Neural-immune cross-talk in gastrointestinal systemic sclerosis

PROJECT OVERVIEW

Systemic sclerosis (SSc) is an incurable autoimmune disease causing fibrosis of the skin, lungs, and gastrointestinal (GI) system. The fibrotic damage accrued leads to significant and progressive symptoms, and may ultimately result in organ failure and death. Patient reported outcomes highlight GI symptoms as the most frequently disabling and impactful manifestations of SSc. These can include severe reflux, diarrhoea, constipation, and intestinal failure. Yet, despite their severity, the underlying mechanisms driving pathology are poorly understood, and there are no disease-modifying treatments.

A key feature established from historical post-mortem studies is that the enteric nervous system is highly disrupted in SSc, in association with immune infiltration and tissue fibrosis. This leads to abnormal gut function, contractility, and resulting clinical disease. It is increasingly clear that neural-immune interaction is a key driver of pathology across many diseases. Neurotransmitters may signal to immune cells, and in turn, inflammatory mediators such as cytokines and prostaglandins which alter neural function, and ultimately peristalsis. Clinically, there are known correlations between measurement of dysautonomia of the GI tract, and severity of GI disease, however the pathological processes behind it are yet to be explored in SSc.

In this project you will use cutting edge technologies including single cell RNA sequencing and spatial transcriptomics, and light sheet microscopy with tissue clearing, to understand cross talk between the immune system, stromal compartment, and the enteric nervous system.

Uncovering these interactions will not only provide critical new understanding of the pathogenesis of GI disease in SSc, but also have the potential to generalise to other related fibrotic diseases, and to lead to new therapeutic approaches and tools.

KEYWORDS

Systemic sclerosis

Fibrosis

Gastrointestinal disease

Neuro-immune interaction

Autoimmunity

TRAINING OPPORTUNITIES

In this project you will gain broad training in computational biology, including the processing and analysis of single cell and spatial transcriptomic data. You will also learn standard techniques in human immunology, for example flow cytometry and tissue culture, and basic and advanced imaging methodologies including light sheet microscopy. The project may also have a significant clinical and patient contact component depending on the candidate.

KEY PUBLICATIONS

McMahan, Z.H., Kulkarni, S., Chen, J. et al. Systemic sclerosis gastrointestinal dysmotility: risk factors, pathophysiology, diagnosis and management. Nat Rev Rheumatol 19, 166–181 (2023).

Clark KEN, Xu S, Attah M, Ong VH, Buckley CD, Denton CP. Single-cell analysis reveals key differences between early-stage and late-stage systemic sclerosis skin across autoantibody subgroups. Ann Rheum Dis. 2023;82(12):1568-79.

Progatzky F., Shapiro M., Chng SH., Garcia-Cassani B., Classon CH., Sevgi S., Laddach A., Bon-Frauches AC., Lasrado R., Rahim M., Amaniti E-M., Boeing S., Shah K., Entwistle LJ., Suárez-Bonnet A., Wilson MS., Stockinger B., Pachnis V. Nature 2021, 599(125-130).

Friedrich M &  Pohin M & Jackson MA et al. IL-1-driven stromal-neutrophil interaction in deep ulcers identifies a pathotype of therapy non-responsive inflammatory bowel disease patients. Nature Medicine 2021; 27: 1970. 

THEMES

Immunology

Molecular, Cell and Systems Biology

Translational Medicine and Medical Technology

CONTACT INFORMATION OF ALL SUPERVISORS

alexander.clarke@kennedy.ox.ac.uk

franze.progatzky@kennedy.ox.ac.uk

matthias.friedrich@ndm.ox.ac.uk

kristina.clark@ndorms.ox.ac.uk