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Is there a unique stool and blood inflammatory signature in Ankylosing Spondylitis?


Project Description

Ankylosing Spondylitis (AS) is a common inflammatory rheumatic disease of unknown pathogenesis. Multiple genes involved in immune responses are known to contribute and we and others have shown an important role for type 17 immune responses.We propose that AS is triggered aberrant or excessive immune responses to the gut microbiome or its products. Reactive arthritis, a Spondyloarthritis closely related to AS, is known to be triggered by gastrointestinal infections (including Salmonella sp.). Through the Inflammatory Arthritis Microbiome Consortium (IAMC) led by FP, with PB the lead for AS, we have established a curated collection of over 100 well-characterized AS patients with stool and blood samples available.

We will specifically ask the following questions:
Is faecal microbiome associated with HLA-B27 positivity, CARD15 status, or AS disease activity? We will recruit prospectively stool and blood from a control cohort of 35 HLA-B27+ and 35 B27-ve healthy controls (of defined CARD15 genotype) over 45 years of age from the Oxford biobank, to specifically address the question as to the role of HLA-B27. We will compare with the microbiome of 100 AS patients with 100 Rheumatoid Arthritis disease controls recruited by PB and collaborators in the IAMC.

Is there a specific stool inflammatory protein signature in human AS?We will useElisa, luminex and/or cytokine bead array assays to quantify multiple stool inflammatory cytokines and molecules (eg calprotectin, MPO) associated with gut inflammation. We will purify stool leucocytes and characterize their phenotype and function by Intracellular Cytokine Staining Fluorescence Activated Cell Sorting (ICS-FACS).

Does specific AS stool inflammatory signature correlate with blood immunophenotype and/or stool microbiome? We will quantify different leucocyte populations in the matched blood of our AS cohort including myeloid and T cell populations by ICS-FACS, and correlate with HLA-B27 positivity, CARD15 status, AS disease activityand stool immunotype.

Does blood or stool inflammatory signature correlate with subsequent response to anti-TNF, anti-IL7 or anti-GMCSF therapy? AS patients will be treated with biologic therapies as part of routine NHS care or clinical trials.
Ethical permission is already in place for these studies, and all facilities available in the Botnar and/or KIR.

TRAINING OPPORTUNITIES
This project is ideal for a PhD studentship. All the techniques are “up and running” and the student will receive excellent training in immunological techniques including ELISA, FACS, as well as exposure to bioinformatics analysis of microbiome data. The work will be primarily located at the Botnar research centre with some experiments performed at the nearby KIR. The Botnar research institute is on the Oxford University Old Road Site in Headington and, together with the Kennedy Institute (approx. 200m away) comprises NDORMS. The primary supervisor has supervised 9 PhD students, all completed within 3.5 years. A core curriculum of 20 lectures will be taken in the first term of year 1 to provide a solid foundation in musculoskeletal sciences and data analysis. Students will attend Bowness and Powrie lab meetings, weekly departmental meetings and will be expected to attend seminars within the department and those relevant in the wider University. Subject-specific training will be received through our group's weekly supervision meetings. Students will also attend external scientific conferences where they will be expected to present the research findings.

Funding Notes

Interested applicants should have or expect to obtain a first or upper second class BSc degree or equivalent, and will also need to provide evidence of English language competence. The University requires candidates to formally apply online and for their referees to submit online references via the online application system. The application guide and form is found online and the DPhil or MSc by research will commence in October 2019.

References

Al-Mossawi MH, Chen L, Fang H, ….Powrie F, Knight JC, Bowness P. Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis. Nat Commun 2017 Nov 15;8(1):1510.

RysnikO, McHugh K, van Duivenvoorde L, …Bowness P. Non-conventional forms of HLA-B27 are expressed in spondyloarthritis joints and gut tissue. J Autoimmun.2016 Jun;70:12-21.

West NR, Hegazy AN, Owens BMJ, Bullers SJ, …..Oxford IBD Cohort Investigators, Keshav S, Travis SPL, Powrie F. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med. 2017 May;23(5):579-589.

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