Background: Primary Immunodeficiencies (PID) are a heterogenous group of disorders affecting components of the immune system leading to chronic, debilitating conditions that can be difficult to diagnose. Although disease-causing mutations in genes have been characterised, newly identified genetic variants require assessment of the genotype-phenotype relationships that contribute to PID, a key area of our translational research programme (https://medicinehealth.leeds.ac.uk/medicine/staff/3046/dr-sinisa-savic). PIDs can be broadly classified depending on which cell types are predominantly affected. The loss of antibody production in patients is usually attributed to a defect in B cell development or maturation, but may also relate to loss of T cell function. Our understanding of the B cell intrinsic mechanisms and the opportunities for intervention are limited. One factor in this is the lack of suitable systems to faithfully model the process of generating antibody secreting cells. Using enhanced cell culture models developed in our laboratory (https://medicinehealth.leeds.ac.uk/medicine/staff/281/dr-gina-doody) we are now in a position to ask important questions about the role of disease-associated genes in the generation, maintenance and function of antibody secreting cells.
Objectives: This PhD project will utilise our unique model system of in vitro human plasma cell differentiation to analyse how genes associated with immunodeficiencies impact on the biology of these cells and to screen for cell-autonomous defects in antibody production. We have access to the UK’s largest cohort of PID patients through partnership with the BRIDGE-PID project (https://bridgestudy.medschl.cam.ac.uk/pid.shtml) with additional international collaborations.
Novelty: Cellular models of human disease play an increasingly important part in exploring disease mechanism and potential pathways for therapeutic intervention. This project offers the opportunity to pioneer research characterising novel, clinically important mutations, including higher-order genetic interactions, using primary human samples. The supervisory team has extensive professional links, including UKPIN, the UK Systemic Autoinflammatory Disease network, and ImmunAID, that will provide access to additional clinical material and the opportunity to build working relationships that extend beyond the analysis of mutated genes in the context of the B cell lineage. Moreover, this project has the potential to form the basis of a screening tool that could be implemented in clinical setting.
Timeliness: A publication earlier this year, Nature (2020) 583:90, identified novel candidate genes that mediate disease risk for PID and shed light on the interplay between common variants that contribute to the diverse disease presentation. As additional pathogenic variants are reported, it will be important to have model systems in place to understand key physiological aspects, such as antibody production, with the ultimate goal of providing more precise diagnoses and informing clinical decisions.
Experimental approach: The PhD project will integrate a range of approaches including molecular analysis (gene expression, epigenetic profiling and B cell receptor repertoire analysis) with flow cytometry and cellular functional studies. The optimized in vitro modelling allows us to establish detailed maps of responses to defined stimuli that a plasma cell might encounter. These can be integrated into bioinformatic models to allow the prediction of disease phenotypes.
Benefits of being in the DiMeN DTP: This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
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