Caracterización funcional de variantes en genes del sistema del complemento asociadas con patología
Loading...
Download
Official URL
Full text at PDC
Publication date
2024
Defense date
13/07/2023
Authors
Advisors (or tutors)
Editors
Journal Title
Journal ISSN
Volume Title
Publisher
Universidad Complutense de Madrid
Citations
Exportar
Citation
Abstract
El sistema del complemento es un componente de la inmunidad innata que actúa como una de las primeras barreras en la defensa frente a infecciones. Gran parte de su actividad depende de la vía alternativa, la cual se activa de manera espontánea e inespecífica, y constituye un loop de amplificación de la activación del complemento. Para evitar que por esta vía se genere daño a tejidos propios existe una batería de reguladores de membrana y solubles encargadas de evitar este daño. Variantes en algunos de estos reguladores se han asociado con el desarrollo de patologías, como el síndrome hemolítico urémico atípico y la glomerulopatía de C3. Factor H es el principal regulador de la vía alternativa y para el que se ha identificado el mayor número de variantes en ambas patologías. A pesar de que es una de las proteínas que mejor se conoce del complemento y para la que se han caracterizado funcionalmente un mayor número de variantes, existen muchas otras para las que se desconoce su impacto. Este "vacío" se debe a que aún con todo el conocimiento generado sobre factor H es difícil predecir de manera fiable el impacto de algunas variantes, y a que la caracterización funcional no es un proceso rutinario en los centros de diagnóstico. Además, con estas patologías también se han asociado variantes en las proteínas relacionadas con factor H, originadas por varios eventos de duplicación parcial de factor H. A diferencia del regulador, para estas proteínas se desconoce cuál es su papel en la activación y regulación del complemento y el impacto fisiológico que puedan tener las variantes identificadas. Para abordar estos 2 aspectos en esta tesis se han caracterizado mediante 2 estrategias diferentes el impacto de un total de 108 variantes de factor H de significado incierto asociadas al síndrome hemolítico urémico atípico y/o la glomerulopatía de C3, y se han analizado los ligandos y las propiedades activadoras/reguladoras de la proteína 1 relacionada con factor H y variantes en su extremo C-terminal asociadas al síndrome hemolítico urémico atípico...
The complement system is a component of innate immunity that acts as one of the first barriers in the defense against infections. Much of its activity depends on the alternative pathway, which is activated spontaneously and non-specifically, and constitutes an amplification loop of complement activation. To prevent this pathway from causing damage to host tissues, there is a battery of membrane and soluble regulators in charge of avoiding this damage. Variants in some of these regulators have been associated with the development of pathologies such as atypical hemolytic uremic syndrome and C3 glomerulopathy. Factor H is the main regulator of the alternative pathway and for which the largest number of variants has been identified in both pathologies. Although it is one of the best known complement proteins and for which the largest number of variants have been functionally characterized, there are many others for which its impact is unknown. This "gap" is due to the fact that even with all the knowledge generated on factor H it is difficult to reliably predict the impact of some variants, and that functional characterization is not a routine process in diagnostic centers. In addition, variants in factor H related proteins, originated from multiple partial duplication events of factor H, have also been associated with these pathologies. Unlike the regulator, the role of these proteins in the activation and regulation of complement and the physiological impact that the identified variants may have are unknown. To address these 2 aspects in this thesis, the impact of a total of 108 factor H variants of uncertain significance associated with atypical hemolytic uremic syndrome and/or C3 glomerulopathy have been characterized by 2 different strategies, and the ligands and activating/regulatory properties of factor H related protein 1 and variants on its C-terminal end associated with atypical hemolytic uremic syndrome have been analyzed...
The complement system is a component of innate immunity that acts as one of the first barriers in the defense against infections. Much of its activity depends on the alternative pathway, which is activated spontaneously and non-specifically, and constitutes an amplification loop of complement activation. To prevent this pathway from causing damage to host tissues, there is a battery of membrane and soluble regulators in charge of avoiding this damage. Variants in some of these regulators have been associated with the development of pathologies such as atypical hemolytic uremic syndrome and C3 glomerulopathy. Factor H is the main regulator of the alternative pathway and for which the largest number of variants has been identified in both pathologies. Although it is one of the best known complement proteins and for which the largest number of variants have been functionally characterized, there are many others for which its impact is unknown. This "gap" is due to the fact that even with all the knowledge generated on factor H it is difficult to reliably predict the impact of some variants, and that functional characterization is not a routine process in diagnostic centers. In addition, variants in factor H related proteins, originated from multiple partial duplication events of factor H, have also been associated with these pathologies. Unlike the regulator, the role of these proteins in the activation and regulation of complement and the physiological impact that the identified variants may have are unknown. To address these 2 aspects in this thesis, the impact of a total of 108 factor H variants of uncertain significance associated with atypical hemolytic uremic syndrome and/or C3 glomerulopathy have been characterized by 2 different strategies, and the ligands and activating/regulatory properties of factor H related protein 1 and variants on its C-terminal end associated with atypical hemolytic uremic syndrome have been analyzed...
Description
Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 13-07-2023