The role of idiotype-specific immunity in antigen receptor diversity

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Millar10PhD.pdf

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Decl_IS_Millar10PhD.pdf

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http://eprints.org/relation/isVersionOf http://etheses.bham.ac.uk/id/document/40652 http://eprints.org/relation/isVolatileVersionOf http://etheses.bham.ac.uk/id/document/40652 http://eprints.org/relation/ispreviewThumbnailVersionOf http://etheses.bham.ac.uk/id/document/40652 archive 4031 disk0/00/00/15/20 2015-01-05 14:31:33 2019-01-23 09:54:20 2015-01-05 14:31:33 thesis show 0 Millar David George Cobbold Mark University of Birmingham The role of idiotype-specific immunity in antigen receptor diversity unpub QR180 RC0254 10col_mede Was a full embargo, option D, until December 2014, now option C until 31/1/2018 Lymphocytes express antigen receptors which are formed by re-arrangement of gene segments. Mutations acquired during this process, predominantly in the complementarity determining regions (CDRs), result in generation of non-germline sequences. Through analysing the CDR3 sequence, this study attempts to determine whether editing of the lymphocyte repertoire is present in an HLA-dependant manner. Data presented demonstrates a decrease frequency of CDR3-derived HLA-A2 binding peptides in HLA-A2+ donors (0.03% (SYFPEITHI) and 0.35% (BIMAS)) compared with HLA-A2- donors (0.24% (SYFPEITHI, p=0.01) and 0.54% (BIMAS, p=0.19)). Trends similar to those seen in HLA-A2 were observed in other HLA alleles as well suggesting that there may be a process by which potentially dangerous B cell populations are edited from the B cell repertoire. Similar analysis of the TCR CDR3 did not reveal any such process in all of the HLA alleles tested suggesting that there is no immunoediting of the T cell repertoire. Simultaneously, this study attempts to determine the processing and presentation of CDR3-derived peptides at the cell surface using lymphocyte antigen receptor models containing CDR3-encoded viral epitopes. The apparent presence of these peptides on the cell surface leads to the hypothesis that antibodies enter the antigen processing pathway and potentially deliver an immunogenic peptide to a target cell. Using antibodies specific for B cells, this study has shown that cells labelled with an antibody-peptide complex are targeted and lysed by cytotoxic CD4+ T cells in a peptide-specific manner. The use of such technology in antibody immunotherapy may be of considerable therapeutic benefit. 2010-12 2010-08 graduation eng author unchecked This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. public 362 University of Birmingham Institute of Cancer Studies d_ph mrc 2010-12 graduation