Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/150443
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | Ballestar Tarín, Esteban | - |
dc.contributor.author | Lorente-Sorolla Martínez-Acítores, Clara | - |
dc.contributor.other | Universitat de Barcelona. Facultat de Medicina | - |
dc.date.accessioned | 2020-02-17T10:42:12Z | - |
dc.date.available | 2020-06-20T05:10:23Z | - |
dc.date.issued | 2019-12-20 | - |
dc.identifier.uri | http://hdl.handle.net/2445/150443 | - |
dc.description.abstract | [eng] This doctoral thesis describes the participation of epigenetic mechanisms, and more specifically DNA methylation, in innate immune responses against pathogens. Innate immunity is the first barrier of defense against infection. Monocytes, which are part of this innate response, orchestrate the host’s antimicrobial protective responses by phagocyting and releasing various inflammatory cytokines to kill microorganisms. In addition, monocytes differentiate into macrophages and dendritic cells, which are also responsible for antigenic presentation and the consequent activation of adaptive responses. In recent years, it has been described that cells of the innate system have immune memory, responding in a more effective (trained immunity) or attenuated (endotoxin tolerance) way, against second infections. It is necessary to improve our knowledge about the cellular and molecular mechanisms that take place after an infection. The immune response is highly controlled and regulated by complex networks formed by signaling cascades, transcription factors and epigenetic mechanisms, among others. Sepsis is defined as a life-threating organic dysfunction caused by a dysregulated response to infection. Immune response in sepsis is characterized by an initial systemic inflammation followed by a state of immunosuppression, in which the immune cells acquire a tolerated phenotype, thus constituting a pathological model for the study of innate memory. In this thesis, we have studied potential DNA methylation changes in monocytes from patients with sepsis. We have described for the first time the existence of DNA methylation alterations in patients with sepsis compared to healthy controls. In addition, we have observed that DNA methylation changes correlate with IL-10 and IL-6 levels, which are increased in patients with sepsis. Between genes that show altered methylation, we found some related to IL-1 and TLR signaling and the JAK/STAT pathway, relevant pathways in the immune response against infectious agents. Finally, we also found that methylation in relevant genes is associated with organ dysfunction in septic patients. In parallel, we have performed in vitro studies on monocytes after toll-like receptor (TLR) stimulation to unravel the role of DNA methylation in the acquisition of innate memory. Statistical analysis of the data revealed specific demethylation after stimulation of TLRs. We have seen how genes relevant to monocyte function and physiology are regulated by DNA demethylation. In addition, we observed an overexpression of those genes that are specifically demethylated after LPS stimulation. The study of DNA methylation during these inflammatory processes may reveal new therapeutic strategies to reverse the immune tolerance state. | - |
dc.description.abstract | [spa] En esta tesis doctoral se han estudiado los mecanismos epigenéticos asociados a la respuesta inmune innata contra patógenos y a la adquisición de memoria innata. La sepsis se define como una disfunción orgánica causada por una respuesta desregulada del huésped a la infección. La respuesta inmune durante la sepsis se caracteriza por una fase inicial de inflamación sistémica seguida de un estado de inmunosupresión, en el cual las células inmunes adquieren un fenotipo tolerizado, y constituye un modelo patológico para el estudio de la memoria innata. En esta tesis, hemos obtenido el perfil de metilación del DNA de monocitos de pacientes con sepsis. Hemos descrito por primera vez cambios en la metilación de estos monocitos en comparación con los controles sanos. Además, hemos observado alteraciones en la metilación del DNA en relación con los niveles de las citoquinas IL-10 e IL-6, que están incrementadas en los pacientes. Entre los genes que muestran una metilación alterada, encontramos algunos relacionados con la señalización de IL-1 y TLR y la vía JAK/STAT, rutas relevantes en la defensa inmune contra agentes infecciosos. Finalmente, hemos encontrado también que la metilación en genes relevantes se asocia con la disfunción orgánica en los pacientes sépticos. En paralelo, hemos realizado estudios in vitro en monocitos tras la estimulación de los receptores tipo Toll para estudiar el papel potencial de la metilación del DNA en la adquisición de memoria innata. El análisis estadístico de los datos reveló una desmetilación específica tras la estimulación. Hemos visto como genes relevantes para la función y fisiología de los monocitos están regulados por la desmetilación del DNA. Además, hemos observado una sobreexpresión de aquellos genes que se desmetilan específicamente tras la estimulación con LPS. La desmetilación podría tener un papel modulador durante la adquisición de tolerancia a endotoxinas y su estudio durante estos procesos inflamatorios podría revelar nuevas estrategias terapéuticas para revertir el estado de inmunotolerancia en la respuesta inmune. | - |
dc.format.extent | 165 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Universitat de Barcelona | - |
dc.rights | (c) Lorente-Sorolla, 2019 | - |
dc.source | Tesis Doctorals - Facultat - Medicina | - |
dc.subject.classification | Epigenètica | - |
dc.subject.classification | Immunologia | - |
dc.subject.classification | ADN | - |
dc.subject.classification | Infeccions | - |
dc.subject.other | Epigenetics | - |
dc.subject.other | Immunology | - |
dc.subject.other | DNA | - |
dc.subject.other | Infections | - |
dc.title | Mechanisms of epigenetic regulation relevant to innate responses against pathogens | - |
dc.type | info:eu-repo/semantics/doctoralThesis | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.date.updated | 2020-02-17T10:42:12Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.tdx | http://hdl.handle.net/10803/668653 | - |
Appears in Collections: | Tesis Doctorals - Facultat - Medicina |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
CLSMA_PhD_THESIS.pdf | 11.19 MB | Adobe PDF | View/Open |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.