TG6 autoimmunity and development of neurological dysfunction
Research type
Research Study
Full title
TG6 autoimmunity and the development of neurological dysfunction in gluten sensitivity related disorders
IRAS ID
288752
Contact name
Marios Hadjivassiliou
Contact email
Sponsor organisation
Sheffield Teaching Hospitals NHS Foundation Trust
Clinicaltrials.gov Identifier
STH21291 , STH number
Duration of Study in the UK
2 years, 0 months, 31 days
Research summary
Research Summary:
The term Gluten Related Disorders (GRD) refers to a spectrum of clinical manifestations triggered by eating gluten in individuals with gluten sensitivities. The most widely known of such disorders is coeliac disease (CD) also known as gluten sensitive enteropathy. Classical CD presents with gastrointestinal symptoms and vitamin deficiencies. Recent research demonstrates that CD can manifest with symptoms outside those related to inflammation of the gut. The most common extraintestinal manifestations present neurologically. These manifestations involve the central (CNS) and peripheral nervous systems (PNS) and can result in the characteristics of Gluten Ataxia (GA) and Gluten Neuropathy (GN), respectively.
The existence of TG6 in the CNS and PNS and its association with neurological manifestations provides an valuable investigational area. The exact mechanisms of how TG6 affects the systems and causes the associated symptoms remains to be determined. Gluten ataxia and gluten neuropathy are devasting conditions affecting many. A diagnostic test identifying those likely to develop the neurological manifestations would enable the implementation of preventative techniques; and the diagnosis of the group presenting with idiopathic neurological symptoms that are in fact due to GRD would allow for treatment of these symptoms through a gluten free diet. Subsequently, this research has the potential to improve the quality of lives of many.
This project aims to investigate the pathophysiology of neurological dysfunction in GRD with an emphasis on TG6 autoimmunity.
Summary of Results:
Our results have shown that the cerebellum is a particular site of inflammation in people with Gluten ataxia and that both antibody-driven (humoral) as well as cell-driven (cytotoxic) immune responses contribute to the cerebellar damage. We have also shown that antibodies against TG6 of IgA class (mucosal) are present in the cerebrospinal fluid of a subpopulation of people with Gluten ataxia, indicating possible breakdown of the blood-brain barrier and antibody/ plasma cell circulation from the gut to the brain. Additionally, we analysed the gene expression in patients with Gluten ataxia and controls and showed that the pathways of protein degradation and energy production are significantly unregulated in people with Gluten ataxia, indicating an adaptive response to stress that could lead to cell death. Lastly, our results demonstrated that plasma cells against TG6 can be found in the gut of people with Gluten ataxia indicating that the immune reaction contributing to cerebellar degeneration in Gluten ataxia could start in the gut, where gluten is absorbed.
REC name
North of Scotland Research Ethics Committee 2
REC reference
20/NS/0117
Date of REC Opinion
12 Oct 2020
REC opinion
Favourable Opinion