memory T cell reservoir that provides potent and rapid effector memory responses, positioning this compartment as a potential major contributor to immunological memory.
- Published
- 2017
33. The alarmin IL-33 promotes regulatory T-cell function in the intestine
- Author
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Oliver J. Harrison, Ahmed N. Hegazy, Thomas Krausgruber, Elizabeth A. Wohlfert, Chris Schiering, Benjamin M. J. Owens, Anja Fröhlich, Johanna Pott, Julia Bollrath, Yasmine Belkaid, Agnieszka Chomka, Thibault Griseri, Max Löhning, Padraic G. Fallon, Fiona Powrie, and Krista Adelmann
- Subjects
Male ,Colon ,Regulatory T cell ,medicine.medical_treatment ,Inflammation ,Thymus Gland ,Interleukin-23 ,T-Lymphocytes, Regulatory ,Inflammatory bowel disease ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Transforming Growth Factor beta ,medicine ,Animals ,Immunity, Mucosal ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,biology ,Interleukins ,FOXP3 ,Receptors, Interleukin ,Transforming growth factor beta ,Colitis ,Interleukin-33 ,medicine.disease ,Intestines ,Mice, Inbred C57BL ,Interleukin 33 ,Disease Models, Animal ,medicine.anatomical_structure ,Cytokine ,Immunology ,biology.protein ,Female ,medicine.symptom ,Signal Transduction ,030215 immunology - Abstract
FOXP3(+) regulatory T cells (Treg cells) are abundant in the intestine, where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that Treg cells acquire tissue-specific adaptations that facilitate their survival and function; however, key host factors controlling the Treg response in the intestine are poorly understood. The interleukin (IL)-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites, where it functions as an endogenous danger signal, or alarmin, in response to tissue damage. Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease patients, suggesting a role for this cytokine in disease pathogenesis. In the intestine, both protective and pathological roles for IL-33 have been described in murine models of acute colitis, but its contribution to chronic inflammation remains ill defined. Here we show in mice that the IL-33 receptor ST2 is preferentially expressed on colonic Treg cells, where it promotes Treg function and adaptation to the inflammatory environment. IL-33 signalling in T cells stimulates Treg responses in several ways. First, it enhances transforming growth factor (TGF)-β1-mediated differentiation of Treg cells and, second, it provides a necessary signal for Treg-cell accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of inflammatory bowel disease, restrained Treg responses through inhibition of IL-33 responsiveness. These results demonstrate a hitherto unrecognized link between an endogenous mediator of tissue damage and a major anti-inflammatory pathway, and suggest that the balance between IL-33 and IL-23 may be a key controller of intestinal immune responses.
- Published
- 2014
34. Author Correction: c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont
- Author
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Richard Bonneau, Oliver J. Harrison, Ren Yi, Yi Ding, Dan R. Littman, Yasmine Belkaid, Carolina Galan, Mo Xu, Christy Au, and Maria Pokrovskii
- Subjects
030203 arthritis & rheumatology ,0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Multidisciplinary ,Competing interests ,Statement (logic) ,Published Erratum ,Political science ,Vedanta ,Equity (finance) ,Law and economics - Abstract
In this Letter, the ‘Competing interests’ statement should have stated: ‘D.R.L. consults for and has equity in Vedanta Biosciences.’ The original Letter has not been corrected.
- Published
- 2019
35. Should resuscitative thoracotomy be performed in the pre-hospital phase of care?
- Author
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Oliver J Harrison and David Lockey
- Subjects
medicine.medical_specialty ,Resuscitative thoracotomy ,business.industry ,medicine.medical_treatment ,Major trauma ,Traumatic cardiac arrest ,Critical Care and Intensive Care Medicine ,medicine.disease ,Surgery ,Cardiac tamponade ,Emergency Medicine ,medicine ,Thoracotomy ,Tamponade ,Stab wound ,business ,Penetrating trauma - Abstract
Penetrating thoracic trauma is increasing in the UK and elsewhere and immediate transfer to a Major Trauma Centre with cardio-thoracic expertise is usually optimal management. Pre-hospital traumatic cardiac arrest has an extremely poor prognosis. Performing thoracotomy before arrival in hospital has produced neurologically intact survivors in several case series. The technique described involves rapid clamshell thoracotomy and release of pericardial tamponade. Favourable outcomes appear to be associated with a single stab wound to the heart causing cardiac tamponade. Pre-hospital thoracotomy is described in the current European Resuscitation Guidelines and courses for non-surgeons are now taught at the Royal College of Surgeons of England and at the Surgical Skills Training Centre at Newcastle Freeman Hospital. It is likely that further survivors will be reported as the technique becomes more widely used. Alternatives to pre-hospital thoracotomy in the future for patients with hypovolaemic cardiac arrest may include resuscitative endovascular balloon occlusion of the aorta and pre-hospital extended preservation and resuscitation.
- Published
- 2013
36. Innate immune activation in intestinal homeostasis
- Author
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Oliver J. Harrison and Kevin J. Maloy
- Subjects
Pattern recognition receptors ,Review ,Inflammatory bowel diseases ,Biology ,Interleukin-23 ,digestive system ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Intestinal mucosa ,Cell Movement ,Immunity ,Animals ,Homeostasis ,Humans ,Immunology and Allergy ,Genetic Predisposition to Disease ,Lymphocytes ,Intestinal Mucosa ,030304 developmental biology ,Nod-like receptor ,Inflammation ,0303 health sciences ,Polymorphism, Genetic ,Innate immune system ,Innate lymphoid cell ,CCL18 ,Pattern recognition receptor ,NOD-like receptor ,Bacterial Infections ,biochemical phenomena, metabolism, and nutrition ,Immunity, Innate ,3. Good health ,Immunology ,bacteria ,030215 immunology - Abstract
Loss of intestinal immune regulation leading to aberrant immune responses to the commensal microbiota are believed to precipitate the chronic inflammation observed in the gastrointestinal tract of patients with inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis. Innate immune receptors that recognize conserved components derived from the microbiota are widely expressed by both epithelial cells and leucocytes of the gastrointestinal tract and play a key role in host protection from infectious pathogens; yet precisely how pathogenic and commensal microbes are distinguished is not understood. Furthermore, aberrant innate immune activation may also drive intestinal pathology, as patients with IBD exhibit extensive infiltration of innate immune cells to the inflamed intestine, and polymorphisms in many innate immunity genes influence susceptibility to IBD. Thus, a balanced interaction between the microbiota and innate immune activation is required to maintain a healthy mutualistic relationship between the microbiota and the host, which when disturbed can result in intestinal inflammation.
- Published
- 2016
37. The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation
- Author
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Claire Pearson, Adam Laing, Simon P. Forman, Richard K. Grencis, Oliver J. Harrison, Amin E. Moghaddam, Anna Katharina Simon, Johanna Pott, Quentin J. Sattentau, Kevin J. Maloy, Agnieszka M. Kabat, Thomas Riffelmacher, and Lucie Abeler-Dörner
- Subjects
0301 basic medicine ,autophagy ,Mouse ,QH301-705.5 ,Science ,T cell ,Immunology ,IBD ,Cell ,Autophagy-Related Proteins ,Biology ,T-Lymphocytes, Regulatory ,General Biochemistry, Genetics and Molecular Biology ,T helper cells ,Mice ,03 medical and health sciences ,Th2 Cells ,0302 clinical medicine ,mucosal immunology ,Interleukin 25 ,medicine ,Animals ,Biology (General) ,ATG16L1 ,Mice, Knockout ,General Immunology and Microbiology ,General Neuroscience ,Autophagy ,Innate lymphoid cell ,FOXP3 ,General Medicine ,Inflammatory Bowel Diseases ,3. Good health ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Mucosal immunology ,Medicine ,Carrier Proteins ,Gene Deletion ,Research Article ,030215 immunology - Abstract
A polymorphism in the autophagy gene Atg16l1 is associated with susceptibility to inflammatory bowel disease (IBD); however, it remains unclear how autophagy contributes to intestinal immune homeostasis. Here, we demonstrate that autophagy is essential for maintenance of balanced CD4+ T cell responses in the intestine. Selective deletion of Atg16l1 in T cells in mice resulted in spontaneous intestinal inflammation that was characterized by aberrant type 2 responses to dietary and microbiota antigens, and by a loss of Foxp3+ Treg cells. Specific ablation of Atg16l1 in Foxp3+ Treg cells in mice demonstrated that autophagy directly promotes their survival and metabolic adaptation in the intestine. Moreover, we also identify an unexpected role for autophagy in directly limiting mucosal TH2 cell expansion. These findings provide new insights into the reciprocal control of distinct intestinal TH cell responses by autophagy, with important implications for understanding and treatment of chronic inflammatory disorders. DOI: http://dx.doi.org/10.7554/eLife.12444.001, eLife digest The gut presents a puzzle to our immune system. Immune cells must rapidly respond to antigens produced by harmful bacteria, but food and the beneficial bacteria that inhabit the gut also produce antigens that our immune system must tolerate. Inappropriate immune responses in the gut can lead to inflammatory bowel disease, a debilitating disease with no current cure. We do not fully understand why these harmful inflammatory responses arise, but we know that genetic factors are important. Mutations in genes that affect a process known as autophagy – a pathway that breaks down and recycles unwanted material inside cells – make inflammatory bowel disease more likely to develop, but exactly how they do so remains unclear. T helper cells are crucial controllers of intestinal immune responses and changes in their numbers and behaviour occur during inflammatory bowel disease. Kabat et al. explored how the autophagy pathway affects these key immune cells in mice. Blocking autophagy in T cells altered the balance of different types of T helper cells in the gut. A crucial population of regulatory T cells, which keep inflammatory responses in check, was lost. At the same time, another population of T cells expanded: the T helper 2 (TH2) cells that are responsible for driving allergies. As a result, the mice developed intestinal inflammation and produced antibodies against gut bacteria and food. Overall, Kabat et al.’s results show that autophagy defects can alter the balance of different types of T cells in the gut, leading to inflammation in the intestine. These observations contribute to our understanding of how genetic changes may influence susceptibility to inflammatory bowel disease. They also suggest that drugs that activate autophagy could help to treat diseases associated with changes in regulatory T cells or TH2 cells, including inflammatory bowel disease and allergies. It will now be important to test this and to confirm whether similar changes in T cells are present in humans that have mutations in autophagy genes. DOI: http://dx.doi.org/10.7554/eLife.12444.002
- Published
- 2016
38. Author response: The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation
- Author
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Adam Laing, Thomas Riffelmacher, Claire Pearson, Johanna Pott, Amin E. Moghaddam, Richard K. Grencis, Anna Katharina Simon, Simon P. Forman, Quentin J. Sattentau, Kevin J. Maloy, Oliver J. Harrison, Lucie Abeler-Dörner, and Agnieszka M. Kabat
- Subjects
03 medical and health sciences ,030219 obstetrics & reproductive medicine ,0302 clinical medicine ,business.industry ,Intestinal inflammation ,030220 oncology & carcinogenesis ,Autophagy ,Medicine ,business ,Gene ,ATG16L1 ,Cell biology - Published
- 2016
39. IL-1ß mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4(+) Th17 cells
- Author
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Mark Asquith, Kevin J. Maloy, Fiona Powrie, Oliver J. Harrison, Chris Schiering, Margherita Coccia, Burkhard Becher, University of Zurich, and Maloy, Kevin J
- Subjects
Cell Survival ,Colon ,T cell ,Interleukin-1beta ,Immunology ,610 Medicine & health ,Inflammation ,Biology ,10263 Institute of Experimental Immunology ,CD5 Antigens ,Interleukin-23 ,Article ,Helicobacter Infections ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immunity ,medicine ,Interleukin 23 ,Animals ,Immunology and Allergy ,Lymphocytes ,skin and connective tissue diseases ,030304 developmental biology ,Receptors, Interleukin-1 Type I ,2403 Immunology ,0303 health sciences ,Innate immune system ,Interleukin-17 ,Innate lymphoid cell ,Receptors, Interleukin-1 ,Interleukin ,Colitis ,Immunity, Innate ,3. Good health ,body regions ,Mice, Inbred C57BL ,medicine.anatomical_structure ,2723 Immunology and Allergy ,570 Life sciences ,biology ,Th17 Cells ,Interleukin 17 ,medicine.symptom ,Helicobacter hepaticus ,Granulocytes ,030215 immunology - Abstract
IL-1β promotes chronic intestinal inflammation through recruitment of granulocytes, activation of ILCs, accumulation of pathogenic T cells, and promotion of Th17 responses., Although very high levels of interleukin (IL)-1β are present in the intestines of patients suffering from inflammatory bowel diseases (IBD), little is known about the contribution of IL-1β to intestinal pathology. Here, we used two complementary models of chronic intestinal inflammation to address the role of IL-1β in driving innate and adaptive pathology in the intestine. We show that IL-1β promotes innate immune pathology in Helicobacter hepaticus–triggered intestinal inflammation by augmenting the recruitment of granulocytes and the accumulation and activation of innate lymphoid cells (ILCs). Using a T cell transfer colitis model, we demonstrate a key role for T cell–specific IL-1 receptor (IL-1R) signals in the accumulation and survival of pathogenic CD4+ T cells in the colon. Furthermore, we show that IL-1β promotes Th17 responses from CD4+ T cells and ILCs in the intestine, and we describe synergistic interactions between IL-1β and IL-23 signals that sustain innate and adaptive inflammatory responses in the gut. These data identify multiple mechanisms through which IL-1β promotes intestinal pathology and suggest that targeting IL-1β may represent a useful therapeutic approach in IBD.
- Published
- 2012
- Full Text
- View/download PDF
40. 953 Adaptive responses to skin microbe control the pathogenesis of experimental psoriasis
- Author
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Samira Tamoutounour, Saeko Nakajima, Oliver J. Harrison, Seong-Ji Han, Mariana J. Kaplan, E. Merrill, Yasmine Belkaid, C. Hurabielle, and Michail S. Lionakis
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Pathogenesis ,business.industry ,Psoriasis ,Immunology ,Medicine ,Cell Biology ,Dermatology ,business ,medicine.disease ,Molecular Biology ,Biochemistry - Published
- 2018
41. Non-classical Immunity Controls Microbiota Impact on Skin Immunity and Tissue Repair
- Author
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Ivan Vujkovic-Cvijin, Nicholas Collins, Thomas M. Kristie, Barbara Rehermann, Samira Tamoutounour, Seong-Ji Han, Alejandro V. Villarino, Jesse H. Arbuckle, Chyung Ru Wang, Jahangheer S. Shaik, Shurjo K. Sen, Jonathan L. Linehan, Yasmine Belkaid, Margery G. Smelkinson, John J. O'Shea, Jason M. Brenchley, Giorgio Trinchieri, Amiran Dzutsev, Allyson L. Byrd, Nicolas Bouladoux, Oliver J. Harrison, and Stephan P. Rosshart
- Subjects
0301 basic medicine ,T-Lymphocytes ,Transgene ,Mice, Transgenic ,Inflammation ,CD8-Positive T-Lymphocytes ,Adaptive Immunity ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,Immune system ,Immunity ,MHC class I ,Staphylococcus epidermidis ,medicine ,Animals ,Skin immunity ,Symbiosis ,Skin ,Bacteria ,Effector ,Microbiota ,Histocompatibility Antigens Class I ,Acquired immune system ,Cell biology ,030104 developmental biology ,Gene Expression Regulation ,biology.protein ,medicine.symptom - Abstract
Summary Mammalian barrier surfaces are constitutively colonized by numerous microorganisms. We explored how the microbiota was sensed by the immune system and the defining properties of such responses. Here, we show that a skin commensal can induce T cell responses in a manner that is restricted to non-classical MHC class I molecules. These responses are uncoupled from inflammation and highly distinct from pathogen-induced cells. Commensal-specific T cells express a defined gene signature that is characterized by expression of effector genes together with immunoregulatory and tissue-repair signatures. As such, non-classical MHCI-restricted commensal-specific immune responses not only promoted protection to pathogens, but also accelerated skin wound closure. Thus, the microbiota can induce a highly physiological and pleiotropic form of adaptive immunity that couples antimicrobial function with tissue repair. Our work also reveals that non-classical MHC class I molecules, an evolutionarily ancient arm of the immune system, can promote homeostatic immunity to the microbiota.
- Published
- 2018
42. 648 Candida albicans colonization exacerbates skin inflammation in a murine model of psoriasis
- Author
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Saeko Nakajima, Yasmine Belkaid, Oliver J. Harrison, E. Merrill, and Jonathan L. Linehan
- Subjects
0301 basic medicine ,biology ,business.industry ,Inflammation ,Cell Biology ,Dermatology ,biology.organism_classification ,medicine.disease ,Biochemistry ,Microbiology ,03 medical and health sciences ,030104 developmental biology ,Murine model ,Psoriasis ,medicine ,Colonization ,medicine.symptom ,Candida albicans ,business ,Molecular Biology - Published
- 2017
43. 625 Differential diversity of staphylococcal strains shapes cutaneous response in atopic dermatitis
- Author
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Allyson L. Byrd, Oliver J. Harrison, Yasmine Belkaid, Weng-Ian Ng, Julie A. Segre, Sean Conlan, S. Cassidy, Heidi H. Kong, and Clayton Deming
- Subjects
media_common.quotation_subject ,Immunology ,medicine ,Cell Biology ,Dermatology ,Atopic dermatitis ,Biology ,medicine.disease ,Molecular Biology ,Biochemistry ,Differential (mathematics) ,Diversity (politics) ,media_common - Published
- 2017
44. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model
- Author
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Stefanie Kirchberger, Oliver J. Harrison, Rose L. Szabady, Fiona Powrie, O Boulard, Emily E. Thornton, Fanny Franchini, and Daniel J. Royston
- Subjects
STAT3 Transcription Factor ,Colorectal cancer ,Colon ,medicine.medical_treatment ,Immunology ,Inflammation ,Biology ,Article ,Interleukin 22 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Helicobacter ,medicine ,Immunology and Allergy ,Animals ,Antigens, Ly ,Humans ,Cell Lineage ,Lymphocytes ,Phosphorylation ,030304 developmental biology ,0303 health sciences ,Natural Cytotoxicity Triggering Receptor 1 ,Interleukins ,Innate lymphoid cell ,Cancer ,Epithelial Cells ,medicine.disease ,Colitis ,Ulcerative colitis ,digestive system diseases ,3. Good health ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,Cytokine ,Cell Transformation, Neoplastic ,CD4 Antigens ,Colonic Neoplasms ,Disease Progression ,medicine.symptom ,030215 immunology - Abstract
Neutralization of IL-22 production from colonic innate lymphoid cells reduces dysplasia in bacterial-induced colon cancer by reducing proliferation of epithelial cells via reduced activation of Stat3., Patients with inflammatory bowel disease (IBD) have an increased risk of colon cancer. However, the immune cells and cytokines that mediate the transition from intestinal inflammation to cancer are poorly understood. We show that bacteria-induced colon cancer is accompanied by differential accumulation of IL-17+IL-22+ colonic innate lymphoid cells (cILCs), which are phenotypically distinct from LTi and NK-22 cells, and that their depletion in mice with dysplastic inflammation blocks the development of invasive colon cancer. Analysis of the functional role of distinct Type 17 cytokines shows that although blockade of IL-17 inhibits some parameters of intestinal inflammation, reduction in dysplasia and colorectal cancer (CRC) requires neutralization of IL-22 indicating a unique role for IL-22 in the maintenance of cancer in this model. Mechanistic analyses showed that IL-22 selectively acts on epithelial cells to induce Stat3 phosphorylation and proliferation. Importantly, we could detect IL-22+CD3+ and IL-22+CD3− cells in human CRC. Our results describe a new activity of IL-22 in the colon as a nonredundant mediator of the inflammatory cascade required for perpetuation of CRC, highlighting the IL-22 axis as a novel therapeutic target in colon cancer.
- Published
- 2013
45. T cell depletion protects against alveolar destruction due to chronic cigarette smoke exposure in mice
- Author
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Joseph P. Foley, Donald C. Carpenter, Oliver J. Harrison, Gregory A. Logan, Patrick T. Walsh, Brian Bolognese, Edward Long, and Patricia L. Podolin
- Subjects
Pulmonary and Respiratory Medicine ,CD4-Positive T-Lymphocytes ,Physiology ,medicine.medical_treatment ,Pulmonary disease ,Gene Expression ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Lymphocyte Depletion ,Mice ,Pulmonary Disease, Chronic Obstructive ,Physiology (medical) ,Medicine ,Cigarette smoke ,Animals ,Caspase 7 ,Immunosuppression Therapy ,COPD ,business.industry ,Caspase 3 ,Interleukin-17 ,Smoking ,Lung volume measurement ,T-cell depletion ,Immunosuppression ,Cell Biology ,Cigarette smoke exposure ,medicine.disease ,Mice, Inbred C57BL ,Pulmonary Alveoli ,Disease Models, Animal ,Neutrophil Infiltration ,Immunology ,Lymphocyte activation ,Cyclosporine ,Female ,Tobacco Smoke Pollution ,business ,Lung Volume Measurements - Abstract
The role of T cells in chronic obstructive pulmonary disease (COPD) is not well understood. We have previously demonstrated that chronic cigarette smoke exposure can lead to the accumulation of CD4+ and CD8+ T cells in the alveolar airspaces in a mouse model of COPD, implicating these cells in disease pathogenesis. However, whether specific inhibition of T cell responses represents a therapeutic strategy has not been fully investigated. In this study inhibition of T cell responses through specific depleting antibodies, or the T cell immunosuppressant drug cyclosporin A, prevented airspace enlargement and neutrophil infiltration in a mouse model of chronic cigarette smoke exposure. Furthermore, individual inhibition of either CD4+ T helper or CD8+ T cytotoxic cells prevented airspace enlargement to a similar degree, implicating both T cell subsets as critical mediators of the adaptive immune response induced by cigarette smoke exposure. Importantly, T cell depletion resulted in significantly decreased levels of the Th17-associated cytokine IL-17A, and of caspase 3 and caspase 7 gene expression and activity, induced by cigarette smoke exposure. Finally, inhibition of T cell responses in a therapeutic manner also inhibited cigarette smoke-induced airspace enlargement, IL-17A expression, and neutrophil influx in mice. Together these data demonstrate for the first time that therapeutic inhibition of T cell responses may be efficacious in the treatment of COPD. Given that broad immunosuppression may be undesirable in COPD patients, this study provides proof-of-concept for more targeted approaches to inhibiting the role of T cells in emphysema development.
- Published
- 2013
46. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature
- Author
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Nicolas Bouladoux, Shruti Naik, Jonathan L Linehan, Seong-Ji Han, Oliver J Harrison, Roxanne Tussiwand, Kenneth M Murphy, Miriam Merad, Julia A Segre, and Yasmine Belkaid
- Subjects
Immunology ,Immunology and Allergy - Abstract
The skin represents the body’s primary interface with the environment, acting as the first line of physical and immunological defense. This organ is also home to trillions of microbes (bacteria, fungi and viruses) that play an important role in tissue homeostasis and local immunity. Skin microbial communities are highly diverse and can be remodeled over time or in response to environmental challenges. How in the context of this complexity, individual commensals may differentially modulate skin immunity and what the consequences of these responses for tissue physiology are remain unclear. Here, we demonstrate that defined commensals dominantly impact skin immunity and identify the cellular mediators involved in this specification. In particular, colonization with Staphylococcus epidermidis induces IL-17A+CD8+T cells that home to the epidermis, enhance innate barrier immunity and limit pathogen invasion. These commensal-specific T cell responses result from the coordinated action of skin resident dendritic cell subsets and are not associated with inflammation, revealing that tissue resident cells are poised to sense and respond to alterations in microbial communities. This dialogue may represent an evolutionary means by which the skin immune system uses fluctuating commensal clues to calibrate barrier immunity and provide heterologous protection against invasive pathogens. Altogether these findings reveal that the skin immune landscape is a highly dynamic environment that can be rapidly and specifically remodeled by encounters with defined commensals, findings that have profound implications for our understanding of tissue specific immunity and pathologies.
- Published
- 2016
47. 462 Murine intestinal commensal bacteria modulate the cutaneous inflammatory response to imiquimod
- Author
-
E. Merrill, Oliver J. Harrison, Vanessa K. Ridaura, Michael H. Askenase, Yasmine Belkaid, and S. Nakijama
- Subjects
business.industry ,Inflammatory response ,Immunology ,medicine ,Imiquimod ,Cell Biology ,Dermatology ,business ,Commensalism ,Molecular Biology ,Biochemistry ,medicine.drug - Published
- 2016
48. Airway infiltration of CD4+ CCR6+ Th17 type cells associated with chronic cigarette smoke induced airspace enlargement
- Author
-
Oliver J. Harrison, Brian Bolognese, Patrick T. Walsh, Patricia L. Podolin, Edward Long, and Joseph P. Foley
- Subjects
Receptors, CCR6 ,medicine.medical_treatment ,T cell ,Immunology ,Autoimmunity ,C-C chemokine receptor type 6 ,medicine.disease_cause ,Pathogenesis ,Chemokine receptor ,Interferon-gamma ,Mice ,T-Lymphocyte Subsets ,medicine ,Immunology and Allergy ,Animals ,Lung ,medicine.diagnostic_test ,business.industry ,Interleukin-17 ,Smoking ,Pneumonia ,Mice, Inbred C57BL ,Disease Models, Animal ,Bronchoalveolar lavage ,Cytokine ,medicine.anatomical_structure ,Pulmonary Emphysema ,Interleukin-4 ,business ,Bronchoalveolar Lavage Fluid ,CD8 - Abstract
Recently, patients with tobacco smoke induced emphysema have been shown to exhibit classical signs of T cell mediated autoimmunity characterized by autoantibody production and Th1 type responses. As the recently described Th17 type subset has been found to play a role in the pathogenesis of a number of autoimmune diseases previously considered to be Th1 driven, we sought to examine whether a Th17 type response was associated with airspace enlargement in a murine model of emphysema. Six to eight months exposure of mice to inhalation of mainstream cigarette smoke led to progressive airspace enlargement as defined by morphometric analysis. Flow cytometric analysis of the bronchoalveolar lavage (BAL) from these mice demonstrated a significant increase in the overall number of both CD4+ and CD8+ T cells present. These cells were subsequently examined for skewing towards a Th1, Th2 or Th17 phenotype by intracellular cytokine analysis. Distinct populations of BAL CD4+ T cells were found to express IFN-gamma or IL-17 demonstrating the presence of both a Th1 and Th17 type response. No expression of the Th2 associated cytokine IL-4 was detected. Further analysis of this Th17 subset demonstrated that the majority of cells with this effector phenotype express the chemokine receptor CCR6. Together these data identify a novel T cell subset associated with pulmonary inflammation as a result of cigarette smoke exposure. Given the reported roles of CCR6 and IL-17 in promoting pulmonary inflammation, this subset may play an important role in the pathogenesis of cigarette smoke induced autoimmunity.
- Published
- 2008
49. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature
- Author
-
Jonathan L. Linehan, Sarah Himmelfarb, Roxanne Tussiwand, Oliver J. Harrison, Shruti Naik, Sean Conlan, Clayton Deming, Mariam Quinones, Kenneth M. Murphy, Heidi H. Kong, Yasmine Belkaid, Seong-Ji Han, Julia A. Segre, Nicolas Bouladoux, Allyson L. Byrd, Jason M. Brenchley, Christoph Wilhelm, and Miriam Merad
- Subjects
0303 health sciences ,Multidisciplinary ,Inflammation ,Context (language use) ,Dendritic cell ,Biology ,biochemical phenomena, metabolism, and nutrition ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,Immunity ,Immunology ,medicine ,Skin immunity ,bacteria ,medicine.symptom ,Tissue homeostasis ,030304 developmental biology ,030215 immunology - Abstract
The skin represents the primary interface between the host and the environment. This organ is also home to trillions of microorganisms that play an important role in tissue homeostasis and local immunity. Skin microbial communities are highly diverse and can be remodelled over time or in response to environmental challenges. How, in the context of this complexity, individual commensal microorganisms may differentially modulate skin immunity and the consequences of these responses for tissue physiology remains unclear. Here we show that defined commensals dominantly affect skin immunity and identify the cellular mediators involved in this specification. In particular, colonization with Staphylococcus epidermidis induces IL-17A(+) CD8(+) T cells that home to the epidermis, enhance innate barrier immunity and limit pathogen invasion. Commensal-specific T-cell responses result from the coordinated action of skin-resident dendritic cell subsets and are not associated with inflammation, revealing that tissue-resident cells are poised to sense and respond to alterations in microbial communities. This interaction may represent an evolutionary means by which the skin immune system uses fluctuating commensal signals to calibrate barrier immunity and provide heterologous protection against invasive pathogens. These findings reveal that the skin immune landscape is a highly dynamic environment that can be rapidly and specifically remodelled by encounters with defined commensals, findings that have profound implications for our understanding of tissue-specific immunity and pathologies.
- Published
- 2015
- Full Text
- View/download PDF
50. Regulatory T Cells and Immune Tolerance in the Intestine
- Author
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Oliver J. Harrison and Fiona Powrie
- Subjects
Antigen-Presenting Cells ,Biology ,T-Lymphocytes, Regulatory ,General Biochemistry, Genetics and Molecular Biology ,Immune tolerance ,Immune system ,Immunity ,Transforming Growth Factor beta ,Immunopathology ,Immune Tolerance ,Humans ,Antigen-presenting cell ,Immunity, Cellular ,Microbiota ,Models, Immunological ,Transforming growth factor beta ,biochemical phenomena, metabolism, and nutrition ,Interleukin-10 ,Gastrointestinal Tract ,Intestines ,Interleukin 10 ,Immunology ,biology.protein ,Adaptation ,Erratum ,Perspectives - Abstract
A fundamental role of the mammalian immune system is to eradicate pathogens while minimizing immunopathology. Instigating and maintaining immunological tolerance within the intestine represents a unique challenge to the mucosal immune system. Regulatory T cells are critical for continued immune tolerance in the intestine through active control of innate and adaptive immune responses. Dynamic adaptation of regulatory T-cell populations to the intestinal tissue microenvironment is key in this process. Here, we discuss specialization of regulatory T-cell responses in the intestine, and how a breakdown in these processes can lead to chronic intestinal inflammation.
- Published
- 2013
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