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Title: Genetic variation contributing to autoimmune disease
Author: Rainbow, Daniel
ISNI:       0000 0004 8507 8818
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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Genetic variants influencing the IL-2 signaling pathway, including IL2RA , which encodes CD25, the alpha chain of the IL-2 receptor, are enriched in autoimmune diseases. Regulatory T cells (Tregs) are vital to the maintenance of a balanced immune system. They require IL-2 for their survival and by expressing high levels of CD25 are exquisitely sensitive to this cytokine. My thesis has focused on (1) accurate quantification and understanding of the heterogeneous nature of Tregs and (2) analysing phenotypes determined by IL2RA variants associated with autoimmune disease. FOXP3 is the lineage-defining transcription factor of Tregs and stable expression is dependent on the demethylation of the Treg Specific Demethylated Region (TSDR) within intron 1 of the FOXP3 gene. I developed and validated a high-throughput and sensitive method to measure the TSDR methylation and used the assay to define the heterogeneous nature of Tregs. The genetic association of IL2RA with autoimmune disease is complex and is explained by five independent signals, which have been termed the A, C, D, E and F haplotypes. Genotype-to-phenotype correlations have previously been identified for the A and D haplotypes but here I dissected IL2-RA gene polymorphisms and its mRNA expression in detail. I showed that the C haplotype results in decreased IL2RA mRNA expression, seen only in activated CD4 + T cells and the F haplotype correlates with decreased expression in ex vivo and activated B cells, and activated monocytes. The sequence relationship between disease-protective haplotypes was assessed across divergent populations. Finally, I have identified IL2RA mRNA expression phenotypes not associated with disease serving as a reminder that not all changes in gene expression correlate with a known disease haplotype.
Supervisor: Wicker, Linda ; Todd, John Sponsor: Wellcome Trust ; JDRF
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Human genetics