Date of Award

2015

Document type

Thesis

Degree Name

MD (Medical Doctor)

First Supervisor

Professor Conor C. Murphy

Second Supervisor

Dr. Joan Ní Gabhann

Keywords

Sjögren’s Syndrome, MicroRNA

Abstract

Sjögren’s syndrome (SS) is a systemic autoimmune disorder characterized by lymphocytic infiltration into exocrine glands. While dry eyes and mouth are the most common presentation, immune complex deposition may lead to systemic manifestations.In SS related DED (SSUDED), a combination of reduced aqueous tear production as a result of lacrimal gland destruction and increased tear osmolarity leads to inflammatory damage at the ocular surface. microRNAs (miR) are known to alter the expression of inflammatory cytokines, which play an important role in the pathogenesis and progression of SS. The main aim of this study was to identify miRs that potentially contribute to primary SS (pSS) in a case control study. In addition, a comprehensive assessment of DED signs, SS disease indices and quality of life (QOL) in SS was undertaken.

Twenty pSS patients satisfying the AmericanUEuropean Consensus Group classification criteria (AECG) were recruited to this study. Age and sex matched healthy controls (HC) were evaluated for comparison. Prior to commencing profiling studies impression cytology (IC) was evaluated and optimised as a means of isolating miR and mRNA from primary conjunctival epithelial cells (CEC). Subsequently mRNA isolated from CEC of pSS and HC were sent for miR and mRNA microarray screening. These studies identified a panel of miRs and mRNAs with differential expression in pSS patients compared to HC. Bioinformatic analysis predicted two promising potential interactions; 1 ) Pellino3 (PELI3), a known negative regulator of type I interferon with miRU-744-U5p and 2) Early Growth Factor 1 (EGR1), a gene previously linked in SS studies with miRU3613U3p. Validation studies demonstrated significantly different expression patterns of these miRs and genes in patients compared to HC, indicating that they may potentially contribute to disease pathogenesis. Supporting this experiments using miR mimics, antagomiR and luciferase reporter assays confirmed that PELI3 is a direct target of miRU-744-U5p. Clinical and disease indices assessment gave an insight on pSS in an Irish cohort. We also confirmed the benefit of utilising both vision related QOL and global QOL XIX assessments to investigate functional status and well being of SSUDED. Overall we have identified novel miRs and targets from CECs that may become a potential biomarker for diagnosis and therapeutic target for pSS disease.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

20.1 MB

Comments

A thesis submitted for the degree of Doctor of Medicine from the Royal College of Surgeons in Ireland in 2015.

Available for download on Saturday, May 12, 2018

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