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1.
J Allergy Clin Immunol ; 153(5): 1355-1368, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38310974

RESUMO

BACKGROUND: Eosinophilic esophagitis (EoE) is an increasingly common inflammatory condition of the esophagus; however, the underlying immunologic mechanisms remain poorly understood. The epithelium-derived cytokine IL-33 is associated with type 2 immune responses and elevated in esophageal biopsy specimens from patients with EoE. OBJECTIVE: We hypothesized that overexpression of IL-33 by the esophageal epithelium would promote the immunopathology of EoE. METHODS: We evaluated the functional consequences of esophageal epithelial overexpression of a secreted and active form of IL-33 in a novel transgenic mouse, EoE33. EoE33 mice were analyzed for clinical and immunologic phenotypes. Esophageal contractility was assessed. Epithelial cytokine responses were analyzed in three-dimensional organoids. EoE33 phenotypes were further characterized in ST2-/-, eosinophil-deficient, and IL-13-/- mice. Finally, EoE33 mice were treated with dexamethasone. RESULTS: EoE33 mice displayed ST2-dependent, EoE-like pathology and failed to thrive. Esophageal tissue remodeling and inflammation included basal zone hyperplasia, eosinophilia, mast cells, and TH2 cells. Marked increases in levels of type 2 cytokines, including IL-13, and molecules associated with immune responses and tissue remodeling were observed. Esophageal organoids suggested reactive epithelial changes. Genetic deletion of IL-13 in EoE33 mice abrogated pathologic changes in vivo. EoE33 mice were responsive to steroids. CONCLUSIONS: IL-33 overexpression by the esophageal epithelium generated immunopathology and clinical phenotypes resembling human EoE. IL-33 may play a pivotal role in the etiology of EoE by activating the IL-13 pathway. EoE33 mice are a robust experimental platform for mechanistic investigation and translational discovery.


Assuntos
Esofagite Eosinofílica , Interleucina-13 , Interleucina-33 , Animais , Humanos , Camundongos , Modelos Animais de Doenças , Esofagite Eosinofílica/imunologia , Esofagite Eosinofílica/genética , Esofagite Eosinofílica/patologia , Eosinófilos/imunologia , Mucosa Esofágica/patologia , Mucosa Esofágica/imunologia , Esôfago/patologia , Esôfago/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-13/metabolismo , Interleucina-33/genética , Interleucina-33/imunologia , Interleucina-33/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
2.
J Allergy Clin Immunol ; 152(2): 469-485.e10, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37028525

RESUMO

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are critical mediators of type 2 respiratory inflammation, releasing IL-5 and IL-13 and promoting the pulmonary eosinophilia associated with allergen provocation. Although ILC2s have been shown to promote eosinophil activities, the role of eosinophils in group 2 innate lymphoid cell (ILC2) responses is less well defined. OBJECTIVE: We sought to investigate the role of eosinophils in activation of ILC2s in models of allergic asthma and in vitro. METHODS: Inducible eosinophil-deficient mice were exposed to allergic respiratory inflammation models of asthma, such as ovalbumin or house dust mite challenge, or to innate models of type 2 airway inflammation, such as inhalation of IL-33. Eosinophil-specific IL-4/13-deficient mice were used to address the specific roles for eosinophil-derived cytokines. Direct cell interactions between ILC2s and eosinophils were assessed by in vitro culture experiments. RESULTS: Targeted depletion of eosinophils resulted in significant reductions of total and IL-5+ and IL-13+ lung ILC2s in all models of respiratory inflammation. This correlated with reductions in IL-13 levels and mucus in the airway. Eosinophil-derived IL-4/13 was necessary for both eosinophil and ILC2 accumulation in lung in allergen models. In vitro, eosinophils released soluble mediators that induced ILC2 proliferation and G protein-coupled receptor-dependent chemotaxis of ILC2s. Coculture of ILC2s and IL-33-activated eosinophils resulted in transcriptome changes in both ILC2s and eosinophils, suggesting potential novel reciprocal interactions. CONCLUSION: These studies demonstrate that eosinophils play a reciprocal role in ILC2 effector functions as part of both adaptive and innate type 2 pulmonary inflammatory events.


Assuntos
Asma , Imunidade Inata , Camundongos , Animais , Eosinófilos/metabolismo , Interleucina-33/metabolismo , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Interleucina-4/metabolismo , Linfócitos , Pulmão , Citocinas/metabolismo , Asma/metabolismo , Inflamação/metabolismo , Alérgenos/metabolismo
3.
J Allergy Clin Immunol ; 152(6): 1550-1568, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37652141

RESUMO

BACKGROUND: Basal zone hyperplasia (BZH) and dilated intercellular spaces (DISs) are thought to contribute to the clinical manifestations of eosinophilic esophagitis (EoE); however, the molecular pathways that drive BZH remain largely unexplored. OBJECTIVE: We sought to define the role of IL-13-induced transcriptional programs in esophageal epithelial proliferation in EoE. METHODS: We performed RNA sequencing, bioinformatics, Western blot, reverse transcriptase quantitative PCR, and histologic analyses on esophageal biopsies from healthy control and patients with EoE, primary esophageal cells derived from patients with EoE, and IL-13-stimulated esophageal epithelial keratinocytes grown at the air-liquid interface (EPC2-ALI). Genetic (shRNA) and pharmacologic (proteolysis-targeting chimera degrader) approaches and in vivo model of IL-13-induced esophageal epithelial remodeling (Krt5-rtTA x tetO-IL-13Tg) were used to define the role of signal transducer and activator of transcription 3 (STAT3) and STAT6 and secreted frizzled-related protein 1 (SFRP1) in esophageal epithelial proliferation. RESULTS: RNA-sequencing analysis of esophageal biopsies (healthy control vs EoE) and EPC2-ALI revealed 82 common differentially expressed genes that were enriched for putative STAT3 target genes. In vitro and in vivo analyses revealed a link between IL-13-induced STAT3 and STAT6 phosphorylation, SFRP1 mRNA expression, and esophageal epithelial proliferation. In vitro studies showed that IL-13-induced esophageal epithelial proliferation was STAT3-dependent and regulated by the STAT3 target SFRP1. SFRP1 mRNA is increased in esophageal biopsies from patients with active EoE compared with healthy controls or patients in remission and identifies an esophageal suprabasal epithelial cell subpopulation that uniquely expressed the core EoE proinflammatory transcriptome genes (CCL26, ALOX15, CAPN14, ANO1, and TNFAIP6). CONCLUSIONS: These studies identify SFRP1 as a key regulator of IL-13-induced and STAT3-dependent esophageal proliferation and BZH in EoE and link SFRP1+ esophageal epithelial cells with the proinflammatory and epithelial remodeling response in EoE.


Assuntos
Esofagite Eosinofílica , Humanos , Esofagite Eosinofílica/patologia , Interleucina-13/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Células Epiteliais/metabolismo , RNA Mensageiro/metabolismo , Proliferação de Células
4.
J Allergy Clin Immunol ; 151(3): 595-606, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36872039

RESUMO

Continuing insight into the molecular mechanisms of atopic disorders has enabled the development of biologics to precisely target these diseases. Food allergy (FA) and eosinophilic gastrointestinal disorders (EGIDs) are driven by similar inflammatory molecular mechanisms and exist along the same atopic disease spectrum. Therefore, many of the same biologics are being investigated to target key drivers of mechanisms shared across the disease states. The enormous potential of biologics for the treatment of FA and EGIDs is highlighted by the significant increases in the number of ongoing clinical trials (more than 30) evaluating their use in these disease states, as well as by the recent US Food and Drug Administration approval of dupilumab for the treatment of eosinophilic esophagitis. Here we discuss past and current research into the use of biologics in FA and EGIDs and their potential role in improving treatment options in the future, with the need to have biologics widely clinically available.


Assuntos
Produtos Biológicos , Enterite , Esofagite Eosinofílica , Hipersensibilidade Alimentar , Estados Unidos , Humanos , Criança
5.
J Allergy Clin Immunol ; 152(6): 1382-1393, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37660987

RESUMO

The Consortium of Eosinophilic Gastrointestinal Diseases and The International Gastrointestinal Eosinophil Researchers organized a day-long symposium at the 2022 Annual Meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured a review of recent discoveries in the basic biology and pathogenesis of eosinophilic gastrointestinal diseases (EGIDs) in addition to advances in our understanding of the clinical features of EGIDs. Diagnostic and management approaches were reviewed and debated, and clinical trials of emerging therapies were highlighted. Herein, we briefly summarize the breakthrough discoveries in EGIDs.


Assuntos
Asma , Enterite , Eosinofilia , Esofagite Eosinofílica , Gastrite , Humanos , Estados Unidos , Enterite/diagnóstico , Enterite/terapia , Asma/diagnóstico , Asma/terapia
6.
Allergy ; 78(1): 192-201, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35899466

RESUMO

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic allergic disease associated with type 2 inflammation and epithelial barrier dysfunction. The etiology is unknown, however, genetic heritability studies suggest environmental factors play a key role in pathogenesis. Detergents, such as sodium dodecyl sulfate (SDS), are common ingredients in household products such as dish soap and toothpaste. We hypothesized detergent exposure decreases epithelial barrier function and induces esophageal inflammation. METHODS: Immortalized esophageal epithelial cells (EPC2) were cultured in air-liquid interface (ALI) and exposed to SDS. Barrier function/activity was assessed by transepithelial electrical resistance (TEER), FITC-dextran flux, and RT-PCR. Additionally, SDS-treated mouse esophageal organoids were evaluated for morphology. To investigate the effects of SDS in vivo, mice were treated with 0.5% SDS in drinking water for 14 days. Esophagi were assessed by gross morphology, histopathology, protein expression, and bulk RNA sequencing. RESULTS: When EPC2 cells were exposed to SDS (5 µg/ml) for 96 h, TEER decreased (p = 0.03), and FITC-dextran flux increased (p = 0.0002). mRNA expression of IL-33 increased 4.5-fold (p = 0.02) at 6 h and DSG1 decreased (p < 0.0001) by 72 h. Disrupted epithelial integrity was noted in SDS-treated esophageal organoids. When mice were exposed to SDS, they showed increased esophageal width, chemokine, and metalloprotease levels. Mice treated with SDS also showed increased IL-33 protein expression, basal zone hyperplasia, CD4+ cell infiltration, and esophageal eosinophilia. RNA sequencing revealed upregulation of immune response pathway genes. CONCLUSION: Exposure to SDS decreases esophageal barrier integrity, stimulates IL-33 production, and promotes epithelial hyperplasia and tissue eosinophilia. Detergents may be a key environmental trigger in EoE pathogenesis.


Assuntos
Detergentes , Esofagite Eosinofílica , Animais , Camundongos , Detergentes/efeitos adversos , Células Epiteliais/metabolismo , Hiperplasia/patologia , Inflamação/metabolismo , Interleucina-33/metabolismo
7.
Exp Physiol ; 108(6): 874-890, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37184360

RESUMO

NEW FINDINGS: What is the central question of this study? What are the physiological roles of cardiomyocyte-derived tetrahydrobiopterin (BH4) in cardiac metabolism and stress response? What is the main finding and its importance? Cardiomyocyte BH4 has a physiological role in cardiac metabolism. There was a shift of substrate preference from fatty acid to glucose in hearts with targeted deletion of BH4 synthesis. The changes in fatty-acid metabolic profile were associated with a protective effect in response to ischaemia-reperfusion (IR) injury, and reduced infarct size. Manipulating fatty acid metabolism via BH4 availability could play a therapeutic role in limiting IR injury. ABSTRACT: Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) synthases in which its production of NO is crucial for cardiac function. However, non-canonical roles of BH4 have been discovered recently and the cell-specific role of cardiomyocyte BH4 in cardiac function and metabolism remains to be elucidated. Therefore, we developed a novel mouse model of cardiomyocyte BH4 deficiency, by cardiomyocyte-specific deletion of Gch1, which encodes guanosine triphosphate cyclohydrolase I, a required enzyme for de novo BH4 synthesis. Cardiomyocyte (cm)Gch1 mRNA expression and BH4 levels from cmGch1 KO mice were significantly reduced compared to Gch1flox/flox (WT) littermates. Transcriptomic analyses and protein assays revealed downregulation of genes involved in fatty acid oxidation in cmGch1 KO hearts compared with WT, accompanied by increased triacylglycerol concentration within the myocardium. Deletion of cardiomyocyte BH4 did not alter basal cardiac function. However, the recovery of left ventricle function was improved in cmGch1 KO hearts when subjected to ex vivo ischaemia-reperfusion (IR) injury, with reduced infarct size compared to WT hearts. Metabolomic analyses of cardiac tissue after IR revealed that long-chain fatty acids were increased in cmGch1 KO hearts compared to WT, whereas at 5 min reperfusion (post-35 min ischaemia) fatty acid metabolite levels were higher in WT compared to cmGch1 KO hearts. These results indicate a new role for BH4 in cardiomyocyte fatty acid metabolism, such that reduction of cardiomyocyte BH4 confers a protective effect in response to cardiac IR injury. Manipulating cardiac metabolism via BH4 could play a therapeutic role in limiting IR injury.


Assuntos
Miócitos Cardíacos , Traumatismo por Reperfusão , Camundongos , Animais , Miócitos Cardíacos/metabolismo , Traumatismo por Reperfusão/metabolismo , Óxido Nítrico Sintase/metabolismo , Infarto/metabolismo , Ácidos Graxos/metabolismo
8.
Curr Allergy Asthma Rep ; 23(8): 443-451, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37233851

RESUMO

PURPOSE OF REVIEW: The prevalence and incidence of allergic disease have been rising in Westernized countries since the twentieth century. Increasingly, evidence suggests that damage to the epithelium initiates and shapes innate and adaptive immune responses to external antigens. The objective of this review is to examine the role of detergents as a potential risk factor for developing allergic disease. RECENT FINDINGS: Herein, we identify key sources of human detergent exposure. We summarize the evidence suggesting a possible role for detergents and related chemicals in initiating epithelial barrier dysfunction and allergic inflammation. We primarily focus on experimental models of atopic dermatitis, asthma, and eosinophilic esophagitis, which show compelling associations between allergic disease and detergent exposure. Mechanistic studies suggest that detergents disrupt epithelial barrier integrity through their effects on tight junction or adhesion molecules and promote inflammation through epithelial alarmin release. Environmental exposures that disrupt or damage the epithelium may account for the increasing rates of allergic disease in genetically susceptible individuals. Detergents and related chemical compounds represent possible modifiable risk factors for the development or exacerbation of atopy.


Assuntos
Asma , Dermatite Atópica , Esofagite Eosinofílica , Humanos , Detergentes/efeitos adversos , Inflamação
9.
Dig Dis Sci ; 68(6): 2406-2413, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36973521

RESUMO

BACKGROUND: Food-specific immunoglobulin G4 (FS-IgG4) is associated with eosinophilic esophagitis (EoE); however, it is not clear whether production is limited to the esophagus. AIMS: To assess FS-IgG4 levels in the upper gastrointestinal tract and plasma and compare these with endoscopic disease severity, tissue eosinophil counts, and patient-reported symptoms. METHODS: We examined prospectively banked plasma, throat swabs, and upper gastrointestinal biopsies (esophagus, gastric antrum, and duodenum) from control (n = 15), active EoE (n = 24), and inactive EoE (n = 8) subjects undergoing upper endoscopy. Patient-reported symptoms were assessed using the EoE symptom activity index (EEsAI). Endoscopic findings were evaluated using the EoE endoscopic reference score (EREFS). Peak eosinophils per high-power field (eos/hpf) were assessed from esophageal biopsies. Biopsy homogenates and throat swabs were normalized for protein content and assessed for FS-IgG4 to milk, wheat, and egg. RESULTS: Median FS-IgG4 for milk and wheat was significantly increased in the plasma, throat swabs, esophagus, stomach, and duodenum of active EoE subjects compared to controls. No significant differences for milk- or wheat-IgG4 were observed between active and inactive EoE subjects. Among the gastrointestinal sites sampled, FS-IgG4 levels were highest in the esophagus. Esophageal FS-IgG4 for all foods correlated significantly across all sites sampled (r ≥ 0.59, p < 0.05). Among subjects with EoE, esophageal FS-IgG4 correlated significantly with peak eos/hpf (milk and wheat) and total EREFS (milk). EEsAI scores and esophageal FS-IgG4 levels did not correlate. CONCLUSIONS: Milk and wheat FS-IgG4 levels are elevated in plasma and throughout the upper gastrointestinal tract in EoE subjects and correlate with endoscopic findings and esophageal eosinophilia.


Assuntos
Esofagite Eosinofílica , Hipersensibilidade Alimentar , Imunoglobulina G , Trato Gastrointestinal Superior , Humanos , Imunoglobulina G/sangue , Estudos Prospectivos , Estudos de Casos e Controles , Eosinófilos , Endoscopia Gastrointestinal , Biomarcadores , Trato Gastrointestinal Superior/metabolismo , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso
10.
J Med Genet ; 59(1): 65-74, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34006618

RESUMO

BACKGROUND: Wolfram syndrome (WFS) is a rare disorder characterised by childhood-onset diabetes mellitus and progressive optic atrophy. Most patients have variants in the WFS1 gene. We undertook functional studies of WFS1 variants and correlated these with WFS1 protein expression and phenotype. METHODS: 9 patients with a clinical diagnosis of WFS were studied with quantitative PCR for markers of endoplasmic reticulum (ER) stress and immunoblotting of fibroblast protein extracts for WFS1 protein expression. Luciferase reporter assay was used to assess ATF-6 dependent unfolded protein response (UPR) activation. RESULTS: 6 patients with compound heterozygous nonsense mutations in WFS1 had no detectable WFS1 protein expression; 3 patients with missense variants had 4%, 45% and 48% WFS1 protein expression. One of these also had an OPA1 mutation and was reclassified as autosomal dominant optic atrophy-plus syndrome. There were no correlations between ER stress marker mRNA and WFS1 protein expression. ERSE-luciferase reporter indicated activation of the ATF6 branch of UPR in two patients tested. Patients with partial WFS1 expression showed milder visual acuity impairment (asymptomatic or colour blind only), compared with those with absent expression (registered severe vision impaired) (p=0.04). These differences remained after adjusting for duration of optic atrophy. CONCLUSIONS: Patients with WFS who have partial WFS1 protein expression present with milder visual impairment. This suggests a protective effect of partial WFS1 protein expression on the severity and perhaps progression of vision impairment and that therapies to increase residual WFS1 protein expression may be beneficial.


Assuntos
Regulação da Expressão Gênica , Proteínas de Membrana/genética , Mutação , Atrofia Óptica/genética , Fenótipo , Síndrome de Wolfram/genética , Adolescente , Adulto , Códon sem Sentido , Feminino , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Síndrome de Wolfram/metabolismo , Adulto Jovem
11.
J Clin Immunol ; 42(6): 1321-1329, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35729475

RESUMO

PURPOSE: The incidence of severe combined immunodeficiency (SCID) in the USA was reported as 1 in 58,000 live births. In Arizona, it was anticipated that newborn screening would identify two to four cases of SCID per year. This estimate did not consider ethnic nuances in Arizona, with higher percentages of Native American and Hispanic populations compared to national percentages. The true incidence of SCID and non-SCID T cell lymphopenia has not previously been reported in Arizona. METHODS: A retrospective chart review was performed on all abnormal SCID newborn screening (NBS) tests in Arizona from January 1, 2018, to December 31, 2019, using data from the Arizona Department of Health Services and the Phoenix Children's Hospital's electronic medical record [IRB# 20-025]. RESULTS: Seven infants were diagnosed with SCID, yielding an incidence of 1 in 22,819 live births. Four of these infants had Artemis-type SCID. Thirteen infants were identified with an abnormal initial NBS which ultimately did not lead to a diagnosis of SCID. Four of these infants were diagnosed with congenital syndromes associated with T cell lymphopenia. Infants of Hispanic ethnicity were over-represented in this cohort. CONCLUSION: Over 2 years, NBS in Arizona confirmed an incidence more than 2.5 times that reported nationally. This increased incidence is likely reflective of Arizona's unique population profile, with a higher percentage of Native American population. The findings in our non-SCID cohort are in alignment with previously published data, except for an increased percentage of infants of Hispanic/Latino ethnicity, possibly reflecting Arizona's increased percentage of Hispanic/Latino population compared to the general US population.


Assuntos
Linfopenia , Imunodeficiência Combinada Severa , Arizona/epidemiologia , Criança , Humanos , Lactente , Recém-Nascido , Linfopenia/diagnóstico , Linfopenia/epidemiologia , Triagem Neonatal , Estudos Retrospectivos , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/epidemiologia
13.
Clin Gastroenterol Hepatol ; 19(6): 1151-1159.e14, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32434067

RESUMO

BACKGROUND & AIMS: Gastrointestinal side effects are common during oral immunotherapy (OIT) and eosinophilic esophagitis (EoE) is a potential complication. We aimed to characterize eosinophilic gastrointestinal responses to peanut OIT, in which peanut protein is given orally, with incremental increases in dose over time. METHODS: Twenty adults with IgE-mediated peanut allergy were randomly assigned to groups given peanut OIT (n = 15) or placebo (n = 5); 1 additional subject withdrew before randomization. Serial gastrointestinal biopsies were collected at baseline (n = 21, 0 weeks), following dose escalation (n = 10, 52 weeks), and during the maintenance phase (n = 11, 104 weeks). Endoscopic findings were characterized using the EoE endoscopic reference score. Biopsies were assessed for eosinophils per high-power field (eos/hpf) and other pathology features using EoE histologic scoring system scores. We performed immunohistochemical analyses of eosinophil peroxidase deposition, quantified using automated image analysis. RESULTS: At baseline, no subjects reported current gastrointestinal symptoms. However, 3 of the 21 subjects (14%) had esophageal peak eosinophil counts ≥15 eos/hpf and all subjects had dilated intercellular spaces (DIS). OIT induced or exacerbated esophageal eosinophilia (EE) at 52 weeks in most subjects (peak eosinophil counts >5 eos/hpf in 6 of 7 patients [86%]; peak eosinophil counts ≥15 eos/hpf in 4 of 7 patients [57%]). One subject met clinicopathologic criteria for EoE and withdrew; no significant changes in esophageal peak eosinophil counts were observed in the placebo group. EE in the OIT group corresponded with significant increases in EoE histologic scoring system scores and deposition of eosinophil peroxidase. In 4 of 6 participants (67%), OIT-induced EE and gastrointestinal eosinophilia resolved by the end of the maintenance phase. Gastrointestinal symptoms were not clearly associated with EE or gastrointestinal eosinophilia. CONCLUSIONS: In this pilot study, we found that peanut OIT-induced EE and gastrointestinal eosinophilia are usually transient and are not always associated with gastrointestinal symptoms. Clinicaltrials.gov no: NCT02103270.


Assuntos
Esofagite Eosinofílica , Hipersensibilidade a Amendoim , Adulto , Arachis , Eosinófilos , Humanos , Imunoterapia/efeitos adversos , Hipersensibilidade a Amendoim/terapia , Projetos Piloto
14.
Pediatr Dev Pathol ; 24(6): 513-522, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34176359

RESUMO

BACKGROUND: Diagnosis of non-esophageal eosinophilic gastrointestinal disorders requires quantification of tissue eosinophils. Our objective was to evaluate eosinophil peroxidase (EPX) immunohistochemistry (IHC) as a method for histologic diagnosis of eosinophilic gastritis (EG) and eosinophilic duodenitis (EoD). METHODS: We performed a retrospective analysis of biopsies from pediatric EG/EoD cases and controls. Subjects with EG or EoD had ≥30 eosinophils per high power field (eos/hpf) in ≥5 hpf in the stomach and/or ≥3 hpf in the duodenum, respectively. Controls had no histopathologic diagnosis recorded. Tissue eosinophil counts were assessed by hematoxylin & eosin stains. EPX stains were assessed using a unique histopathologic scoring system. Slides were digitized and EPX+ staining area/mm2 was quantified by image analysis. RESULTS: Twenty-six EG/EoD cases and 40 controls were analyzed. EPX scores and EPX/mm2 levels were markedly elevated in EG/EoD (p ≤ 0.0001). Eosinophil density (eos/mm2) correlated strongly with EPX scores and EPX/mm2 levels in the stomach (r ≥ 0.77) and moderately with EPX scores and EPX/mm2 levels in the duodenum (r ≥ 0.52); (p < 0.0001). EPX quantification identified EG/EoD subjects with high diagnostic accuracy (EPX score: AUC = 1 for EG and EoD; EPX/mm2: AUC = 0.98 (95%CI 0.96-1) for EG, AUC = 0.91 (95%CI 0.81-1) for EoD). CONCLUSION: EPX-based assessment of eosinophilic inflammation may facilitate automated histologic diagnosis.


Assuntos
Enterite , Esofagite Eosinofílica , Biópsia , Criança , Peroxidase de Eosinófilo , Eosinofilia , Eosinófilos , Gastrite , Humanos , Imuno-Histoquímica , Estudos Retrospectivos
15.
Dig Dis Sci ; 66(3): 775-783, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32248390

RESUMO

BACKGROUND: Diagnosis of eosinophilic esophagitis (EoE) requires manual quantification of tissue eosinophils. Eosinophil peroxidase (EPX) is an eosinophil-specific, cytoplasmic granule protein released during degranulation. AIMS: The objective of this study was to evaluate image analysis of EPX immunohistochemistry as an automated method for histologic diagnosis of EoE. METHODS: We performed a secondary analysis of prospectively collected esophageal biopsies obtained from adult subjects with EoE and controls. Tissue sections were stained with hematoxylin and eosin (H&E) and evaluated for peak eosinophils per high power field (eos/hpf). The same slides were de-stained and re-stained to detect EPX for direct comparison. Slides were digitized, and EPX staining area/mm2 was quantified using image analysis. Paired samples were compared for changes in EPX staining in treatment responders and non-responders. RESULTS: Thirty-eight EoE cases and 49 controls were analyzed. Among EoE subjects, matched post-treatment biopsies were available for 21 responders and 10 non-responders. Baseline EPX/mm2 was significantly increased in EoE subjects and decreased in treatment responders. EPX quantification correlated strongly with eos/hpf (r = 0.84, p < 0.0001) and identified EoE subjects with high diagnostic accuracy (AUC 0.95, p < 0.0001). The optimal diagnostic EPX-positive pixel/area threshold was 17,379 EPX/mm2. Several controls (5/49) with < 15 eos/hpf on H&E staining exceeded this cutoff. CONCLUSIONS: EPX/mm2 correlates strongly with eos/hpf, accurately identifies subjects with EoE, and decreases in treatment responders. Automated quantification of intact eosinophils and their degranulation products may enhance pathologic assessment. Future studies are needed to correlate EPX/mm2 with symptoms, endoscopic findings, and esophageal distensibility.


Assuntos
Peroxidase de Eosinófilo/análise , Esofagite Eosinofílica/diagnóstico , Eosinófilos/enzimologia , Processamento de Imagem Assistida por Computador/métodos , Imuno-Histoquímica/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos de Casos e Controles , Esôfago/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Coloração e Rotulagem/métodos , Adulto Jovem
16.
Dis Esophagus ; 34(1)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33016307

RESUMO

As the awareness among gastroenterologists regarding endoscopic features suggesting eosinophilic esophagitis is increasing, individuals without symptoms of esophageal dysfunction are increasingly being found to have esophageal eosinophilia on biopsies performed during upper gastrointestinal endoscopies. However, the course of disease and the management of these asymptomatic individuals with esophageal eosinophilia remain elusive. In this review, we propose a definition of asymptomatic individuals with esophageal eosinophilia and discuss the prevalence, risk factors, and course of disease of this specific patient group. Furthermore, we have established a diagnostic and therapeutic pathway based on the most recent available data.


Assuntos
Esofagite Eosinofílica , Adulto , Biópsia , Endoscopia , Esofagite Eosinofílica/diagnóstico , Humanos , Prevalência
17.
J Clin Rheumatol ; 27(8S): S627, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33492030

RESUMO

BACKGROUND: PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) syndrome is diagnosed clinically. Adult-onset PFAPA syndrome is rare and often has a more diverse clinical presentation that its childhood counterpart. This is the first reported case of adult-onset PFAPA syndrome with complete response to lingual tonsillectomy. CASE SUMMARY: A 41-year-old man was evaluated for periodic fevers associated with uvulitis, cervical lymphadenitis, pharyngitis, and lower extremity rash. He had a variable response to steroids and was intolerant of colchicine. Laboratory workup revealed intermittent elevation of erythrocyte sedimentation rate and C-reactive protein level. Computed tomography neck and laryngoscopy confirmed adenoidal and lingual tonsillar hypertrophy. He underwent adenoidectomy and lingual tonsillectomy with resolution of symptoms. CONCLUSIONS: Hypertrophy of the remaining lymphoid structures within Waldeyer's ring may be associated with remote recurrence of PFAPA syndrome after tonsillectomy. Lingual tonsillectomy may be an alternative treatment strategy in select patients with PFAPA, prominent lingual hypertrophy, and incomplete response to steroids.


Assuntos
Linfadenite , Faringite , Estomatite Aftosa , Tonsilectomia , Adulto , Criança , Febre/diagnóstico , Febre/etiologia , Febre/terapia , Humanos , Linfadenite/diagnóstico , Linfadenite/cirurgia , Masculino , Faringite/diagnóstico , Faringite/etiologia , Faringite/cirurgia , Estomatite Aftosa/diagnóstico , Estomatite Aftosa/cirurgia
18.
Oncology ; 98(5): 318-320, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32182611

RESUMO

BACKGROUND: Bullous pemphigoid (BP) is a rare autoimmune blistering condition characterized by antibodies to the structural proteins BP1 and BP2 at the dermal-epidermal junction. The link between BP and malignancy remains unclear. Due to the rarity of the disease, there have been few studies with small sample sizes characterizing the association between BP and malignancy. OBJECTIVES: There were two main goals of this retrospective cohort study: (1) to look at the associated risk of malignancy in patients with BP compared to controls and (2) to compare the rates of malignancy in two separate hospitals with differing patient populations. METHOD: We reviewed the medical records of 99 patients diagnosed with BP observed between 2014 and 2019. 66 patients were from Keck Hospital and 33 were from Los Angeles County/University of Southern California (LAC/USC) Hospital. Each patient was age- and sex-matched to a control from the same hospital. RESULTS: Malignancies occurred in 26 BP patients and 29 controls. 7 of the BP patients from LAC/USC Hospital (21.2%) and 19 patients from Keck Hospital (28.8%) had malignancies. CONCLUSIONS: Overall, we did not find an increased risk of malignancy in BP patients compared to controls, nor did we find a statistically differing rate of malignancy in BP patients from various socioeconomic and ethnic backgrounds.


Assuntos
Neoplasias/epidemiologia , Penfigoide Bolhoso/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Estudos Retrospectivos
20.
Eur Respir J ; 53(5)2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30728205

RESUMO

The inflammatory responses in chronic airway diseases leading to emphysema are not fully defined. We hypothesised that lung eosinophilia contributes to airspace enlargement in a mouse model and to emphysema in patients with chronic obstructive pulmonary disease (COPD).A transgenic mouse model of chronic type 2 pulmonary inflammation (I5/hE2) was used to examine eosinophil-dependent mechanisms leading to airspace enlargement. Human sputum samples were collected for translational studies examining eosinophilia and matrix metalloprotease (MMP)-12 levels in patients with chronic airways disease.Airspace enlargement was identified in I5/hE2 mice and was dependent on eosinophils. Examination of I5/hE2 bronchoalveolar lavage identified elevated MMP-12, a mediator of emphysema. We showed, in vitro, that eosinophil-derived interleukin (IL)-13 promoted alveolar macrophage MMP-12 production. Airspace enlargement in I5/hE2 mice was dependent on MMP-12 and eosinophil-derived IL-4/13. Consistent with this, MMP-12 was elevated in patients with sputum eosinophilia and computed tomography evidence of emphysema, and also negatively correlated with forced expiratory volume in 1 s.A mouse model of chronic type 2 pulmonary inflammation exhibited airspace enlargement dependent on MMP-12 and eosinophil-derived IL-4/13. In chronic airways disease patients, lung eosinophilia was associated with elevated MMP-12 levels, which was a predictor of emphysema. These findings suggest an underappreciated mechanism by which eosinophils contribute to the pathologies associated with asthma and COPD.


Assuntos
Eosinófilos/imunologia , Interleucina-13/imunologia , Pneumonia/etiologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Enfisema Pulmonar/etiologia , Idoso , Animais , Asma/imunologia , Asma/patologia , Modelos Animais de Doenças , Eosinófilos/patologia , Feminino , Humanos , Interleucina-4/imunologia , Macrófagos Alveolares/patologia , Masculino , Metaloproteinase 12 da Matriz/imunologia , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Análise Multivariada , Pneumonia/imunologia , Pneumonia/patologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/imunologia , Enfisema Pulmonar/patologia , Análise de Regressão , Sistema Respiratório/fisiopatologia
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