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Introdução: Esofagite eosinofílica (EoE) é uma desordem clínico-patológica, caracterizada por sintomas de disfunção esofágica e alterações histopatológicas com inflamação composta principalmente por eosinófilos, sendo necessário, pelo último consenso, 15 ou mais eosinófilos/campo microscópico de grande aumento (cmga). Contudo, esse achado histopatológico geralmente está acompanhado de outras alterações morfológicas na mucosa esofágica que fazem parte do quadro de resposta inflamatória e que têm sido cada vez mais investigadas. Objetivos: Descrever achados histopatológicos em biópsias de pacientes pediátricos e adolescentes com EoE e compará-las aos de pacientes com quadro clínico de epigastralgia. Material e métodos: Foram analisadas biópsias esofágicas, sendo dezessete com diagnóstico de EoE e dezessete com epigastralgia. Analisaram-se aspectos histopatológicos e imuno-histoquímicos, como número máximo de eosinófilos, alongamento das papilas, hiperplasia de células da camada basal, espaços intercelulares, microabscessos e expressão de CD1a. Resultados: Entre os achados histopatológicos, alongamento das papilas e hiperplasia da camada basal foram observados em todos os participantes com EoE e em nenhuma amostra do grupo epigastralgia. Aumento do espaço intercelular foi encontrado em todos os pacientes com EoE e em 29,41% dos pacientes com epigastralgia. Conclusões: A quantidade de eosinófilos pode não mostrar por si só a complexidade da EoE. Estudos futuros devem ser realizados tentando definir se algum achado morfológico pode ajudar no diagnóstico diferencial entre EoE e eosinofilia esofágica responsiva ao inibidor de bomba de prótons e se poderiam ser utilizados para acompanhamento da eficácia do tratamento da EoE. / Introduction: Eosinophilic esophagitis (EoE) is a clinical-pathological disorder, characterized by symptoms related to esophageal dysfunction and histopathological alterations with inflammatory reactions primarily composed of eosinophils, being necessary, by the last consensus, 15 or more eosinófilos / high-power field (hpf). However, this histopathological finding is usually accompanied by other morphological changes in the esophageal mucosa that are part of an inflammatory response that has been increasingly investigated. Objective: To describe the histopathological findings from biopsies of pediatric and adolescent patients with EoE and to compare them with those from patients with clinical symptoms of epigastralgia. Material and methods: The results of esophageal cultures from biopsies were analyzed, seventeen with EoE diagnosis and seventeen with epigastralgia. The histopathological and immunohistochemical aspects, such as maximum number of eosinophils, papillary elongation, basal cell hyperplasia, dilatation of intercellular spaces, microabscesses, and CD1a expression were analyzed. Results: Among the histopathological findings, papillary elongation and basal cell layer hyperplasia were observed in all participants with EoE and in any of the sample of the epigastralgia group. Dilated intercellular space was found in all patients with EoE and in 29.41% of patients with epigastralgia. Conclusions: The amount of eosinophils may not by itself show the complexity of EoE. Future studies should be carried out in order to determine if any morphological findings may help in the differential diagnosis between EoE and proton-pump inhibitor-responsive esophageal eosinophilia, and whether they could be used to monitor the effectiveness of the EoE treatment. / Dissertação (Mestrado)

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The esophageal epithelium is a stratified squamous tissue. Maintenance of the esophageal epithelial proliferation-differentiation gradient is critical as esophageal epithelium is the first line barrier to prevent penetration of digestive contents, while abnormal epithelial repair contributes to remodeling and disease development. Autophagy has been demonstrated to play roles in esophageal pathologies both benign and malignant, however, the role of autophagy in normal esophageal biology remains elusive. We hypothesize that autophagy may contribute to the maintenance of the proliferation/differentiation gradient under homeostasis in the esophageal epithelium. To investigate the role of autophagy in esophageal epithelium under homeostatic conditions and in response to the carcinogen 4-nitroquinoline 1-oxide (4NQO), we utilize a novel mouse model with tamoxifen-inducible, squamous epithelial-specific Atg7 (autophagy-related 7) conditional knockout. We report that genetic autophagy inhibition in squamous epithelium under homeostatic conditions resulted in enhanced proliferation of esophageal basal cells and increased thickness of epithelium, whether challenging these mice with 4NQO-induced dramatic weight loss that further displayed perturbed epithelial tissue architecture evaluated by histological and biochemical analyses. To characterize cells with high and low levels of autophagic vesicle (AV) content functionally and molecularly, we sorted esophageal basal cells based upon fluorescence of the AV-identifying dye Cyto-ID. We then used transmission electron microscopy validate increased AVs in esophageal basal cells with high AV level (Cyto-IDHigh) as compared to their counterparts with low AV level (Cyto-IDLow). Cyto-IDHigh esophageal basal cells displayed limited organoid formation capability upon initial plating but passaged more efficiently as compared to Cyto-IDLow esophageal basal cells. By RNA-Seq we identified increased autophagy in Cyto-IDHigh esophageal basal cells along with decreased cell cycle progression, the latter of which was confirmed by cell cycle analysis. scRNA-Seq of 3D organoids generated by Cyto-IDLow and Cyto-IDHigh cells identified expansion of 3 cell populations, enrichment of G2/M-associated genes in the Cyto-IDHigh group. Ki67 expression was also increased in organoids generated by Cyto-IDHigh cells, including in cells located beyond the outermost basal cell layer. Taken together, these studies provide evidence that ATG7 contributes to homeostasis of esophageal epithelium, in which esophageal basal cells with high level of AVs exhibit limited proliferation. When esophageal basal cells with high AV level are cultured in 3D organoid assays, they exhibit increased self-renewal and enhanced proliferative capacity extending beyond the outermost basal cell layer.Maintenance of the esophageal proliferation-differentiation gradient is a key to support proper functioning of the esophagus and its dysregulation can lead to the development of esophageal pathologies. Published studies provide evidence of epithelial-fibroblast crosstalk in the development of subepithelial fibrosis, a typical type of tissue remodeling found in patients with eosinophilic esophagitis (EoE). The current paradigm presents EoE as a progressive fibrostenotic disease of the esophagus in which aged patients develop fibrosis as a function of disease chronicity. We hypothesize that age of esophageal epithelium may affect EoE presentation. To directly test the impact of age upon EoE disease presentation, we treated young and aged mice with MC903/Ovalbumin to induce EoE inflammation for the same time period. We found increased thickness of lamina propria in aged mice with EoE as compared to their young counterparts, suggesting that age-associated alterations in esophageal biology contribute to EoE-associated fibrosis. To evaluate the impact of esophageal epithelial cell age on EoE-associated fibrosis, we generated primary esophageal epithelial cell lines from young and aged mice and determined the effects of these cells on fibroblast contractility in collagen plug contraction assays in vitro. These studies revealed that esophageal epithelial cells from aged mice limited fibroblast contractility less efficiently than those from their young counterparts. To identify potential signaling pathways through which aged esophageal epithelial cells may stimulate fibrotic remodeling, we conducted cytokine array analysis. We found 6 cytokines/soluble factors that have not previously been linked to EoE but may contribute to fibrotic remodeling. Taken together, this dissertation provides (1) foundation for further studies evaluating the role of autophagy and mechanisms of its regulation in the context of normal homeostasis and carcinogen-induced stress as well as (2) identification of age-associated factors that may contribute to fibrotic remodeling that may aid in the design of strategies toward early detection, prevention, and therapy of fibrostenotic EoE. / Biomedical Sciences

Introduction: Eosinophilic Esophagitis (EoE) is a rare allergic inflammatory disease affecting approximately 1-4 in every 10,000 individuals in the United States. With the dramatic increase in prevalence of EoE in recent years and the increasing use of the internet as a source of health care information, we sought to evaluate the educational quality of EoE videos on YouTube. Methods: We performed a YouTube search using the keyword “eosinophilic esophagitis” from September 8-27, 2016. All available videos were included and analyzed for video characteristics, source, and content. Source was further classified as health-care provider, alternative-medicine provider, patient and/or patient's parents, company, media, or professional society. A scoring system was created based on current guidelines to evaluate the quality of information (-10 to +30 points).Negative points were assigned for misleading information. Six blinded reviewers scored each video independently. Results: Two hundred and nine videos were analyzed, with a median of 507 views, 1 like, 0 dislikes, and 0 comments. More video presenters were male (50.9%), and the most commonly depicted race was Caucasian (73.6%). The most common type of video source was professional society (39.7%), and the least represented video source was company and media (8.6%). Among the four video sources, the mean scores showed a statistically significant difference from each other (pConclusion: Youtube videos on EoE were shown to be a poor source of valid health care information. Videos by health care providers were a better source of information compared to other sources. This study reiterates the need for higher quality educational videos on EoE by the medical community.

Esofagite Eosinofílica é uma doença inflamatória crônica restrita ao esôfago e imune mediada por antígenos. Sua prevalência descrita varia desde 0,4%, numa população geral, até 15% em pacientes com sintomas de disfagia. Já se conhece sua associação com doenças atópicas, anafilaxia e alergia alimentar, sendo o leite de vaca um dos principais alimentos envolvidos. Existem relatos recentes de casos em que pacientes foram diagnosticados com esofagite eosinofílica após serem submetidos à imunoterapia oral com o alimento causador de sua alergia alimentar mediada por IgE. Porém, em nenhum destes casos foi avaliado previamente se os mesmos pacientes já não apresentavam eosinofilia esofágica latente e/ou sintomas subjetivos sugestivos da doença. Considerando que, atualmente, um dos tratamentos mais promissores para alergia alimentar é a imunoterapia oral, justificou-se a necessidade de entender se esofagite eosinofílica seria de fato uma complicação do tratamento, ou se seria uma condição pré ou coexistente. Portanto, o objetivo deste trabalho foi avaliar a frequência de eosinofilia esofágica em pacientes com anafilaxia à proteína do leite de vaca. Foram analisados 89 pacientes matriculados no ambulatório de alergia alimentar do HC-FMUSP, com mediana de idade de 8 anos e que apresentavam anafilaxia ao leite de vaca. Todos foram submetidos à endoscopia digestiva alta com biópsias de esôfago, estomago e duodeno. Dados demográficos, comorbidades atópicas, uso de medicações e sintomas gastrointestinais foram analisados e comparados. A frequência de eosinofilia esofágica foi de 38,2% (34 de 89 pacientes). Em 15 dos 34 pacientes com eosinofilia esofágica, foi completada a investigação para esofagite eosinofílica com uso de inibidor de bomba de prótons em dose plena por 8 semanas antes de uma segunda endoscopia. Identificou-se, portanto, cinco pacientes (7,1%) com eosinofilia esofágica responsiva a inibidor de bomba de prótons e 10 pacientes com esofagite eosinofílica (14,2%). No grupo total de pacientes com eosinofilia esofágica (n=34) encontrou-se 29,4% de pacientes com quadro clínico gastrointestinal ausente; 23,5% oligossintomáticos, e apenas 47% com sintomas sugestivos de disfunção esofágica e, destes últimos, nem todos apresentavam sintomas esofágicos persistentes. Pode-se concluir que a frequência de esofagite eosinofílica descrita no grupo estudado foi significativamente superior à estimada na população geral e uma das mais altas descritas em grupos de pacientes com fatores de risco específicos. Também foi observada uma grande parcela de pacientes com eosinofilia esofágica, sendo muitos assintomáticos ou oligossintomáticos, surgindo o questionamento se esta não seria uma doença latente, de início precoce, insidioso e não relacionada diretamente como complicação de tratamentos atuais / Eosinophilic esophagitis is a chronic inflammatory disease, which occurs in the esophagus and is immune mediated by antigens. Its observed prevalence varies between 0.4% in the general population to 15% in patients with dysphagia. Its association with atopic diseases, anaphylaxis and food allergy has already been recognized. Cow\'s milk is one of the main food sources involved. There are recent reports of cases in which patients were diagnosed with eosinophilic esophagitis after being submitted to oral immunotherapy with the food that causes the IgE mediated allergy. However, in none of these cases was it previously determined if the same patients did not already present latent esophageal eosinophilia and/or subjective symptoms suggestive of the disease. Considering that, currently, one of the most promising treatment for food allergy is oral immunotherapy, the need to understand if eosinophilic esophagitis could be a treatment complication, or if it is a coexistent or preexistent condition, is justified. Therefore, the objective of this study was to evaluate esophageal eosinophilia frequency in patients with anaphylaxis to cow\'s milk protein. We analyzed eighty-nine patients registered in the Food Allergy Unit of the HCFMUSP, with a median age of 8 years, who presented cow\'s milk anaphylaxis. All of them were submitted to digestive endoscopy as well as esophagus, stomach, and duodenum biopsies. We also analyzed and compared demographic data, atopic comorbidities, use of medication, and gastrointestinal symptoms. The frequency of esophageal eosinophilia was 38.2% (34 of 89 patients). In 15 of the 34 patients with esophageal eosinophilia, full investigation for the disease was carried out using a proton pump inhibitor at full dose for eight weeks prior to a second endoscopy. From this, five patients (7.1%) had the proton pump inhibitor-responsive esophageal eosinophilia phenotype, and ten patients were diagnosed with eosinophilic esophagitis (14.2%). In the whole group of patients with esophageal eosinophilia (n = 34), it was found 29.4% of patients with an absent gastrointestinal clinical condition, 23.5% were oligosymptomatic, and only 47% had symptoms suggestive of esophagic dysfunction. Of these, not all presented persistent esophagic symptoms. It is possible to conclude that the frequency of eosinophilic esophagitis observed in this group was significantly higher than the estimated for the general population, and one of the highest observed in groups of patients with specific risk factors. A large portion of patients with esophageal eosinophilia were oligosymptomatic or asymptomatic, raising the question if this would not in fact be a latent disease, with a precocious beginning, insidious and not directly related to current treatments complications