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The contribution of ERAP1 and Natural Killer cells to the pathogenesis of Ankylosing Spondylitis

The contribution of ERAP1 and Natural Killer cells to the pathogenesis of Ankylosing Spondylitis
The contribution of ERAP1 and Natural Killer cells to the pathogenesis of Ankylosing Spondylitis
Ankylosing Spondylitis (AS) is an autoimmune condition of the sacro-iliac region at the base of the spine. The pathogenesis of the disease is unknown despite strong genetic links with HLA-B27 and ERAP1. HLA-B27 is present in ~95% of AS patients and polymorphisms within ERAP1 have been shown to distinguish AS cases from controls. ERAP1 is an ER-resident aminopeptidase that trims peptides for binding to MHC Class I molecules, including HLA-B27, in antigen presentation to CD8+ T cells. No specific peptides have been found to induce disease and the disease is unlikely to be CD8+ T cell driven, suggesting that changes in the whole peptide repertoire may instead be important for disease generation through induction of other cell types. Natural Killer cells also interact with MHC Class I molecules through Killer immunoglobulin like receptors and have been previously implicated in AS, with AS patients having higher percentages of natural killer cells in the peripheral blood than controls. Here I show that the sequence of the peptide bound to HLA-B27 can affect NK cell activation and begin to create a panel of amino acids at key positions that are activating or inhibitory. I have shown that ASassociated ERAP1 allotype combinations induce more NK cell activation than controls due to a reduction in cell surface FHC expression. Further to this I show how these changes in NK cell activation can alter the cytokine profile of the surrounding PBMC population. In addition I have looked into how different alleles of HLA-B27 are associated with disease and show that peptides bound to HLA-B*2709 can inhibit NK cell activation in an NK cell dependent manner, while peptide-B*2705 complexes bind NK cells in an ERAP1- independent manner. This work taken together provides some interesting possibilities to explain the events that lead to AS disease.
University of Southampton
Wellington, Dannielle, Marie
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Wellington, Dannielle, Marie
675931a2-122b-464c-9aff-9be9879580fc
James, Edward
7dc1afb7-d326-4050-89fc-1f4e2a1a19a4
Elliott, Timothy
16670fa8-c2f9-477a-91df-7c9e5b453e0e

Wellington, Dannielle, Marie (2016) The contribution of ERAP1 and Natural Killer cells to the pathogenesis of Ankylosing Spondylitis. University of Southampton, Doctoral Thesis, 215pp.

Record type: Thesis (Doctoral)

Abstract

Ankylosing Spondylitis (AS) is an autoimmune condition of the sacro-iliac region at the base of the spine. The pathogenesis of the disease is unknown despite strong genetic links with HLA-B27 and ERAP1. HLA-B27 is present in ~95% of AS patients and polymorphisms within ERAP1 have been shown to distinguish AS cases from controls. ERAP1 is an ER-resident aminopeptidase that trims peptides for binding to MHC Class I molecules, including HLA-B27, in antigen presentation to CD8+ T cells. No specific peptides have been found to induce disease and the disease is unlikely to be CD8+ T cell driven, suggesting that changes in the whole peptide repertoire may instead be important for disease generation through induction of other cell types. Natural Killer cells also interact with MHC Class I molecules through Killer immunoglobulin like receptors and have been previously implicated in AS, with AS patients having higher percentages of natural killer cells in the peripheral blood than controls. Here I show that the sequence of the peptide bound to HLA-B27 can affect NK cell activation and begin to create a panel of amino acids at key positions that are activating or inhibitory. I have shown that ASassociated ERAP1 allotype combinations induce more NK cell activation than controls due to a reduction in cell surface FHC expression. Further to this I show how these changes in NK cell activation can alter the cytokine profile of the surrounding PBMC population. In addition I have looked into how different alleles of HLA-B27 are associated with disease and show that peptides bound to HLA-B*2709 can inhibit NK cell activation in an NK cell dependent manner, while peptide-B*2705 complexes bind NK cells in an ERAP1- independent manner. This work taken together provides some interesting possibilities to explain the events that lead to AS disease.

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DWellington final thesis - Version of Record
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Published date: September 2016
Organisations: University of Southampton, Cancer Sciences

Identifiers

Local EPrints ID: 408721
URI: http://eprints.soton.ac.uk/id/eprint/408721
PURE UUID: 92cdff0b-7f3a-4ba8-b941-abd1e444a000
ORCID for Edward James: ORCID iD orcid.org/0000-0001-8638-7928
ORCID for Timothy Elliott: ORCID iD orcid.org/0000-0003-1097-0222

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Date deposited: 27 May 2017 04:02
Last modified: 18 Feb 2021 17:07

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Contributors

Author: Dannielle, Marie Wellington
Thesis advisor: Edward James ORCID iD
Thesis advisor: Timothy Elliott ORCID iD

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