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1. Investigating the cellular causes of HLA-B27 associated spondyloarthritis

spondylitis-project-figure.pngLeft: Droplet-based single-cell RNA-sequencing analysis of 22,000 immune cells from 7 patients with spondyloarthritis. Right: Inflammation in spondyloarthritis is thought to involve dysregulation of a tissue repair circuit that comprises of both immune and stromal cells.

Ankylosing spondylitis (AS) is a common form of inflammatory arthritis. It is a highly heritable, polygenic disease for which the strongest genetic association is with the MHC I molecule HLA-B*27. Despite this and other associations with genes of the innate and adaptive immune systems, the cellular and molecular causes of the disease remain enigmatic. Normally first detected in sacroiliac joints, AS is typified by enthesitis – inflammation at sites of muscle attachment to bone - which can lead to abnormal bone growth. Outside the joints, other sites subject to repeated mechanical stress are also prone to inflammation in AS. Inflammation of the eye, for example, is very common in AS patients and is also independently associated with HLA-B27. In one possible model, HLA-B27 mediated inflammation at entheseal (or entheseal-like sites) may involve the dysregulation of a homeostatic tissue repair circuit. In work recently funded by Versus Arthritis we are leading a single-cell genomics-based study of biopsy samples in order to discover and characterize the cells that cause and respond to inflammation in HLA-B27 positive AS patients. We aim to help patients by aiding early disease detection and by providing a rational basis for development of curative therapeutics. This work is made possible by a close partnership between a team of scientists and clinicians that include Professor Paul Bowness, Dr Sri Sharma and Dr Jonathan Sherlock and Professor Chris Buckley.

2. Investigating fibroblast heterogeneity in rheumatoid arthritis

rhematoid-arthritis-project-figure.pngRheumatoid arthritis involves thickening of the joint synovium (left panel). Single-cell analysis identified five populations of stromal cells in a mouse model (Mm STIA) that show similarity to cells found in human disease (Hs RA) (centre and right panels).  

Although fibroblasts have an established role in the pathogenesis of immune mediated inflammatory disease, their ontology and functional heterogeneity is poorly characterised.  In a recent collaboration with Professor Chris Buckley we used a single-cell approach to characterise distinct populations of synovial and stromal cells that drive inflammation and damage in mouse model of rheumatoid arthritis (Croft et. al., Nature 2019). In work supported by the MRC we are extending this research to model synovial fibroblast phenotypes across the disease course and investigate their developmental origins.

3. Mapping the cell types present in healthy human joints

Reference maps of healthy human tissues are vital for understanding how signalling between stromal and immune cell populations becomes dysregulated in inflammatory diseases and for the interpretation of genetic information from genome wide association studies (GWAS). In order to inform our investigations of ankylosing spondylitis and rheumatoid arthritis we are using single-cell transcriptomics to build atlases of the cells present in embryonic and adult human joints. This work is funded by the MRC as part of the global Human Cell Atlas (HCA) initiative. 

4. Investigating the role of mononuclear phagocytes in inflammatory bowel disease

In the healthy gut, macrophages maintain an anergic phenotype and play essential roles in the maintenance of intestinal homeostasis. In contrast to other tissues of the body, in which macrophages have an embryonic origin, macrophages of the gut derive largely from circulating blood monocytes. In inflammatory bowel diseases such as Crohn's Disease and ulcerative colitis intestinal monocyte recruitment is greatly increased and both monocytes and macrophages are known sources of pro-inflammatory cytokines such as IL-23. In collaboration with the groups of Professor Irina Udalova and Professor Fiona Powrie we are using functional and single-cell genomics approaches to study mononuclear cell heterogeneity during intestinal inflammation. 

5. The role of thymic epithelial cells in central tolerance 

The adaptive immune system employs stochastic somatic V(D)J recombination to generate a diverse T-cell receptor repertoire capable of recognising unknown foreign antigens. For this strategy to succeed, T-cells acquiring self-reactive receptors must be deleted or directed to a regulatory fate. In large part, T-cell selection is centrally guided by thymic epithelial cells (TEC) which challenge naïve T-cells with a near-complete molecular mirror of self-antigens. This unusual ability of TEC to promiscuously express virtually all protein coding genes is poorly understood but depends on the autoimmune regulator, Aire, a factor essential for the avoidance of autoimmunity. In collaborative work with Professors’ Georg Hollander and Chris Ponting, we are using single cell genomics approaches to study the mechanics of promiscuous gene expression in TEC. This work is funded by a Wellcome Trust Strategic Award.