The role of the IL-23/IL-17 pathway in enthesitis and bone formation at the axial and peripheral enthesis

The seronegative spondyloarthropathies (SpA) include psoriatic arthritis (PsA), and ankylosing spondylitis (AS), Crohn’s Disease and ulcerative colitis related arthropathy. These diseases are associated with inflammation of enthesis in both the peripheral (commonly associated with PsA) and axial skeleton (commonly associated with Axial SpA and AS). Evidence from clinical trials showed that blockade of either TNF or IL-17 axis cytokines is effective in AS and PsA but IL-23 blockade failed in AS. The reasons behind IL-23 blockade failure in the spine are the subject of intense scientific debate and the IL-23/IL-17 cytokine axis at the enthesis needs re-evaluation.

<p>IL-23 blockade failure in the spine in AS has been the subject of intense scientific debate and the IL-23/IL-17 cytokine axis at the enthesis needs elucidation. At the spinal entheses, our group has confirmed a population of gamma delta-T-cells that do not express the IL-23 receptor, but can produce IL-17A. Despite this strong adaptive immune driven disease there has been very little focus on adaptive immune cell population production of IL-17A independent of IL-23. &nbsp;We have reported that the normal human spinal enthesis has a population of tissue resident memory T-cells including CD4+ and CD8+ T-cells. &nbsp;The CD4+ population are capable of producing IL-17A protein and appears to be independent of IL-23 (Watad et al ARD 2020). &nbsp; &nbsp;A clear population of CD8+ T-cells that had inducible TNF, but not IL-17A was also evident at the normal enthesis (Watad et al ARD). The objective of this research is to define IL-23 immunobiology at peripheral and axial entheses towards refining disease therapy. Using either magnetic cell isolation or FACS sorter, you will isolate T cells from perientheseal soft tissue for cell stimulation/inhibition assays. &nbsp;&nbsp;</p> <p>In addition, there are evidence to indicate that IL-23/IL-17 pathway is involved in entheseal bone formation in spondyloarthropathy. The effect of IL-23/IL-17 pathway on bone formation is a complex one, in particular, the role of stromal cells and/or mesenchymal stem cells (MSCs) at the entheseal sites. MSCs and stromal cells may be influenced by the IL-23/IL-17 pathway that can affect both adipogenesis and osteogenesis in these cells. IL-17A and TNF has been shown to modulate adipogenesis, osteogenesis and stromal function in spinal entheseal MSCs (Russell et al 2021 Cells). Working with Dr Mark Harland and Dr Darren Newton you use single cell RNAseq technology, from 10X Genomics, and bioinformatics to identify the transcriptomic expression profiles of immune cells from patients with spondyloarthritis and identify the cells that interact or influence MSCs/stromal biology.</p> <h5>Aims and objectives</h5> <ul> <li>The key objective of the proposed work is to explain the immunobiology of IL-23 differences between axial and peripheral enthesis.&nbsp;</li> <li>Determine the role of IL-23/IL-17 pathway in adipogenesis and osteogenesis in MSCs or stromal cells from entheseal tissues.</li> </ul> <h5>Research Methodologies</h5> <p>The project will involve a mix of biochemistry, immunology, tissue culture and some molecular biology techniques. You will be involved in liaising with surgical teams at the Leeds General Infirmary and at Chapel Allerton Hospitals with spine, hip and knee sample collection. You will extract immune and MSC cells either mechanically or by collagenase digestion. The extracted cells will be cultured for biological assays (stimulation and/or drug inhibition) and their cytokine/chemokines responses will be measured using multiplex assays or ELISAs and/or by FACS analysis. In addition, you will be using single cell RNAseq and/or CITE-seq technologies (University of York) to study the IL-23/IL-17 axis and cross-talking properties. Training in all the methodologies will be given.</p> <h5>Environment</h5> <p>The successful candidate will register in the School of Medicine, Leeds Institute of Rheumatic and Musculoskeletal Medicine, and will be based at the Wellcome Trust Brenner Building at the St. James&rsquo;s University Hospital site.</p> <h5>References</h5> <ul> <li>Bridgewood, C., et al., Interleukin-23 pathway at the enthesis: The emerging tory of enthesitis in spondyloarthropathy. 2020 Immunol. Rev. 295(1): 27-47. DOI: 10.1111/imr.12840</li> <li>Croft, A.P., et al., Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature, 2019. 570(7760): p. 246-251. DOI: 10.1038/s41586-019-1263-7</li> <li>Russell, T., et al, IL-17A and TNF modulate normal human psinal entheseal bone and soft tissue mesenchymal stem cell osteogenesis, adipogenesis and stromal function. 2010 Cells, 10: 341. <a href="https://doi.org/10.3390/cells10020341">https://doi.org/10.3390/cells10020341</a>.</li> <li>McGonagle, D.G., et al., The role of IL-17A in axial spondyloarthritis and psoriatic arthritis: recent advances and controversies. Ann Rheum Dis, 2019. 78(9): p. 1167-1178. DOI: 10.1136/annrheumdis-2019-215356</li> <li>Watad, A., et al., Normal human enthesis harbours conventional CD4+ and CD8+ T cells with regulatory geatures and inducible IL-17A and TNF expression. Ann.Rheum.Dis. 79, 8:1044-1054. DOI: 10.1136/annrheumdis-2020-217309</li> </ul>

<p>To apply for this scholarship opportunity applicants should complete an <a href="https://biologicalsciences.leeds.ac.uk/research-degrees/doc/how-to-apply">online application form</a> and attach the following documentation to support their application.&nbsp;</p> <ul> <li>a full academic CV</li> <li>degree certificate and transcripts of marks</li> <li>Evidence that you meet the University&#39;s minimum English language requirements (if applicable)</li> </ul> <p>To help us identify that you are applying for this scholarship project please ensure you provide the following information on your application form;</p> <ul> <li>Select PhD in Medicine as your programme of study</li> <li>Give the full project title and name the supervisors listed in this advert</li> <li>For source of funding please state you are applying for a Jenssen Funded Scholarship</li> </ul> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p> <p><em>As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education. Across all Faculties we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+ and people with disabilities. Applicants will always be selected based on merit and ability.</em></p>

You should hold a strong first degree equivalent to a UK 2:1 or above in a biological or medical science subject area. Applicants should have a keen interest in inflammation and/or a Master degree in Biology. You should be comfortable working in a highly dynamic and collaborative environment. An ideal candidate will be self motivated, a good communicator and have strong interpersonal skills.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements in IELTS and TOEFL tests for PhD, MSc, MPhil, MD are: &bull; British Council IELTS - score of 6.5 overall, with no element less than 6.0 &bull; TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

<p>This opportunity is funded by Janssen. The scholarship will attract an annual tax-free stipend of &pound;17,668 (based on the 2022/23 stipend rate) each year for up to 3 years subject to satisfactory progress. Academic fees will also be paid at the UK fee rate. Due to limited funding we can only consider applicants for this position who are eligible for UK fee status. This position must commence no later than 1 September 2023.</p>

<p>We strongly encourage applicant to contact the supervisor(s) for informal discussion about the suitability of the project before applying to the University</p> <p>Dr Chi Wong:&nbsp; &nbsp;e:<a href="mailto:t.macleod@leeds.ac.uk">c.h.wong@leeds.ac.uk</a></p> <p>Dr Tom Macleod:&nbsp; e: <a href="mailto:t.macleod@leeds.ac.uk">t.macleod@leeds.ac.uk</a></p> <p>Professor Dennis McGonagle:&nbsp; e: <a href="mailto:d.g.mcgonagle@leeds.ac.uk">d.g.mcgonagle@leeds.ac.uk</a></p> <p>For further information about the application process please contact the Admissions team<br /> e:&nbsp;<a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p>