DiMeN Doctoral Training Partnership: What fundamental dysregulation of the immune system underpins the development of rheumatoid arthritis?

This project will take place in the Musculoskeletal Research Group at Newcastle University (John Isaacs, Arthur Pratt and Amy Anderson) and at Janssen Research and Development in Belgium (Anish Suri).

Rheumatoid arthritis (RA) is a disorder of uncertain pathogenesis. It is an ‘immune-mediated inflammatory disease’, in which a dysregulated immune system leads to a chronic inflammatory state focused on the joints, but also affecting other organ systems such as the lungs and cardiovascular system. (https://www.ncbi.nlm.nih.gov/pubmed/27916980)

Whilst the genetics of RA clearly point to a primary disorder of the immune system, the precise abnormalities that trigger the disease are not known. However, there is a prodromal state, that can last for up to 15 years, when circulating autoantibodies are present in healthy individuals destined to later develop RA. Thus B-cell immune tolerance is breached many years before disease onset. For 3-5 years before joint inflammation starts there is ‘epitope spreading’ and affinity maturation of these autoantibodies, as well as isotype switching, which suggests the involvement of T-cells at this stage of the disease. (http://www.nature.com/nri/journal/v10/n8/full/nri2804.html)
Over recent years the management of RA has improved enormously, such that a disease that was previously severely disabling can be brought into remission in up to half of patients. This has been the consequence of earlier diagnosis, so-called ‘treat-to-target’ strategies, and the advent of potent biologic drugs that target cytokines and immune cells. However, the outlook for the remaining 50% of patients is less good, many still developing joint damage, disability and premature cardiovascular disease. (http://www.clinmed.rcpjournal.org/content/14/Suppl_6/s50.long)

Such has been the progress with RA treatment that there is now enthusiasm for potentially preventative strategies, focussed on high-risk individuals such as first-degree relatives of RA patients who carry relevant autoantibodies. For such strategies to be effective, however, will require a deeper understanding of the fundamental immune abnormalities underpinning RA.
Recently, the MRC-ABPI RA-MAP consortium performed a systems immunology analysis of 275 patients presenting for the first time with RA. These individuals were recruited at their first early arthritis clinic visit, prior to treatment, and followed for up to 18 months. At each visit the progress of their disease was documented, and blood collected for a variety of analyses, including transcriptional profiling, proteomics and flow cytometry. Aliquots of blood were also stored for future investigation. (http://www.ra-map.com/)
Ongoing RA-MAP analyses are studying the immune abnormalities in patient with active RA but a critical question is whether these are still detectable when patients achieve remission. This will inform us whether there is a ‘residual’ signature of RA, even in patients who are symptom-free. Identification of such a signature would be highly informative – in terms of novel therapeutic targets but also in determining when immune dysregulation is first detectable in the ‘pre-disease’ period - prevention of RA may only be possible prior to such a signature appearing.

One of the major interests of our research group is the induction of therapeutic tolerance in diseases such as rheumatoid arthritis, enabling us to ‘switch’ off’ active disease using a short-term intervention.
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264217/)

In order to develop and test tolerogenic therapies, however, we require disease-specific biomarkers that will provide surrogate outcome measures during clinical trials. RA-MAP was designed to inform the development of such biomarkers, and an analysis of the remission state will also provide essential information.

The aim of this studentship will be to study RA-MAP samples from 6- and 12-month time-points, comparing patients who have active disease and those in remission. There will also be a comparison with equivalent samples from healthy individuals. The project will incorporate techniques such as Cytometry Time of Flight (CyTOF) analysis, as well as transcriptional analyses of the T-cell receptor repertoire in peripheral blood. These are multi-dimensional analytical techniques that provide very large amounts of data. Whilst initial analyses will focus on a relatively small number of individuals, samples will be studied from two time points, and ultimately analyses may be extended to additional patients from the RA-MAP cohort (n=275). Later on, the student may be required to study one or more additional RA cohorts for comparison, such as the North-East Arthritis Cohort. As well as learning relevant laboratory techniques, training in bioinformatics and biostatistics will form an essential part of the studentship.