Floare, Mara-Luciana (2023) TG6 Autoimmunity and the development of neurological manifestations of gluten sensitivity. PhD thesis, University of Sheffield.
Abstract
Gluten sensitivity has long been recognised for its small bowel involvement, however pioneering research in the field provides evidence for the presence of neurological manifestations that can exist in combination with, or independent of the gastrointestinal symptoms. Amongst all neurological manifestations of gluten sensitivity, gluten ataxia (GA) is the most commonly occurring one, accounting for up to 40% of cases of idiopathic sporadic ataxia. The selective degeneration of the cerebellum as a result of Purkinje cells (PC) loss is recognised as the neuropathological hallmark of GA, and the brain resident transglutaminase 6 (TG6) has been proposed as the primary autoantigen in GA. However, despite its prevalence and detrimental impact on the quality of life of those affected, the aetiology and neuropathological basis of GA are still poorly defined.
Initial data presented in this thesis indicates extensive expression of TG6 in the CNS whilst detailed immunohistochemical assessment of microglia (MHC-II, Iba-1 and CD68) and astrocytes (GFAP) performed in the CNS of 4 GA cases, 5 ataxia controls and 7 neurologically healthy controls demonstrates a significant upregulation of microglial immune activation in the cerebellar granular layer, molecular layer and cerebellar white matter, providing evidence for the involvement of humoral immune-mediated processes in GA pathogenesis. Immunological characterisation of serum and cerebrospinal fluid (CSF) samples from patients with GA demonstrates cross-reactivity of serum IgA anti-TG6 antibodies with cerebellar PC and supports the presence of IgA anti-TG6 antibodies in the CSF of patients with GA, albeit at low titres. Additionally, in the current study the expression of TG6 in Spodoptera frugiperda cells using a Bacmid system followed by its purification by chromatography allowed the visualisation of TG6-plasma cells in gut biopsies from patients with GA, findings which suggest a potential gut-localised origin to TG6 autoimmunity.
Evidence presented in this thesis highlights the importance of microglia in the pathogenesis of GA and proposes BBB breakdown and TG6-plasma cell differentiation as potential avenues responsible for facilitating and/or preventing disease progression.
Metadata
Supervisors: | Hadjivassiliou, Marios and Simpson, Julie |
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Keywords: | Ataxia, gluten sensitivity, neuroinflammation, MHC-II, gut-brain axis, |
Awarding institution: | University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield) |
Academic unit: | Neuroscience |
Depositing User: | Dr Mara-Luciana Floare |
Date Deposited: | 27 Mar 2024 16:35 |
Last Modified: | 27 Mar 2024 16:35 |
Open Archives Initiative ID (OAI ID): | oai:etheses.whiterose.ac.uk:34415 |
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