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Title: Glycomic and glycoproteomic studies of immune disorders
Author: Wu, Gang
ISNI:       0000 0004 5994 1534
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Sugar oligomers which are linked to proteins and lipids play important roles in a large number of biological processes. These sugars are referred to as glycans. In the immune system, almost all key proteins are glycosylated. Glycans regulate the migration, recognition, activation, and apoptosis of immune cells, as well as the activities of antibodies. Owing to glycan complexity, the study of glycosylation is challenging. Mass spectrometry (MS) is a state-of-the-art technology which is ideally suited to investigating glycosylation, because of its ultra-high sensitivity and resolution, as well as its ability to analyze individual molecules in a complex, heterogeneous mixture. In this thesis, mass spectrometry was used to investigate the abnormal glycosylation of two newly discovered immune disorders: a hyper IgE syndrome and a congenital disorder of glycosylation (CDG). In the hyper IgE syndrome, a total set of glycans on leukocytes was analysed (glycomic studies). A reduction in tri- and tetra-antennary glycans was observed in the patients. In addition, substantially increased levels of hybrid glycans were detected in a patient with more severe symptoms, and decreased fucosylation was found on their neutrophils. Site specific glycosylation analysis (glycoproteomic studies) was done on IgE, and 6 of 7 potential N-glycosylation sites on this antibody were mapped, which did not show significant glycosylation changes. In the CDG, tri-glucosylated high mannose glycans were observed, which helped the identification of an ER glucosidase I defect. Mass spectrometry was also used to investigate engineered antibodies which are designed to treat immune disorders. A dramatic increase in sialylation was observd in an IgG1 after introducing point mutations in the Fc region, and a considerable amount of high mannose glycans were detected in an IgG1 hexamer.
Supervisor: Haslam, Stuart ; Dell, Anne Sponsor: Imperial College London
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral