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


Project Description

Background: 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.

Applicants are expected to hold, or about to obtain, a minimum upper second class undergraduate degree (or equivalent) in immunology subject area or equivalent. A Masters degree in a relevant subject and/or experience in flow cytometry is desirable.
For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

Funding Notes

This project is funded by Arthritis Research UK Centre for Genetics and Genomics with RCUK stipend. The starting date will be September 2019 for 3 years. If you are interested please make direct contact with the Supervisor to discuss the project. You MUST also submit an online application form - choose PhD Immunology

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.

References

Rao DA, Gurish MF, Marshall JL, Slowikowski K, Fonseka CY, Liu Y, Donlin LT, Henderson LA, Wei K, Mizoguchi F, Teslovich NC, Weinblatt ME, Massarotti EM, Coblyn JS, Helfgott SM, Lee YC, Todd DJ, Bykerk VP, Goodman SM, Pernis AB, Ivashkiv LB, Karlson EW, Nigrovic PA, Filer A, Buckley CD, Lederer JA, Raychaudhuri S, Brenner MB. “Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis.” Nature. 2017 Feb 1;542(7639):110-114. Impact factor: 40

Marre ML, McGinty JW, Chow IT, DeNicola ME, Beck NW, Kent SC, Powers AC, Bottino R, Harlan DM, Greenbaum CJ, Kwok WW, Piganelli JD, James EA. “Modifying Enzymes are Elicited by ER Stress, Generating Epitopes that are Selectively Recognized by CD4+ T Cells in Patients With Type 1 Diabetes.” Diabetes. 2018 Apr 13. pii: db171166. doi:
10.2337/db17-1166.

Viatte S, Plant D, Han B, Fu B, Yarwood A, Thomson W, Symmons DPM, Worthington J, Young A, Hyrich KL, Morgan AW, Wilson AG, Isaacs JD, Raychaudhuri S, Barton A. “Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response.” JAMA. 2015 Apr 28;313(16):1645-56. Impact factor: 44

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