Coventry University Featured PhD Programmes
Imperial College London Featured PhD Programmes
Coventry University Featured PhD Programmes

Restoring order to the joint: identifying the cellular drivers of treatment refractory rheumatoid arthritis


Institute of Inflammation and Ageing

Dr A P Croft Sunday, May 30, 2021 Funded PhD Project (UK Students Only)
Birmingham United Kingdom Bioinformatics Cell Biology Genomics Immunology

About the Project

Research interests/description of main research theme:

Background

The immune mechanisms underlying treatment refractory rheumatoid arthritis (RA) (defined as the sequential failure of multiple biologic disease modifying anti-rheumatic drugs, bDMARDs) are poorly understood. Our recent work on the heterogeneity of tissue resident synovial cells has revealed distinct subsets of fibroblasts and macrophages with critical roles in determining if inflammation either resolves or persists. We have shown that the expansion of immune-modulatory synovial fibroblasts (THY1+ CD34+) driven by vascular endothelial NOTCH-3 signaling is associated with chronic joint inflammation. These fibroblasts, lose their immune protective functions and instead amplify inflammation, producing pathogenic levels of chemokines and cytokines that drive leucocyte accumulation. In contrast, tissue resident MerTK+ synovial macrophages are pro-resolving, having the capacity to negatively regulate inflammation by inducing a repair phenotype in synovial fibroblasts.

We hypothesize that refractory RA results from an epigenetically imprinted change in the phenotype of

THY1+ CD34+ fibroblasts that maintains these cells in a persistent pathogenic state, leading to their

failure to respond to negative regulation by MerTK+ tissue macrophages. As a result, joint homeostasis

cannot be re-established and inflammation persists.

Our preliminary data has identified immune-modulatory fibroblast subsets that are enriched in the sub-lining tissue of the synovial membrane and expanded in the inflamed joints of patients with active RA. The adoptive transfer of these immune effector fibroblasts into the inflamed joint leads to a more severe and persistent inflammatory arthritis. Mixed cell organoids of human endothelial cells and fibroblasts revealed that NOTCH-3 signaling from the vascular endothelium induced this immunomodulatory phenotype and analysis of fibroblasts isolated at different stages of inflammatory arthritis revealed distinct, cell subset specific gene expression programs associated with different phases of inflammation. These findings collectively suggest that phenotypic plasticity exists within the immunomodulatory fibroblast populations in the joint, during inflammation. We propose that this plasticity in fibroblast phenotype is lost in chronic inflammation, due to epigenetic modifications that result in the persistent induction of a ‘transformed’ cell phenotype in distinct subsets of immune effector fibroblasts that persist in chronic treatment refractory disease.

Aims

We will test the hypothesis that refractory RA is the result of an epigenetically imprinted, inflammatory driven, pathogenic phenotype in THY1+ CD34+ immune-modulatory fibroblasts resulting in their failure to respond to negative regulation by MerTK+ pro-resolving synovial macrophages.

Key objectives:

1. Identify the phenotype, location and proportions of THY1+ CD34+ fibroblasts and MerTK+ macrophages in synovial tissue from patients with refractory RA compared to those in clinical remission.

2. Establish the regulatory networks that drive specific programs of gene expression associated with the

maintenance of a pathogenic state in specific fibroblast subsets.

3. Determine how fibroblast-macrophage interactions result in alterations of activation status and phenotype of THY1+ CD34+ fibroblasts in treatment refractory RA.

Candidate: The candidate will join a warm and friendly research group based within the internationally recognised Rheumatology Research Group within the Centre for Translational Inflammation Research and institute of inflammation and ageing. They will be provided with full support and training in all aspects of their PhD. Our group has extensive expertise in stromal cell biology, single cell genomics and digital imaging platforms. The student will benefit from being part of the Rheumatoid Arthritis Pathogenesis Centre of Excellence a partnership between the Universities of Oxford, Glasgow, Birmingham and Newcastle (RACE; http://www.race-gbn.org/). 

We are looking for an outstanding student with a strong background in immunology. They should have a commitment to research in inflammation/immunology and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject. 

For information about the research activities in our laboratory, please visit:

https://www.race-gbn.org

https://www.birmingham.ac.uk/research/inflammation-ageing/index.aspx

https://www.birmingham.ac.uk/research/inflammation-ageing/rheumatology-research-group.aspx

How to apply

Informal enquiries should be directed to Dr Adam P Croft

Applications should be directed to Adam P. Croft (email ). 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.


Funding Notes

This post is funded by Versus Arthritis and is a 4-year post. The post is only open to UK residents due to funding restrictions.

References

1. Croft, A. P. et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570, 246–251 (2019).
2. Alivernini S et al. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat Med. 2020 Aug;26(8):1295–306.
3. Wei K et al. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature. 2020 Jun;582(7811):259–64.
Search Suggestions

Search Suggestions

Based on your current searches we recommend the following search filters.



FindAPhD. Copyright 2005-2021
All rights reserved.