6 results on '"Natalia Jaeger"'
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2. MASS CYTOMETRY ANALYSIS OF CROHN’S DISEASE-LIKE PHENOTYPE OF THE ILEOANAL POUCH FOLLOWING ILEAL POUCH-ANAL ANASTOMOSIS FOR ULCERATIVE COLITIS
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Siyan Cao, Marina Cella, Natalia Jaeger, Matthew Ciorba, Guadalupe Oliva Escudero, Alexandra Gutierrez, Richard Rood, Deborah Rubin, Parakkal Deepak, and Marco Colonna
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Hepatology ,Gastroenterology ,Immunology and Allergy - Abstract
BACKGROUNDS For patients with medically refractory ulcerative colitis (UC), total proctocolectomy and ileal pouch-anal anastomosis (IPAA) has been the definitive surgery of choice. Approximately 10% of patients who were initially diagnosed with UC and underwent an IPAA, subsequently develop a condition referred to as Crohn’s disease-like phenotype of ileoanal pouch (CDP). CDP is typified by ulcers in the pre-pouch ileum, stricture involving the pouch or pre-pouch ileum, and/or fistulas. The etiology of CDP remains unknown and remains difficult to diagnose and treat. To define the mucosal immunology of CDP, we analyzed ileal samples from patients with CDP and patients with a normal pouch and pre-pouch ileum using mass cytometry (CyTOF). METHODS Ileal mucosal biopsies from patients with a history of CDP with long-segmental pre-pouch ileitis (n=10) and those with a normal pouch and pre-pouch ileum after IPAA for UC (n=9) were collected during routine pouchoscopy, frozen in medium, and processed, barcoded and analyzed in one CyTOF experiment. Data were analyzed by using viSNE for dimensionality reduction and CITRUS for clustering in Cytobank. RESULTS Compared with patients with a normal pouch/ileum, we observed the following in ileal samples from CDP based on viSNE analysis (Figure 1): 1) A decreased abundance of CD8+CD103+ tissue-resident T cells (TRM). This result is similar to data from colonic mucosal samples in patients with UC (our internal data not shown here and others), but unlike data from prior studies derived from inflamed ileal mucosal specimens in patients with CD (native bowel anatomy without IPAA) which had increased CD8+ TRM. 2) An increase in CD4+CD103-CD161+ Th17 cells previously linked to an activated Th17 phenotype in Crohn’s disease specimens. 3) Increased CD4+CD103-CD45RA+ T cells associated with reduced IL-10/IL-4 and increased TNF-a in IBD. 4) A higher abundance of CD4+CD103-TIGIT+ T cells that were previously shown to predict severity of pediatric IBD. 5) A decrease in CD8+CD103+CD127+ TRM in CDP, although its role in IBD is unclear. The findings from viSNE were confirmed by CITRUS (Figure 2). Further analyses of pouch samples as well as ileal samples from UC and CD with native GI anatomy (for comparison) using CyTOF and scRNAseq are currently underway. CONCLUSIONS We used mass cytometry to identify immune cells specific to ileal mucosa from patients with CDP. Interestingly, immune cells from the inflamed pre-pouch ileum share some features of those from either UC or CD with native bowel anatomy. We also identified an altered immune cell population which appears to be specific to CDP. These data reveal a unique immune landscape of CDP which may serve as a foundation for identifying therapeutic approaches that target specific cell populations for medical management of CDP. more...
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- 2022
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3. GRPR antagonist protects from drug-induced liver injury by impairing neutrophil chemotaxis and motility
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Gustavo B. Menezes, Maurício Menegatti Rigo, Natalia Jaeger, Cristina Bonorino, Rodrigo Dornelles da Silva, Pedro Marques, Bárbara N. Porto, Vinicius Duval da Silva, Rafaela Vaz Sousa Pereira, Maísa Mota Antunes, Débora Moreira Alvarenga, Tiago Giuliani Lopes, and Rafael S. Czepielewski more...
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0301 basic medicine ,Neutrophils ,Immunology ,Mice, Inbred Strains ,Inflammation ,Pharmacology ,Neutrophil Activation ,Receptors, Interleukin-8B ,Mice ,03 medical and health sciences ,Cell Movement ,medicine ,Animals ,Humans ,Immunology and Allergy ,Interleukin 8 ,CXC chemokine receptors ,Cells, Cultured ,Liver injury ,biology ,Chemotaxis ,Interleukin-8 ,Antagonist ,medicine.disease ,Peptide Fragments ,Receptors, Bombesin ,030104 developmental biology ,medicine.anatomical_structure ,Integrin alpha M ,Hepatocyte ,biology.protein ,Bombesin ,Chemical and Drug Induced Liver Injury ,medicine.symptom ,Protein Binding ,Signal Transduction - Abstract
Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF), where hepatocyte necrotic products trigger liver inflammation, release of CXC chemokine receptor 2 (CXCR2) ligands (IL-8) and other neutrophil chemotactic molecules. Liver infiltration by neutrophils is a major cause of the life-threatening tissue damage that ensues. A GRPR (gastrin-releasing peptide receptor) antagonist impairs IL-8-induced neutrophil chemotaxis in vitro. We investigated its potential to reduce acetaminophen-induced ALF, neutrophil migration, and mechanisms underlying this phenomenon. We found that acetaminophen-overdosed mice treated with GRPR antagonist had reduced DILI and neutrophil infiltration in the liver. Intravital imaging and cell tracking analysis revealed reduced neutrophil mobility within the liver. Surprisingly, GRPR antagonist inhibited CXCL2-induced migration in vivo, decreasing neutrophil activation through CD11b and CD62L modulation. Additionally, this compound decreased CXCL8-driven neutrophil chemotaxis in vitro independently of CXCR2 internalization, induced activation of MAPKs (p38 and ERK1/2) and downregulation of neutrophil adhesion molecules CD11b and CD66b. In silico analysis revealed direct binding of GRPR antagonist and CXCL8 to the same binding spot in CXCR2. These findings indicate a new potential use for GRPR antagonist for treatment of DILI through a mechanism involving adhesion molecule modulation and possible direct binding to CXCR2. more...
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- 2017
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4. Heterogeneity of human intestinal intraepithelial T cells and their abnormal distribution in Crohn’s disease revealed at high resolution
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Natalia Jaeger, Ramya Gamini, Marina Cella, Jorge L. Schettini, Mattia Bugatti, Shanrong Zhao, Charles V. Rosadini, Ekaterina Esaulova, Blanda Di Luccia, Baylee Kinnett, Willam Vermi, Maxim N. Artyomov, Thomas A Wynn, Ramnik J Xavier, Scott A. Jelinsky, and Marco Colonna more...
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Immunology ,Immunology and Allergy - Abstract
Crohn’s disease (CD) is a chronic transmural inflammation of intestinal segments caused by dysregulated interaction between microbiome and gut immune system. Recurrent/relapsing CD and resistance to medical treatments result in complications requiring surgery. High-dimensional single-cell profiling approaches, such as scRNA-seq and mass cytometry, have been recently performed on intestinal specimens from patients with IBD and controls. However, most of these studies have analyzed whole mucosal biopsies or the lamina propria (LP) compartment, while few have addressed the intraepithelial lymphocytes (IEL) compartment. Here, we profiled T cells purified from the IEL and LP from terminal ileum resections of adult severe CD cases by single cell technologies. Our study defined a vast heterogeneity of T cell lineages in the IEL compartment. IEL included, among others, unique γδT cell subsets: NKp30+γδ T cells expressing RORγt, which produced IL-26 upon NKp30 engagement and a subset expressing PDGFD and CSF1, which may act on epithelial cells, IEL ILC1s, and macrophages, respectively. We have also observed long-lived memory TCF7+CD8+ T cells expressing DC chemoattractants and TFH subsets that may respond to distinct glutathione-conjugated lipids. CD IEL showed a significant increase of activated TH17, coupled with decreased CD8+ T cells, γδT cells, TFH, and Treg. Conversely, the LP showed increased CD8+ T cells and reduced CD4+ T cells with a relative increase of TH17 over Treg/TFH. Results provide an unbiased view of diversity of cell lineages and their functional states in the intestinal mucosa of controls and CD and identify an altered spatial distribution of T cell subsets between the IEL and the LP compartments. more...
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- 2021
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5. Airway Microbiota-Host Interactions Regulate Secreted Leukocyte Proteinase Inhibitor Levels and Influence Allergic Airway Inflammation
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Natalia Jaeger, Ryan McDonough, Ariel Hernandez-Leyva, Anne Rosen, Naomi G. Wilson, Emilie V. Russler-Germain, Jiani N. Chai, Leonard B. Bacharier, Chyi-Song Hsieh, and Andrew L. Kau
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Immunology ,Immunology and Allergy - Abstract
Mucosal immune responses fine-tuned by naturally evolved interactions with native microbes influence airway inflammation but are not routinely integrated into experimental models. Here, we leverage a recently discovered murine-adapted airway microbe, Bordetella pseudohinzii (Bph), to investigate how chronic colonization impacts mucosal immunity and the development of allergic airway inflammation (AAI). Despite the persistent colonization, we did not observe significant weight loss in Bph colonized mice. Microscopic examination of the lungs demonstrated the formation of lymphoid aggregates, consistent with inducible Bronchus Associated Lymphoid Tissue (iBALT). Airway colonization of mice with Bph elicits an antigen-specific Th17 immune response that aids in controlling bacterial abundance. Remarkably, when animals undergo allergic airway challenge, mice previously colonized with Bph demonstrate protection from AAI. This phenotype corresponded to a reduction in type 2 cytokines, eosinophilic infiltration, goblet cell metaplasia, and airway hyper responsiveness. Colonization with Bph does not appear to impact the degree of allergic sensitization nor the presentation of allergen in the lung. Further, colonization and the Th17 response was associated with increased expression of Secreted Leukocyte Proteinase Inhibitor (SLPI), an antimicrobial peptide with anti-inflammatory properties. We confirmed these findings in humans by showing that higher levels of SLPI correlate both to improved asthma control and the presence of the asthma-associated bacterium, Haemophilus influenzae. We propose that SLPI could be used as a biomarker of beneficial host-commensal relationships in the airway. more...
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- 2020
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6. Airway Microbes modulate Allergic Airway Inflammation through Secreted Leukocyte Proteinase Inhibitor
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Jiani N. Chai, Ariel Hernandez-Leyva, Anne Rosen, Emilie V. Russler-Germain, Leonard B. Bacharier, Natalia Jaeger, Ryan McDonough, Chyi-Song Hsieh, and Naomi G. Wilson
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Allergic airway inflammation ,business.industry ,Proteinase inhibitor ,Immunology ,Immunology and Allergy ,Medicine ,Airway ,business - Published
- 2020
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