Structural and electrostatic analysis of HLA B cell epitopes: Inferences on immunogenicity and prediction of humoral alloresponses
type: CreativeWork
description: Despite the use of potent immunosuppressive agents, injury secondary to the alloimmune response principally directed against mismatched HLA antigens, remains a significant cause of renal transplant dysfunction and loss. One of the principal ways to limit the detrimental effect of immune alloreactivity towards the graft is through minimisation of donor-recipient HLA mismatches, but this has not changed conceptually since the early period of clinical transplantation. The central hypothesis of the research described in this thesis is that assessment of histocompatibility based on evaluation of structural differences between donor and recipient HLA molecules has the potential to improve graft outcomes after kidney transplantation. Amino acid sequence analyses have been central to gaining an understanding of the relative immunogenicity of a mismatched donor HLA antigen in the context of a recipient's HLA repertoire. While these methods offer advantages over basic enumeration of HLA mismatches, regardless of how sophisticated they may be, they are unable to fully describe the intricate nature of the B cell epitope-BCR interaction that initiates a humoral response. This interaction requires, but is not limited to, structural and electrostatic potential complementarity. The aim of this thesis is to describe a fully structural description of HLA immunogenicity through analysis of the three-dimensional physicochemical environment at the surface of the HLA molecule. First, I describe the bioinformatic techniques that integrate HLA sequence and X-ray crystallographic data to produce accurate models of HLA molecular structure and, subsequently, calculate the electrostatic potential in the three-dimensional area surrounding the molecule. Through quantitative comparison of the three-dimensional electrostatic potential on the surface of each HLA molecule, Electrostatic Mismatch Score 3D (EMS-3D) is derived. EMS-3D represents the electrostatic disparity between a group of HLA molecu…
abstract: Despite the use of potent immunosuppressive agents, injury secondary to the alloimmune response principally directed against mismatched HLA antigens, remains a significant cause of renal transplant dysfunction and loss. One of the principal ways to limit the detrimental effect of immune alloreactivity towards the graft is through minimisation of donor-recipient HLA mismatches, but this has not changed conceptually since the early period of clinical transplantation. The central hypothesis of the research described in this thesis is that assessment of histocompatibility based on evaluation of structural differences between donor and recipient HLA molecules has the potential to improve graft outcomes after kidney transplantation. Amino acid sequence analyses have been central to gaining an understanding of the relative immunogenicity of a mismatched donor HLA antigen in the context of a recipient's HLA repertoire. While these methods offer advantages over basic enumeration of HLA mismatches, regardless of how sophisticated they may be, they are unable to fully describe the intricate nature of the B cell epitope-BCR interaction that initiates a humoral response. This interaction requires, but is not limited to, structural and electrostatic potential complementarity. The aim of this thesis is to describe a fully structural description of HLA immunogenicity through analysis of the three-dimensional physicochemical environment at the surface of the HLA molecule. First, I describe the bioinformatic techniques that integrate HLA sequence and X-ray crystallographic data to produce accurate models of HLA molecular structure and, subsequently, calculate the electrostatic potential in the three-dimensional area surrounding the molecule. Through quantitative comparison of the three-dimensional electrostatic potential on the surface of each HLA molecule, Electrostatic Mismatch Score 3D (EMS-3D) is derived. EMS-3D represents the electrostatic disparity between a group of HLA molecu…
author: Mallon, Dermot
language: en
keywords: Transplantation, HLA, Immunogenicity
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/4b9ae7d7-7469-4f13-b131-40feadd1a9bd/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2017-07
date modified: 2026-07-22T22:24:28Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.18767