Functional significance of autoantibodies in inflammatory demyelinating diseases of the central nervous system

Chapple, Katie Jean (2014) Functional significance of autoantibodies in inflammatory demyelinating diseases of the central nervous system. PhD thesis, University of Glasgow.

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Abstract

Multiple Sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system which currently affects approximately 107, 000 people in the UK, with around 5,000 people being newly diagnosed each year. Here, in Scotland, is the highest disease incidence in the world with around 1 in 170 women in Orkney currently living with the disease. These statistics emphasise the importance of researching and understanding this disease, so as to develop better therapeutics to fight MS. This thesis focused on the role of antibodies in MS, a widely studied area. There is already a great deal of published data supporting the presence and function of autoantibodies in disease pathogenesis. A more recent development was the discovery that a significant proportion of paediatric MS and acute disseminated encephalomyelitis (ADEM) patients have autoantibody responses directed against the extra-cellular domain of myelin oligodendrocyte glycoprotein (MOG). It has been shown that MOG-specific autoantibodies can induce demyelination in animal models but as yet, the clinical significance of these antibodies in human disease remains unknown. In animal models, MOG-specific antibodies exacerbate disease and mediate demyelination and it was hypothesis that this would also be the case in patients with multiple sclerosis. This hypothesis was investigated throughout this thesis via two main approaches: (1) Explore the pathogenicity of patient derived IgG using a well-characterised in vitro bioassay. (2) Based on the hypothesis determine the efficacy of depleting or tolerising MOG-reactive B cells in vivo. To study this, the effects of patient sera, which were positive for MOG reactivity, were tested on myelinating neural cell cultures. These studies showed no correlation between the presence of MOG antibodies and demyelination, therefore suggesting that these antibodies did not mediate myelin loss. MOG-specific antibodies were also studied in vivo using MOG-induced experimental autoimmune encephalomyelitis (EAE), a model which reproduces many of the clinical and pathological features of paediatric MS. Two MOG-specific therapeutic approaches were analysed: (i) induction of antigen-specific tolerance using low doses of soluble MOG, and (ii) treatment with a MOG-specific B cell immunotoxin. They both demonstrated MOG-specific immunotherapies can be efficacious. However, increasing evidence indicated full clinical protection would require targeting both MOG-specific T and B cell dependent patho-mechanisms. As these antibodies did not affect the myelin in the bioassay and the MOG-specific treatments had limited beneficial effect in vivo, it raised the question are these autoantibodies irrelevant to human disease? This was addressed by investigating the effects of low titres of MOG-specific antibodies in the absence of complement. The data presented in this thesis showed that autoantibodies, independent of complement, mediated myelin loss, microglial activation and induced chemokine production, processes which could all contribute to disease pathogenesis. Therefore, revealing a new perspective role for antibodies in MS.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Multiple Sclerosis, myelin oligodendrocyte glycoprotein, B cells, autoantibodies, antibodies, pediatric Multiple Sclerosis, antigen-specific therapies, immunotoxin
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RB Pathology
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
R Medicine > RJ Pediatrics
R Medicine > RM Therapeutics. Pharmacology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Funder's Name: UNSPECIFIED
Supervisor's Name: Linington, Prof. Chistopher
Date of Award: 2014
Depositing User: Dr Katie J Chapple
Unique ID: glathesis:2014-5753
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 23 Jan 2015 08:50
Last Modified: 30 Jan 2015 09:38
URI: http://theses.gla.ac.uk/id/eprint/5753

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