Citotoxic and humoral mechamnisms involved in the etiopathogenesis of eosinophilic esophagitis
- Autores: Marina Fortea Guillamon
- Directores de la Tesis: María Vicario Pérez (dir. tes.), Fernando Azpiroz Vidaur (dir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2020
- Idioma: inglés
- Tribunal Calificador de la Tesis: Alfredo José Lucendo Villarín (presid.), Joan Xavier Comella i Carnicé (secret.), Danila Guagnozzi (voc.)
- Programa de doctorado: Programa de Doctorado en Bioquímica, Biología Molecular y Biomedicina por la Universidad Autónoma de Barcelona
- Materias:
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- Resumen
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus characterized by esophageal dysfunction and is associated with a dense infiltrate of intraepithelial eosinophils. EoE causes a considerable deterioration in the quality of life of patients, both children and adults, and epidemiological studies indicate a prevalence increase in the last years. Although the etiopathogenic mechanisms are not fully defined, it is considered an allergic disease, given the clinical and histological response to the elimination of certain allergens and the type of inflammatory infiltrate in the tissue. Currently, its diagnosis is based on the presence of 15 or more eosinophils per high power field in the esophageal epithelium after excluding the presence of other diseases with esophageal eosinophilic infiltrate.
Despite the growing interest in this entity, the mechanisms that trigger the inflammatory response are not entirely elucidated. Thus, the objective of this work was to analyze the participants of the immune response, with special interest in mechanisms leading cytotoxic and humoral responses, and their contribution to the development of EoE. For this, three studies were developed. In the first one, the cellular immune profile of the esophagus was characterized in health. In the second study, the function of CD8 lymphocytes and their modulation after treatment with proton pump inhibitors or with dietary food avoidance, were analyzed, as well as the possible mechanisms in an in vitro cell model. In the third study, the humoral response in the tissue and its modulation after the exclusion diet was evaluated.
In the first part, the phenotypic characterization of T lymphocytes, B lymphocytes, macrophages, mast cells and eosinophils was performed. It showed that except for eosinophils, the all esophageal layers are widely infiltrated by these cells without observing differences in the esophageal regions. Regarding the histological strata, it was identified that the most densely populated, for all cell types, were the vascular papilla and the lamina propria, followed by the epithelium in the case of lymphocytes and the muscular layer in the case of macrophages and mast cells.
The second study revealed a greater infiltration of CD8+ lymphocytes, featured by the activation marker CD2, in patients with EoE, which reversed more effectively in patients treated with an exclusion diet than in patients treated with proton pump inhibitors. In addition, an increase in the expression of several genes related to the activity of CD8 cells was identified as cytotoxic enzymes (granzyme A, granzyme B, granulysin...), proinflammatory interleukins (IL10, IL12B, IL15) and cathepsins related to peptidase activity. In the in vitro model, the Het-1A cell line was used as a model for the study of this disease, however some limitations did not allow to fully developing it. Additionally, ex-vivo esophageal biopsy culture seems to be a more promising approach for the study of cytotoxic mechanisms in the esophageal epithelium.
The third study identified an increase in total immunogloblins (Ig) IgE, IgG and IgG4 and specific IgE and against allergens, expressed in mast cells and plasma cells in the esophagus of patients with EoE. The exclusion diet reversed the production of these immunoglobulins in parallel to clinical improvement.
This thesis contributes to reinforcing the immunological potential of the esophagus and reveals the coexistence of cytotoxic and humoral active mechanisms in the EoE that are modulated by treatment. The presence of specific immunoglobulins against allergens in the esophagus represents a new way for the design of effective diets in patients with EoE and represents an approach to personalized medicine in this disease.
