Somatic Mutations in Primary Sjögren’s Syndrome

Somatic Mutations in Primary Sjögren’s Syndrome Aleksandra Ivovic Despite decades of research and many insightful findings, a complete understanding of the pathogenesis of autoimmune diseases continues to elude us. In this thesis, I explore the hypothesis that somatic mutations may underpin the development and progression of autoimmune disease, specifically primary Sjögren’s syndrome (PSS). PSS is a chronic, systemic autoimmune disease characterized by dysfunction of salivary and lacrimal glands, which is mediated by immune cell infiltration into these tissues. As cells age and divide, they accumulate mutations and structural changes in DNA. These somatic mutations are often inconsequential but sometimes result in cell death, cancerous transformation, or other phenotypes. To describe the somatic mutational landscape of relevant cell types in PSS and investigate whether somatic mutations may have a role in the pathogenesis of this disease, we performed targeted and whole genome sequencing of glandular epithelial cells and tissue-infiltrating T and B lymphocytes from biopsies of minor salivary glands from PSS patients and controls. The results illustrate the mutational trends and clonal dynamics present in immune cells and glandular epithelial cells, suggesting ways in which somatic mutations in key cell types may be affecting disease pathogenesis. To complement the genomic studies and interrogate the lymphocyte cell types present in the salivary glands, I also a performed single cell transcriptome analysis of tissue-infiltrating immune cells. Based on the results of this transcriptomic investigation, I highlight new insights about the phenotypes and activation states of immune cells in the inflamed salivary glands. To our knowledge, this is the first study to perform genomic sequencing of affected tissue and tissue-infiltrating immune cells to investigate the presence of somatic mutations in autoimmune disease. Additionally, this is the first single cell genome-wide transcriptomic investigation of lymphocytes infiltrating minor salivary glands in PSS. The genomic and transcriptional findings of this research contribute novel insights to understanding the molecular origins of primary Sjögren’s syndrome.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Ivovic, Aleksandra

Advisors dc:contributor.advisor

• Campbell, Peter
• Siegel, Richard

• Genomics
• Immunology

Licence

• https://www.repository.cam.ac.uk/bitstreams/242905ce-090f-41f4-bebc-9614075570c0/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.65718

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/318603