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Title: Investigation of cross-reactive antibodies against Plasmodium falciparum-infected erythrocytes
Author: Tan, Joshua Hoong Yu
ISNI:       0000 0004 6497 9588
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Cross-reactive antibodies have recently come into focus as promising tools for targeted vaccine design in the fields of HIV and influenza, but the identification of such antibodies that bind to Plasmodium falciparum-infected erythrocytes has proven difficult due to extensive clonal antigenic variation on the surface of these cells. In this study, I report the identification of cross-reactive human monoclonal antibodies that bind to P. falciparum-infected erythrocytes from most parasite strains tested. These antibodies gained broad reactivity through the insertion of a large piece of DNA between the V and DJ segments of the antibody heavy chain, which is encoded on chromosome 14. The core of the insert, which is the primary element required for binding to the infected erythrocytes, codes for the collagen-binding domain of LAIR1, an immunoglobulin superfamily inhibitory receptor that is encoded on chromosome 19. In each of the donors studied, the LAIR1-containing antibodies were derived from a single B cell clone and acquired mutations that increased binding to infected erythrocytes and reduced binding to collagen. The targets of these antibodies were identified as members of the RIFIN variant surface antigen family. The LAIR1-containing antibodies were able to opsonize and agglutinate P. falciparum-infected erythrocytes, suggesting that they may be useful in reducing parasite burden in vivo. Using newly developed assays, I show that the presence of LAIR1-containing antibodies is not limited to a particular place or population, but can be found quite commonly in individuals from different malaria-endemic areas. These findings demonstrate a novel pathway of antibody diversification by interchromosomal DNA transposition that results in the production of functional antibodies and suggest that RIFIN epitopes that are recognized by the LAIR1-containing antibodies may be potential candidates for the development of a blood-stage malaria vaccine.
Supervisor: Marsh, Kevin ; Bull, Peter Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available