Exploring fibroblast heterogeneity in the formation of TLS in the context of primary Sjögrens syndrome

Asam, Saba (2022). Exploring fibroblast heterogeneity in the formation of TLS in the context of primary Sjögrens syndrome. University of Birmingham. Ph.D.

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Abstract

The immune system is vital in the protection and maintenance of the body in a healthy state against extracellular pathogens, tissue injury and self-antigens (autoimmunity). Tertiary lymphoid structures (TLS) are non-encapsulated immune cell aggregates which can arise in response to pathogenic insult, cancer and tissue transplant in order to support antigen-specific immune responses in non-immune organs. Contrastingly, in the context of inflammation and autoimmunity, TLS can form within permissive tissues and cause tissue damage and destruction. The Barone group has explored the lymphoid function and phenotype of the immunofibroblast which contribute to the formation and organisation of these lymphocytic aggregates in the formation and organisation of TLS. Originally grouped coarsely, fibroblasts have been more recently recognized as a largely heterogeneous population defined by uniquely assigned phenotypes and functions. In this thesis, we deconvolute the stromal cell heterogeneity using scRNAseq in human primary Sjogren’s syndrome (pSS) salivary glands (SG) and inflamed murine SG and explore how these cell populations possibly underpin TLS diversity and organisation. We apply bioinformatic tools to explore mRNA gene expression patterns within cell populations, identifying a CCL21+ CCL19+ “immunopericyte” population which has not yet been explored in the context of TLS prior. We also explore the possible signalling mechanisms engaged within the immunofibroblast and “immunopericyte” populations using the inducible TLS mouse model. This work has created a cellular atlas of the human and mouse pSS SG and the different cell populations present within these primary tissues. This allows for future work to validate the mRNA dataset at the protein level and generate potential novel therapeutic targets at a cell specific level for patients.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):