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(MRC DTP) The role of CD4+ T-cells specific for GRP78 in the pathogenesis of rheumatoid arthritis (RA)

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  • Full or part time
    Dr S Viatte
    Prof A Barton
    Dr J Grainger
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Rheumatoid arthritis (RA) is a complex autoimmune disease of unknown aetiology. Our understanding of mechanisms underlying the cause of the disease is still very limited, which prevents the development of efficient treatment strategies.

The presentation of antigenic peptides to CD4+ T cells by HLA-DRβ1 (an MHC class II protein) on antigen-presenting cells (APC) is hypothesised to be one mechanism initiating the autoimmune response causing RA (James EA, Arthritis Rheumatol, 2014). We have recently identified which genetic variations within HLA-DRB1 are highly associated with an increased severity of RA (Viatte, JAMA, 2015).

Glucose-Regulated Protein 78 (GRP78) has been recently proposed as a shared autoantigen between type 1 diabetes and RA (Marre ML, Diabetes, 2018). In contrary to the other autoantigens, GRP78 seems to have anti-inflammatory properties. It might represent an attempt of the immune system to counterbalance the autoinflammatory process.

Hypothesis: Antigenic peptides derived from GRP78 elicit an immune-suppressive antigen-specific CD4+ T-cell response in RA.

Objectives and Methods:
1) Determine which peptide derived from GRP78 elicits a CD4+ T-cell response in RA
2) Determine the role of GRP78-specific CD4+ T-cells in RA pathogenesis and response to treatment by
i) deeply characterizing their surface phenotype and intracellular cytokine production using flow cytometry
ii) performing single cell RNA-Sequencing including T-Cell Receptor (TCR) sequences to identify expanded clones with either a damaging or protective potential
iii) following up over time a homogenous GRP78-specific CD4+ T-cell population identified under 2) ii) in pre- and post-treatment samples of responders and non-responders of biologic treatments in RA.

Project Outcomes
1) Which peptide derived from GRP78 is most immunogenic in RA will be determined.
2) The heterogeneity of GRP78-specific CD4+ T-cells will be determined and homogenous subpopulations will be identified, with regards to their phenotype, function and carriage of TCRs.
3) The therapeutic potential of some peptides derived from GRP78 will be established or refuted.

Training: Sebastien Viatte will provide training in genetics, in mass cytometry, single cell RNA-Seq and bioinformatic analysis of large dimensional datasets. John Grainger will provide expertise and training in basic immunology and flow cytometry. Anne Barton, the principal investigator of patients cohorts providing samples for this study, will provide expertise in clinical rheumatology (definition and handling of clinical variables, f.e. disease activity, response to treatment), translational and precision medicine. Eddie James will provide GRP78 peptides and HLA-DRβ1 tetramers.

Dr. Sebastien Viatte: https://www.research.manchester.ac.uk/portal/en/researchers/sebastien-viatte(1dfd2a41-2119-4d42-ad99-48064028519c).html

Prof. Anne Barton: https://www.research.manchester.ac.uk/portal/en/researchers/anne-barton(0e893881-5187-414d-8868-0fcd3fa06135).html

Dr. John Grainger: http://www.mccir.manchester.ac.uk/research/areas/inflammatory-cell-function-infection/

Dr. Eddie James: https://www.benaroyaresearch.org/what-is-bri/scientists-and-laboratories/scientific-staff/eddie-james

Entry requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website www.manchester.ac.uk/mrcdtpstudentships

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

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