The impact of respiratory infections in animal models prone to autoimmunity
Author(s)
Ramirez, Alejandro
Abstract
Autoimmune diseases are chronically debilitating diseases which shorten the lifespan and reduce quality of life for sufferers. The aetiology of autoimmunity is largely unknown, despite many genetic and environmental factors hypothesised to have an involvement. Without knowing the exact cause of autoimmune disease, current therapies are limited to slowing down the progression or managing the symptoms of disease, but there are no cures. In this thesis we examine possible causes for the development of autoimmunity, focusing on the immune responses to respiratory pathogens in mouse strains susceptible to inducible autoimmunity. We primarily studied the DBA/I mouse collagen induced arthritis (CIA) model of rheumatoid arthritis (RA) and the effects that Thl and Th2 inducing pathogens, such as influenza A and Cryptococcus neoformans respectively, had upon it. The model is well suited for this study because it mirrors what we believe happens in individuals susceptible t:o autoimmunity. The mouse strain is genetically susceptible but autoimmunity has to be induced or triggered, and this trigger is not random but dependent on defined immune stimuli. We show that C'.neoformans infection, a Th2 inducing encapsulated yeast, can potentially increase early incidence of rheumatic inflammation in CIA. We also show the unusual yet extreme susceptibility of the DBA/1 mouse strain to X31 influenza, which we believe points towards an immune response defect related to their susceptibility to autoimmunity. In later chapters we search for ways in which this susceptibility against influenza can be corrected or treated, in the hope to reveal useful information about both lethal influenza infections and autoimmunity. Furthermore we show promising positive data which includes an increase in survival levels of infected mice, by utilising immunomodulation with E.coli derived deactivated toxins. Attempting to elucidate the root causes of autoimmunity is important to further our understanding of this cluster of diseases so we can design better therapies and cures.
Version
Open Access
Date Awarded
2010
Copyright Statement
Attribution-Non Commercial-No Derivatives 4.0 International Licence (CC BY-NC-ND)
Advisor
Hussell, Tracy
Sponsor
Dorothy Hodgkin Post Graduate Awards, the Kennedy Institute of Rheumatology and Imperial College London.
Publisher Department
National Heart & Lung Institute
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)