Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affects the joints. In the UK, some patients who fail to respond to methotrexate (MTX) and TNF inhibitors (TNFi) are started on rituximab, and 20% will experience a favourable clinical response. Rituximab is the only biologic drug that specifically targets B cells in RA. How the depletion of CD20+ B cells contributes to clinical improvement, and why this occurs only in some patient groups, is unclear. However, these observations support the hypothesis that B cells are involved in the pathogenesis of RA and in the heterogeneity of the disease.
The identification of different pathogenic cell types in different patients with RA might allow the definition of disease endotypes to inform prognosis, stratified medicine and management strategies.
1) To understand the role of B cells in the susceptibility, pathogenesis and response to treatment in RA
2) To identify B-cell subsets in pre-treatment blood samples from patients with RA, that correlate with future response to specific biologic drugs, in order to guide clinical decision (stratified medicine).
Outcomes: The student will gain experience in immunological phenotyping techniques including flow and mass cytometry; genetic profiling techniques; high dimensional data analysis; sophisticated statistical analysis, as well as other generic research competencies. The student will have the opportunity to attend scientific conferences and engagement with patient groups to develop current and future research.
The primary outcome of this project is to identify B cell signature(s) that can be used to guide clinical treatment decisions (allocation of specific patient groups to specific biologic drugs). Additionally, these signatures could be used to identify good rituximab responders preventing long and expensive treatment with MTX/TNFi that will fail. This project enhances stratified medicine and targeted therapy to greatly benefit patients and reduce costly trial and error prescribing.
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with strong laboratory experience in immunology and flow cytometry are encouraged to apply.
Training/techniques to be provided:
1) Pursue the collection and biobanking of peripheral blood mononuclear cells (PBMCs) and immune cells isolated from synovial fluid and disaggregated synovial biopsies from patients with RA, PBMCs from healthy volunteers.
2) Deeply characterise the surface phenotype, intracellular cytokine production, and transcription factors of B cell subsets using flow cytometry and mass cytometry (CyToF).
3) Correlate the presence of specific B cell signatures with disease status (healthy versus RA), disease activity and treatment response to several biologic drugs in RA patients
4) Follow-up specific B cells subsets over time (3, 6 and 12 months) in post-treatment samples in responders and non-responders to various biologic drugs, including rituximab, and compare with pre-treatment samples.
5) Genotype samples from RA patients and healthy volunteers; compute a genetic risk score (GRS) based on established RA susceptibility polymorphisms; correlate the GRS with the level of B cell subsets identified above.
For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk
- Zhang F, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019 Jul;20(7):928-942
- Rao DA, et al. Nature. 2017 Feb 1;542(7639):110-114. doi: 10.1038/nature20810. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis.
- Fonseka CY, Rao DA, Teslovich NC, Korsunsky I, Hannes SK, Slowikowski K, Gurish MF, Donlin LT, Lederer JA, Weinblatt ME, Massarotti EM, Coblyn JS, Helfgott SM, Todd DJ, Bykerk VP, Karlson EW, Ermann J, Lee YC, Brenner MB, Raychaudhuri S. Mixed-effects association of single cells identifies an expanded effector CD4+ T cell subset in rheumatoid arthritis. Sci Transl Med. 2018 Oct 17;10(463).