The metabolomic jigsaw puzzle of immunity and its perturbation in rheumatoid arthritis

Outline of Project:
Metabolomic profiling of serum from patients with early arthritis is able to discriminate between patients who will go on to develop RA and those with self-limiting disease (1). Although there is a very strong correlation between the metabolic profile and inflammation (CRP), the exact source of these serum metabolites is unclear but using in vitro culture of synovial fibroblasts we have recently shown a similarly strong correlation between the metabolites produced and the CRP level in the patient from whom the cells were derived at the time of biopsy (unpublished data). PET imaging using 18F-labeled deoxyglucose has shown that inflamed joints are highly active metabolically with substantial glycolytic activity (2).

This might suggest that the metabolites we see in blood are derived from the joints and specifically the synovial fibroblasts, but the joints also contain a broad population of metabolically active immune cells. Macrophages make up a large proportion of these and we have shown that in vitro these are metabolically heterogeneous with significant differences between M1, M2 macrophages and dendritic cells, which relate to their relative inflammatory activity and ability to function in the hypoxic environment of the joint (unpublished data). Work from Erika Pearce (3), has shown that lymphocytes are also metabolically heterogeneous with, for instance, significant differences in the metabolic requirements and activities of memory CD8 T cells compared to naive CD8 T cells (4). Memory or effector cells have different energy and metabolite requirements since they need to rapidly respond to pathogens by proliferation, secretion of cytokines, and performing effector functions. Thus the cells we find in the joint may be metabolically very different to those in the blood.

To understand the sources of the altered metabolites in serum seen in RA patients we will generate in vitro metabolic profiles of a broad range of types of immune cells cultured under normal oxygen levels (8%), and under the hypoxic conditions found in the joint (3%), since we have found the latter to promote inflammatory cells. Co-cultures of the cells with synovial fibroblasts will allow us to determine if synovial cells perturb the metabolism of the immune cells and if this is reflected in an altered phenotype and function in terms of, for example, secretion of cytokines. Expression and activity of key enzymes regulating the switch between glycolysis and oxidative phosphorylation, for example, pyruvate kinase M2, will be assessed to understand how changes in metabolism in cells in the synovium may come about.

Outlook for the project:
Our previous work on the analysis of bio fluids from arthritis patients has shown the metabolomics has great potential for differentiating between patients and in guiding personalised therapy. To further develop this potential and understand the implications of the metabolic changes we have observed in patients, we need to study their molecular and cellular basis. This may provide novel targets for therapeutic intervention, for example, if we can establish that the metabolic disturbances in the synovial fibroblasts perturb immune cell function and thus perpetuate chronic inflammatory process, it might strongly suggest that the glycolytic pathways which may be hyperactive in the fibroblasts may represent a uniquely drug-able target.

Person Specification:
Applicants should have a strong background in biochemistry, and ideally a background in immunology. They should have a commitment to research in the mechanisms driving human disease and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

How to apply:
Informal enquiries should be directed to Dr Stephen Young
Applications should be directed to Dr Stephen Young (email [Email Address Removed]). To apply, please send:
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.