Biology subjects

Spergel, J. M.

Publications and source records attributed to Spergel, J. M..

3 recordsLinked to original sources

bioRxiv2024

Companion to: A molecular basis for milk allergen immune recognition in eosinophilic esophagitis

BackgroundEosinophilic esophagitis (EoE) is a chronic, type 2 inflammatory disease that is increasing in incidence and has substantial morbidity. Despite being clinically defined as a food allergy, the molecular details of food antigen presentation and recognition by the immune system are unknown. ObjectiveThe objective of this study was to identify and characterize the molecular basis of milk antigen presentation and T cell recognition in a patient with EoE milk allergy. MethodsMilk-expanded TCR clonotypes were identified using ex vivo stimulation followed by single cell RNA with linked, paired TRA and TRB sequencing. HLA restriction and antigen specificity of TCRs were identified using a combination of lentiviral expression, HLA sequencing, antibody blockade, and a peptide library screen. ResultsWe isolated a {beta}-casein specific TCR clonotype (eoeTCR-4) and determined its HLA restriction (HLA-DRB1*07:01) and cognate antigen ({beta}-casein AA 59-78). EoeTCR-4 was not detected among a larger group of subjects and is likely private to EoE Subject 1. ConclusionIn conjunction with the parent manuscript, this companion article provides the first molecular identity of food antigen presentation and immune recognition in EoE. SUMMARYThis manuscript is a companion to the parent manuscript "A molecular basis for milk allergen immune recognition in eosinophilic esophagitis". It provides additional data and detailed methods not provided in the parent manuscript. It is designed to supplement and support the findings and conclusions of the parent manuscript.

immunology↗

bioRxiv2019

Toll-like receptor 2 stimulation augments esophageal epithelial barrier integrity

BackgroundA key concept of the hygiene hypothesis is that the microbiome modulates both epithelial barrier integrity as well as host immune responses. Defective expression of tight junction complex proteins alters this homeostatic process, and plays a role in atopic disorders including eosinophilic esophagitis. We tested the hypothesis that Toll-like receptor 2 (TLR2) stimulation improves esophageal barrier function in a cell-intrinsic manner by upregulation of TJ-protein expression using an in vitro model of human epithelium. MethodsPattern recognition receptor expression was assessed in esophageal epithelial cells from patients with EoE and non-EoE control patients. Functional consequences of TLR2 stimulation were investigated using human esophageal EPC2-hTERT cells in the three-dimensional air-liquid interface culture (ALI) model to evaluate transepithelial electrical resistance (TEER) and FITC-Dextran permeability. Characterization of TLR2-stimulated ALI cultures was performed by histology, immunohistochemistry, western blotting and chromatin immunoprecipitation. ResultsTLR2 stimulation increased TEER (1.28 to 1.31-fold) and decreased paracellular permeability to FITC-Dextran. Notably, TLR2 stimulation-induced increases in TEER were abolished by treatment with anti-TLR2 blocking antibody. Tight junction complex proteins claudin 1 and zonula occludens 1 were increased following TLR2 stimulation, and chromatin immunoprecipitation analysis demonstrated significant increase in histone 4 acetyl binding at the CLDN1 enhancer and promoter following zymosan treatment, implying the occurrence of durable chromatin changes in the esophageal epithelium. ConclusionsOur findings reveal that the TLR2 pathway may play a regulatory role as a mechanism that maintains epithelial barrier homeostasis in the esophagus.

immunology↗

bioRxiv2018

Increasing Rates of Diagnosis, Substantial Co-occurrence, and Variable Treatment Patterns of Eosinophilic Gastritis, Gastroenteritis and Colitis Based on 10 Year Data Across a Multi-Center Consortium

Financial Support and AcknowledgementsSupport for this project was provided through a research training grant as part of the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) (U54 AI117804). CEGIR is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS, and is funded through collaboration between NIAID, NIDDK, and NCATS. CEGIR is also supported by patient advocacy groups including APFED CURED and EFC. This project also received support from NIH T32 DK007634 (CCR).\n\nAuthor DisclosersPatricia Fulkerson: Grant funding from the NIH; Consultant for Genentech, Inc; Research support from Knopp Biosciences, LLC.\n\nGary Falk: Research support from Shire, Celgene, Adare, Regeneron. Consulting for Shire\n\nJonathan M. Spergel: Consultant for Regeneron, DBV Technology, Kaleo; Grant funding from DBV Technology, Aimmune Therapeutics, Food Allergy Research Education; Royalties from UpToDate\n\nNirmala Gonsalves: Royalties from UpToDate; Advisory board for Allakos\n\nSandeep K Gupta: Consultant for Alkalos, Abbott, QOL, Receptos; research support from Shire\n\nGlenn Furuta: Founder of EnteroTrack; Consultant for Shire; Royalties from UpToDate\n\nMarc E. Rothenberg: Consultant for Pulm One, Spoon Guru, ClostraBio, Celgene, Shire, Astra Zeneca, GlaxoSmithKline, Allakos, Adare, Regeneron and Novartis and has an equity interest in the first four listed and Immune Pharmaceuticals, and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust) and UpToDate. M.E.R. is an inventor of patents owned by Cincinnati Childrens.\n\nEvan Dellon: Consultant for Adare, Allakos, Alivio, Banner, Celgen/Receptos, Enumeral, GSK, Regeneron, Shire; Research funding from Adare, Celegene/Receptos, Miraca, Meritage, Nutricia, Regeneron, Shire, Educational grant from Banner, Holoclara\n\nStudy HighlightsO_ST_ABSWhat is current knowledge?C_ST_ABSO_LIEosinophilic gastrointestinal disorders (EGIDs) include eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), gastroenteritis (EGE), and colitis (EC).\nC_LIO_LINon-EoE EGIDs are rare with most studies limited to case reports or review of single center experiences.\nC_LIO_LIThere are no widely established guidelines for the diagnosis of EG, EGE, or EC.\nC_LI\n\nWhat is new here?O_LIIn this multicenter study, EG, EGE, and EC were all diagnosed with increasing frequency over the past decade.\nC_LIO_LIPresenting symptoms are non-specific and do not reliably distinguish between disorders.\nC_LIO_LIThere was no male predominance and the majority of subjects had atopy.\nC_LIO_LICo-occurrence of EG, EGE, and EC diagnoses is common, seen in 41% of patients.\nC_LIO_LIThere is substantial variability between centers in initial treatment approaches.\nC_LI

epidemiology↗