Background: Recent Genome Wide Association Scans (GWAS) have revealed ERAP1 to be associated with a number of autoimmune diseases 1-3. ERAP1 is a protease that trims peptides at the amino-terminus to the correct size for binding to Major Histocompatibility Complex (MHC) class I molecules. The role of ERAP1 has concentrated on peptide production and not on the direct T cell recognition of the generated peptide pool or the consequences for HLA molecule foldng.
Aims and Objectives: To determine how peptide processing by ERAP1 can affect both the T cell recognition and MHC molecule folding using novel antigen processing tools.
1. Developing novel ERAP1 antigen processing tools; We have developed novel MHC class I molecules to address the role of ERAP1 peptide processing in autoimmune associated diseases. MHC class I molecules are composed of a polymorphic heavy chain (HC), non-covalently associated with the light chain 2m and a peptide 8-10 amino acids in length. We have physically linked the peptide-2m-HC as a single protein, referred to as a single chain trimer (SCT). The SCT format allows peptide sequences to be manipulated by either extending, shortening or mutating sequences to reveal their role in T cell activation. N-terminally extend peptide sequences with amino acids that either inhibit or allow over activity of ERAP1 will be generated and expressed stably in mammalian cell lines.
2. Determining the effect of peptides on T cell stimulation and protein folding; The peptide mutants of the SCTs will be examined for their ability to both stimulate T cell proliferation and produce cytokines, which are thought to mediate the pro-inflammatory phenotype in autoimmune disease. By mutating the peptides in the SCT format we can also determine the role of peptide variants in MHC class I folding to examine whether such variants can lead to protein misfolding.
Eligibility and How to Apply:
Please note eligibility requirement:
• Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non-UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above); or APEL evidence of substantial practitioner achievement.
• Appropriate IELTS score, if required.
For further details of how to apply, entry requirements and the application form, see https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/
Please note: Applications should include a covering letter that includes a short summary (500 words max.) of a relevant piece of research that you have previously completed. Applications that do not include the advert reference (e.g. SF18/…) will not be considered.
Deadline for applications: 1st July 2019 for October 2019 start, or 1st December 2018 for March 2019 start
Start Date: October or March
Northumbria University takes pride in, and values, the quality and diversity of our staff. We welcome applications from all members of the community. The University holds an Athena SWAN Bronze award in recognition of our commitment to improving employment practices for the advancement of gender equality and is a member of the Euraxess network, which delivers information and support to professional researchers
1. Guasp P, Barnea E, Gonzalez-Escribano MF, et al. The Behcet's disease-associated variant of the aminopeptidase ERAP1 shapes a low-affinity HLA-B*51 peptidome by differential subpeptidome processing. The Journal of biological chemistry 2017;292(23):9680-89. doi: 10.1074/jbc.M117.789180
2. Hinks A, Martin P, Flynn E, et al. Subtype specific genetic associations for juvenile idiopathic arthritis: ERAP1 with the enthesitis related arthritis subtype and IL23R with juvenile psoriatic arthritis. Arthritis research & therapy 2011;13(1):R12.
3. Reeves E, Colebatch-Bourn A, Elliott T, et al. Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis. Proc Natl Acad Sci U S A 2014;111(49):17594-9. doi: 10.1073/pnas.1408882111
4. Jaat FG, Hasan SF, Perry A, Cookson S, Murali S, Perry JD, Lanyon CV, De Soyza A, Todryk SM. Anti-bacterial antibody and T cell responses in bronchiectasis are differentially associated with lung colonization and disease. Respir Res. 2018 May 30;19(1):106.
5. Walker KM, Okitsu S, Porter DW, Duncan C, Amacker M, Pluschke G, Cavanagh DR, Hill AV, Todryk SM. Antibody and T-cell responses associated with experimental human malaria infection or vaccination show limited relationships. Immunology. 2015 May;145(1):71-81.
6. David B. Guiliano, Helen North, Eleni Panayoitou, Elaine C. Campbell, Amy Cameron, Keith Gould, Simon J. Powis and Antony N. Antoniou “Polymorphisms in the F pocket of HLA-B27 subtypes strongly impact on assembly, chaperone interactions and heavy chain misfolding,” Arthritis and Rheumatology 69, 610-621 2017
7. Esam T. Abualrous, Susanne Fritzsche, Zeynep Hein, Mohammed S. Al-Balushi, Peter Reinink, Louise H. Boyle, Ursula Wellbrock, Antony N. Antoniou and Sebastain Springer “F pocket flexibility influences the tapasin dependence of two differentially disease-associated MHC Class I proteins” European Journal of Immunology 45, 1248-57 2015
8. Joanna Giles, Jackie Shaw, Christopher Piper, Isabel Wong-Baeza, Kirsty McHugh, Anna Ridley, Demin Li, Izabela Lenart, Antony N. Antoniou, Katilin DiGleria, Kimiko Kuroki, Katsumi Maenaka, Paul Bowness and Simon Kollnberger “HLA-B27 homodimers and free heavy chains are stronger ligands for LILRB2 than classical HLA class 1” Journal of Immunology 188, 6184-93, 2012