The idiopathic inflammatory myopathies (IIM) are heterogeneous rare autoimmune conditions characterised by weakness and inflammation of skeletal muscle. The major subtypes of IIM are polymyositis (PM), dermatomyositis (DM) and inclusion body myositis. IIM are complex diseases likely caused by a combination of genetic susceptibility and environmental triggers including exposure to statins, infections and ultraviolet (UV) radiation. A clearer understanding of IIM pathology is important for the development of novel treatments. The aim of this PhD was to investigate the mechanisms involved in the pathogenesis and progression of IIM using three different approaches. In chapter 3 ('Systematic Protein-Protein Interaction and Pathway Analyses in the Idiopathic Inflammatory Myopathies'), an in silico approach was taken to identify potential protein-protein interactions between proteins that may be affected by single-nucleotide polymorphisms (SNPs) associated with IIM and the targets of autoantibodies associated with IIM. This study identified HSPA1A/B, UBE3B, PSMD3 and TRAF6 as genes to prioritise and pointed towards the ubiquitin proteasome pathway as a potentially important pathway in IIM. In chapter 4 ('Genetic background may contribute to the latitude-dependent prevalence of dermatomyositis and anti-TIF1-gamma autoantibodies in adult patients with myositis'), a genetic epidemiology approach was used to investigate the contribution of genetic background versus UV exposure to the distribution of DM in an international cohort of IIM cases and controls (using latitude as a proxy for UV exposure). This study found a novel negative association of the DM autoantibody anti-TIF1-gamma with latitude in the IIM cohort. SNPs associated with PM or DM and Human Leukocyte Antigen (HLA) alleles associated with DM autoantibodies, were modelled for association with latitude in healthy populations. The majority of SNPs and the HLA alleles were found to be associated with latitude in the same direction as the prevalence of the clinical phenotypes in the IIM cohort (negative for DM, positive for PM). Overall, these analyses lent some support to the hypothesis that genetic background, in addition to UV exposure, may contribute to the distribution of DM versus PM. In chapter 5 ('MicroRNA and mRNA profiling in the idiopathic inflammatory myopathies') next generation RNA sequencing was used to profile miRNA and mRNA in whole blood samples from PM, DM and IBM compared to controls. Gene ontology and pathway analyses were performed using GOseq and Ingenuity Pathway Analysis. Dysregulation of miRNAs and opposite dysregulation of predicted target mRNAs in IIM subgroups was validated using RTqPCR and investigated by transfecting human skeletal muscle cells with miRNA mimic. Overall, miRNA and mRNA profiling identified dysregulation of interferon signalling, innate immune and anti-viral responses and T-helper cell pathways. The transfection experiments indicated a possible role for miR-96-5p regulation of ADK in pathogenesis of IIM. Overall, these studies have contributed to our understanding of IIM susceptibility and disease progression and suggested avenues for future research which may ultimately lead to the development of improved diagnosis and treatments for this rare and debilitating group of diseases.
|Date of Award||31 Dec 2018|
- The University of Manchester
|Supervisor||Philip Day (Supervisor), Hector Chinoy (Supervisor) & Janine Lamb (Supervisor)|
- Protein-Protein Interaction