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Title: The role of mannose binding lectin (MBL) in infection and inflammation
Author: Fidler, Katherine
ISNI:       0000 0004 2673 2955
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2007
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From early in life humans come into contact with a wide variety of infectious agents including bacteria, fungi and viruses. However, despite the vast array of potential pathogens, only a minority have the capacity to cause disease in a human host. This is largely due to the efficacy of the human innate and adaptive immune systems. The innate immune system consists of a variety of components including mechanical barriers, secretions, cells, excreted proteins, and serum proteins including the complement components and mannose binding lectin (MBL). MBL is a liver derived, acute phase, circulating serum protein that acts as a pattern recognition molecule. It is able to bind to a range of sugars presented in particular conformations on the surface of microbes and, having bound to its target, it can activate the lectin complement pathway and enhance complement-independent opsonophagocytosis. Over the last decade the biological importance of MBL has become increasingly apparent as indicated by the clinical consequences of the MBL deficient state. This has mainly been addressed by looking at the effect that MBL deficiency has on the susceptibility to a wide range of infections. More recently, interest has focussed on the role that MBL may play in the modulation of inflammation. It is well recognised that individuals differ in their susceptibility to, and severity of, both infectious and non infectious diseases. This raises the question, could the role of inherited factors governing host response to infection and inflammation be important The work described in this thesis investigates the role of MBL in two diseases that both involve an infective and inflammatory component, namely children with the chronic disease cystic fibrosis (CF) and those with acute inflammation/sepsis in intensive care. In clinical studies I show that MBL deficiency is associated with worse pulmonary function tests in adults with CF and an increased risk of death and/or lung transplantation in children with CF. The reasons for this were explored by examining MBL binding to bacterial pathogens seen in CF and by examining bronchoalveolar lavage (BAL) fluid from children with and without CF. Here I show that MBL can be detected in the BALs of children with both acute and chronic respiratory disease but not in the controls. In another study of 142 children admitted to paediatric intensive care, I demonstrate an association between MBL deficiency and the development of the systemic inflammatory response syndrome and an increased severity of sepsis. This effect of MBL is independent of age, sex, ethnicity, polymorphisms in the genes for TNF-a, IL-6, IL-10, angiotensin converting enzyme (ACE), plasma activator inhibitor 1 (PAI-1) and levels of antibodies to endotoxin. The work presented here highlights the importance of MBL in susceptibility to infection and may demonstrate a role for MBL in modifying the inflammatory response. These data may assist in furthering the understanding of mechanisms in disease pathogenesis as well as paving the way for exploratory research into MBL as a potential therapeutic agent.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available