Jack, Dominic Lancelot; (1998) Epidemiological and in vitro studies of mannose-binding lectin (MBL) in host defence. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Human mannose-binding lectin (MBL) is a sugar binding protein found in serum that is thought to play a role in innate immunity by recognising the pattern of carbohydrates presented by many pathogens. On binding to its targets, MBL activates complement (the lectin pathway) via MBL-associated serine proteases (MASP1/2). MBL also enhances phagocytosis by neutrophils and monocytes, and may modify the inflammatory responses of these cells. Deficiency of MBL, caused by homozygosity for structural gene mutations, is associated with a common defect of opsonisation and increased frequencies of infections, particularly in children. There are many areas where the role of MBL in host defence remains unclear. Most studies of MBL association with infection have been retrospective or potentially skewed in recruitment. Prospective studies in this area have been hampered due to the lack of an appropriate method for mutation screening. To address this, a technically simple method for the detection of MBL structural gene mutations was established and its use was piloted for large-scale population screening. This technique was used to establish a link between homozygosity for MBL mutations and susceptibility of HIV positive Zambians to infection by Cryptosporidium parvum. Measurement of MBL serum levels was combined with genotypic data to determine the variability of MBL levels between monozygotic and dizygotic twin pairs. The results obtained indicate that although structural mutations may dictate the overall MBL serum concentration, environmental effects also play an important role. To model MBL interactions in vitro, a set of isogenic mutants of Neisseria meningitidis were investigated. Dramatic differences in MBL binding and complement activation were related to endotoxin structure and sialylation. A slight enhancement of phagocytosis was observed with a delay in neutrophil activation, suggesting a minor role for MBL as a direct opsonin. The results presented in this thesis provide further evidence that MBL plays a role in the pathogenesis of infectious diseases.

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