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Investigating mechanisms that regulate ectopic lymphoid-like structures in inflammation

Hill, David G. 2019. Investigating mechanisms that regulate ectopic lymphoid-like structures in inflammation. PhD Thesis, Cardiff University.
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Abstract

Lymph node-like follicles called ectopic lymphoid-like structures (ELS) often develop in inflamed tissues affected by autoimmunity and cancer. ELS range from co-localised T and B cell aggregates to highly segregated structures displaying germinal centre reactions. As such, ELS can prime local immune responses and influence chronic disease progression. To understand how interleukin (IL)-27 regulates ELS during inflammatory arthritis, studies established an RNA-sequencing and bioinformatics pipeline to characterise joint inflammation in IL-27 receptor (IL-27R)-deficient mice that develop synovial ELS. Molecular pathway analysis revealed that IL-27 shapes the inflammatory response through suppressing genes involved in leukocyte activation, effector T cell function and chemotaxis. Gene set enrichment analysis identified a prominent pathogenic T helper (Th)17 signature in ELS-rich synovitis, which was confirmed by increased infiltration of IL-17-producing T helper cells in the joints of IL-27R-deficient mice. The significance of the Th17/IL-17 axis on ELS development was also investigated in inflammation-associated gastric cancer. The spontaneous development of gastric tumours in gp130Y757F:Y757F mice coincided with the formation of extra-tumoural ELS in the gastric submucosa. Here, ELS displayed T and B cell segregation, reactive germinal centres, and their formation coincided with the temporal induction of homeostatic chemokines. Interestingly, genetic ablation of IL-17 in gp130Y757F:Y757F mice revealed that the early formation of lymphoid aggregates did not require IL-17. Rather, IL-17 was needed for the formation of mature ELS that comprised follicular dendritic cells and germinal centres. In clinical disease, while an ELS gene signature was associated with advanced gastric cancer, it did not indicate a favourable prognosis. The gp130Y757F:Y757F mice represent a new model for the study of ELS in cancer and an opportunity to test novel drugs that may target ELS. The cross-disease roles revealed for the Th17 programme in regulating ELS makes an attractive target for the immunomodulation of ELS-rich arthritis and cancer.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 28 June 2019
Last Modified: 28 Jun 2019 15:43
URI: http://orca-mwe.cf.ac.uk/id/eprint/123766

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