Identifying Pathogenic B cells in Rheumatoid Arthritis

Additional Supervisor: Dr Graeme Cowan (University of Edinburgh)

Background

Rheumatoid Arthritis (RA) is the commonest, most destructive, autoimmune inflammatory arthritis with over 20,000 new cases diagnosed in the UK each year1. Almost half of RA patients are of working age, yet within a year 30% are lost from the workforce2. In addition, within the first decade the majority never experience a drug free remission3. Chronic inflammation also causes pain, fatigue and depression, which are the most life-limiting factors for RA patients.

To find a cure, our research groups have collaborated on a detailed study of pathogenic white blood cells, called B lymphocytes, in the blood and joints of RA patients. B cells play a pivotal role in RA and are the only immune cell type that, once depleted, can lead to a sustained low disease activity lasting months at a time4. Whilst B cell depletion therapy undoubtedly removes pathogenic B (BRA) cells, it also indiscriminately wipes out large numbers of protective B cells. This has led to the reactivation of viral infections, with fatal outcomes. Yet, it conveys the truth that the best chance of a cure is to identify and remove just pathogenic BRA cells. The aim of this project is to identify them.

In Glasgow, through the Scottish Early Rheumatoid Arthritis (SERA) inception cohort, we have generated the most comprehensive, detailed, prospective study of newly diagnosed RA patients in the world. Importantly, we have been able to perform a detailed immuno-phenotyping of the circulating immune system in early RA. This has demonstrated that there are discrete populations that correlate with disease (providing insight into disease pathogenesis). However, in isolation, this does not permit us to stratify patients into those who will or will not respond to therapy. Complementary studies undertaken in Edinburgh have examined over 50,000 B cells from each of 147 RA patients from the SERA cohort, using next-generation-sequencing (NGS). We have discovered that, at diagnosis, most RA patients express significantly higher levels of an unusual subset of B cells, which have class switched to express IgG but continue to express very poorly mutated B-cell receptors (BCRs). Significantly, the frequency of these BRA cells was positively correlated with a poorer subsequent response to first-line therapy [with disease modifying anti rheumatic drugs (DMARDs)]. These BRA cells are stable and enriched within the inflamed RA joint tissue (synovium). As well as expressing unusually hypo-mutated IgG molecules they also fail to express the surface protein called CD27 (i.e. they are IgG+veCD27-ve B cells). When stimulated, they make pro-inflammatory proteins (called cytokines) including TNF-alpha and GM-CSF, suggesting that they are driving chronic inflammation.

Aims

Our main aim is to identify the surface markers, function and specificity of pathogenic IgG+veCD27-ve BRA cells. To do this we will utilize paired blood and synovial B cells from RA patients, from which we have detailed clinical records, and compare them to control osteoarthritis patients. Using next generation sequencing (BCR repertoire sequencing of whole B cell subsets followed by single cell RNASeq) and hybridoma technology we will confirm their subset identity, specificity, stability, cytokine profiles and function. We will verify our findings with specific in vitro assays. This knowledge will lead to a better understanding of the pathogenesis of RA as well as new diagnostic and therapeutic targets.

Training outcomes

The project will address a number of relevant MRC DTP themes enabling the PhD student to develop valuable interdisciplinary skills and experience in human immunology and autoimmunity whilst acquiring quantitative skills in transcriptomics and bioinformatics. As well as providing an excellent doctoral training we expect this project to lead to a number of high profile publications and the opportunity to present cutting edge research at National and International meetings.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location:

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you are encouraged to contact the primary supervisor prior to making your application. Additional information on the application process if available from the link above.

For more information about Precision Medicine visit:

http://www.ed.ac.uk/usher/precision-medicine