- Title
- Genetic and molecular differences of multiple sclerosis subgroups. Is there a failure in viral and aberrant immune cell clearance driving disease course?
- Creator
- Burnard, Sean Michael
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2021
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Thesis synopsis: Multiple Sclerosis (MS) remains a chronic debilitating neurological disease that affects millions of individuals across the globe, which also impacts on their families and the wider community. The aetiology of MS has been attributed to both genetic and environmental components, as well as potential gene-environment interaction. Two long-standing associations with MS are: autoreactive immune cells and viruses. More recently, there has been increasing evidence implicating a role for Natural Killer (NK) cells in MS, particularly since therapeutic efficacy has been attributed to the enhancement of NK cells. NK cells are integral to the control and removal of virally infected and aberrant cells, which could account for both long-standing standing associations in MS. However, NK cells have also been suggested to serve conflicting roles in MS aetiology. The action of NK cells depends on the balance of activating and inhibitory receptors in combination with their respective ligands on a target cells, with variations in the receptor-ligand repertoire across individuals. Using a custom 10 colour flow cytometry panel, comparing stable MS patients off and on various treatments, as well as ‘active’ (relapsing) patients compared to healthy controls, two major NK subsets were evaluated, the ‘immunoregulatory’ (CD56bright CD16dim/ neg) and ‘cytotoxic’ (CD56dim CD16bright) NK subsets, combined with 7 different markers covering NK maturation, activation, cytotoxicity, as well as activating and inhibitory receptors. This study confirmed the correlation for the immunoregulatory subset CD56bright CD16dim/neg with disease severity and identified associations for the cytotoxic subset CD56dim CD16bright with disease severity depending on the proportion and balance of activating and inhibitory receptors that were studied. The data presented in this study may explain the double-edged role of NK cells in MS could be distinguished by the two major NK subsets. To evaluate potential genetic alterations in NK receptors and their ligands that might contribute to MS aetiology, two independent genome-wide associations studies (GWAS) were re-analysed. Conventional GWASs performing ‘single marker analysis’ (SMA) on thousands to millions of SNPs are heavily burdened by multiple testing correction, resulting in increased levels of type II error. Therefore, multi-variate analysis was utilised, incorporating elastic net with a stability selection method by iterative subsampling to detect the potential interaction of loci with MS risk. By performing a targeted analysis on two independent GWAS across two NK receptor loci and the well-established HLA complex that encodes their ligands, new association signals for MS predisposition were identified, including SNPs above and below conventional significance thresholds that were previously undetected and identified genes implicated in biological pathways that can affect NK cell function. Clinically, MS presents as a heterogeneous disease and first manifests as two possible disease courses, relapse-from-onset (RO) or progressive-from-onset (PO); with an ongoing question as to whether PO is genetically distinct from RO? Reperforming the targeted multivariate analysis on the discovery cohort but separated into a RO and PO cohorts and compared to the original combined cohort, revealed unique and common traits associated to both subtypes. In summary, this research provides further evidence for NK cell involvement in MS at a genetic and phenotypic level. The implicated NK subsets, cell surface proteins and genetic alterations could provide new avenues for therapeutic targeting. Furthermore, the targeted multi-variate analysis developed in this thesis revealed signals that would have been missed by conventional approaches and enabled biological insight through the capture of correlated variables. This approach also revealed genetic differences between MS subtypes, and a suggestive warning that analyses combining MS subtypes into a single analysis might mask certain signals and overly inflate others.
- Subject
- multiple sclerosis; natural killer cells; immunogenetics; GWAS
- Identifier
- http://hdl.handle.net/1959.13/1501689
- Identifier
- uon:55164
- Rights
- Copyright 2021 Sean Michael Burnard
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 10 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 750 KB | Adobe Acrobat PDF | View Details Download |