Transcriptional and histological characterisation of the synovium in early inflammatory arthritis

Carr, Hayley Louise (2022). Transcriptional and histological characterisation of the synovium in early inflammatory arthritis. University of Birmingham. Ph.D.

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Abstract

There is a large amount of heterogeneity in early inflammatory arthritis, across disease presentation, clinical manifestations, and response to treatment. This study aimed to capture the heterogeneity seen in tissue morphology and gene expression across BEACON, the Birmingham Early Arthritis Cohort, which includes patients with short duration rheumatoid arthritis (RA), longer duration RA, other persistent inflammatory arthritis, and resolving disease.
A novel H&E scoring system was developed that allows for stratification based on the density and aggregation of the lymphoid infiltrate, resulting in a summary pathotype. This correlated with measures of local and systemic inflammation and may associate with treatment response in RA.
Whole tissue RNA sequencing was used to assess gene expression across the early inflammatory arthritis cohort and highlighted major sources of variation, including the presence of prominent immune cell, adipocyte, and fibroblast signatures. Signatures associated with resolution and response to treatment in RA were identified, with response to treatment being predominantly associated with immune and inflammatory processes. Resolution was associated with reduced activation of the adaptive immune response and increased lipid synthesis when compared to short duration RA, although the implications of these signatures requires further validation.
Overall, this study extended the knowledge of heterogeneity in early inflammatory arthritis and highlights the potential utility of patient stratification for predicting response to treatment. Furthermore, some novel mechanisms of resolution were identified that could lead to the identification of new treatment targets for RA that drive pro-resolution pathways and inhibit pathways associated with persistence.

Type of Work:	Thesis (Doctorates > Ph.D.)
Award Type:	Doctorates > Ph.D.
Supervisor(s):	Supervisor(s) Email ORCID Filer, Andrew UNSPECIFIED UNSPECIFIED Scheel-Toellner, Dagmar UNSPECIFIED UNSPECIFIED Cazier, Jean-Baptiste UNSPECIFIED UNSPECIFIED Raza, Karim UNSPECIFIED UNSPECIFIED
Licence:	All rights reserved
College/Faculty:	Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department:	Institute of Inflammation and Ageing
Funders:	Medical Research Council
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QR Microbiology > QR180 Immunology
URI:	http://etheses.bham.ac.uk/id/eprint/12591

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