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Genetic and cellular mechanisms of autoimmunity in lupus-prone B6.129-Sle16 mice

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Title: Genetic and cellular mechanisms of autoimmunity in lupus-prone B6.129-Sle16 mice
Authors: Buang, Norzawani Binti
Item Type: Thesis or dissertation
Abstract: Genome sequencing and transcriptomic analyses are hypothesis-free approaches to identify genetic variants(s) and biological pathway(s) associated with a disease. T cells are paramount in the pathogenesis of systemic lupus erythematosus (SLE). Hyperactive CD4+ T cells can promote the production of auto-antibodies by offering excessive help to B cells. B6 congenic mice carrying the Sle16 locus (B6.129-Sle16) have increased auto-antibody levels, mild glomerulonephritis, and hyperactive T and B cells. These data indicate that intrinsic T cell abnormalities might drive the lupus-like disease development in B6.129-Sle16 mice. The aim of my thesis was to use exome sequencing and transcriptomic analysis of B6.129-Sle16 T cells from pre-disease mice to identify new candidate gene(s) and pathway(s) in lupus. Exome sequencing analysis uncovered 35 candidate genes with functional variants. RNAseq analysis of CD4+ and CD8+ T cells showed that the PYHIN gene family (Pydc4, Pydc3, Pyhin1 and Ifi204 genes) was the most differentially expressed in B6.129-Sle16 mice compared to B6 controls. PYHIN gene family expression is induced by type I interferon (IFN) and an increased IFN signature is a well-known characteristic in SLE. In my study, using in-vitro, in-vivo and ex-vivo analyses, I found no differences in the expression of IFN-inducible genes nor in pDC activation between B6.129-Sle16 mice and B6 controls. However, I observed that Pydc4 and Ifi204 gene expression could be modulated via anti-CD3 stimulation, indicating that these genes might directly regulate T cell proliferation, independent of type I IFN signalling. Altogether my findings identified new genes relevant to SLE and showed that the lupus-like disease in B6.129-Sle16 mice is independent of type I IFN, supporting the notion that lupus pathogenesis is driven by several mechanisms.
Content Version: Open Access
Issue Date: Aug-2017
Date Awarded: Dec-2017
URI: http://hdl.handle.net/10044/1/75497
DOI: https://doi.org/10.25560/75497
Copyright Statement: Creative Commons Attribution Non-Commercial No Derivatives licence.
Supervisor: Botto, Marina
Carlucci, Francesco
Sponsor/Funder: Universiti Teknologi MARA
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses