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Title: Variation in leukocyte receptor complex genes and disease
Author: Jones, Desmond Charles
ISNI:       0000 0004 2668 7170
Awarding Body: Oxford Brookes University
Current Institution: Oxford Brookes University
Date of Award: 2009
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The human Leukocyte Receptor Complex (LRC) encodes several immunoreceptor gene families that play an important role in immune responses. Many of these loci exhibit a high degree of genetic and functional variation. The work described in this thesis was primarily performed to assess further the variation of several LRC genes and to investigate its relationship with disease susceptibility. Genetic assessment of the LRC locus KIR3DL3 revealed seventeen novel alleles. Rec ombination appeared to be largely responsible for generating the allelic diversity within KIR3DL3. Interspecies sequence comparisons indicated that KIR3DL3 is highly conserved between chimpanzee, gorilla and humans; while further analysis indicated human KIR3DL3 is undergoing purifying selection. In contrast, evidence of positive selection pressure was detected in the human LRC gene LILRE3. In addition to sequence polymorphism, variation in rnRNA splicing of LRC genes may affect their functions and disease association. I have identified a common mechanism of alternative rnRNA splicing which generates transcripts that encode soluble protein isoforms of the majority of human LILR.· The alternative LILR transcripts were detected in cell types that express their membrane-associated isoforms. Expression of the alternative LILREi transcript in transfected cells resulted in the secretion of a soluble ~65Kd LILRB1 protein. Soluble LILRB1 (sLILRB1) protein was also detected in the culture supernatants of monocyte derived dendritic cells. In vitro assays showed that sLILRB 1 could block the interaction between membrane-associated LILRBl and HLA-class 1. sLILRB1 may act as a dominant negative regulator of HLA-Class l-mediated LILRB1 inhibition. Other sLILR may function in a comparable way.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available