PhD Research Project: TG6 autoimmunity in the development of Gluten Ataxia and other neurological m

The term Gluten Related Disorders (GRD) refers to a spectrum of diverse manifestations triggered by the ingestion of gluten (found in wheat, barley and rye) in genetically susceptible individuals. One of the commonest extraintestinal manifestations is gluten ataxia (GA). The identification of transglutaminase 2 (TG2) as the autoantigen in gluten sensitive enteropathy (coeliac disease-CD) was a major breakthrough in understanding the pathophysiology of CD. Previous work by the supervisors led to the identification of TG6 as an autoantigen in GA. Patients with GA have circulating antibodies against TG6. IgA deposits against TG6 can be found in cerebellar tissue in disease, and passive transfer of autoantibodies into the brain precipitates ataxia in animal model. Furthermore mutations in the gene encoding TG6 have been shown to result in ataxia (SCA35). Finally patients with GA show clinical and radiological improvement (NAA/Cr ratio within the vermis of the cerebellum) following the introduction of strict gluten free diet.

The proposed work aims to investigate the mechanism by which TG6 autoimmunity develops and results in cerebellar dysfunction. The work will determine the presence of TG6 specific B cell/plasma cells in duodenal biopsies and if the immunoglobulin produced by these cells is specific to TG6 or cross-reactive with TG2. It will also examine the presence of gluten related antibodies in the cerebrospinal fluid of patients with gluten ataxia. This work will not only contribute to our understanding of the pathophysiology of GA but will also allow for a more sensitive and specific means of diagnosing gluten related neurological dysfunction.

Our aim is to characterize the nature of these cells and respective antibodies by determining whether:

• Duodenal B cells/plasma cells are fully differentiated IgA secreting plasma cells or belong to an immature B cell population.
• The immunoglobulin produced by these cells is specific to TG6 or cross-reactive with TG2.
• The plasma cells and corresponding antibodies against TG6 are present in the cerebrospinal fluid in patients with gluten ataxia.

The detection of autoantigen-specific differentiated effector plasma cells may be a highly specific diagnostic tool, particularly in patients with gluten ataxia who often have ambiguous duodenal biopsy findings as a result of which they are often deprived of a potential treatment. Detection of cells producing TG6-specific autoantibodies on biopsy could therefore facilitate accurate early diagnosis in a Neurology setting as well as identify risk for future neurological problems in patients presenting with gastrointestinal manifestations.

The Royal Hallamshire Hospital cares for over 1700 patients with ataxias, over 900 patients with neurological dysfunction related to gluten sensitivity and over 2000 patients with CD at dedicated ataxia, gluten sensitivity and Coeliac Disease clinics. We have a detailed plan of investigation to select and recruit patients from these clinics and investigate the mechanism of neurological dysfunction in gluten sensitivity. This will be done by looking at cells isolated from small bowel biopsies, CSF examination in patients with Gluten Ataxia and serological assessment of gluten related antibodies. We will investigate the presence of IgA deposits and TG2 and TG6 specific plasma cells in biopsies from ataxia patients to understand whether all neurology patients with gluten sensitivity have underlying TG6-directed autoimmunity at gut level even when serologically negative.

In addition to clarifying how autoimmunity to TG6 develops and leads to neurological dysfunction, this project will help in optimising diagnosis of gluten related neurological dysfunction by identifying specific biomarkers. This would potentially benefit a very large number of patients with neurological disease that is currently progressive but potentially treatable. Early diagnosis will result in stabilisation and prevention of permanent disability.

The NIHR Sheffield Biomedical Research Centre is focused on the pull-through of developments in Neurodegeneration, Neuroinflammation and Cerebrovascular disease into early phase clinical trials. Research in these areas is supported by cross-cutting themes of Advanced Medical Imaging, Genomic Medicine and Bioinformatics, and in silico medicine. The Sheffield BRC brings together outstanding scientists from the University of Sheffield Departments of Neuroscience and Engineering in multidisciplinary research institutes SITraN and INSIGNEO to improve the treatment and care of people living with chronic neurological disorders.

See this project proposal in full as well as our other training positions: http://www.sitran.org/study-us/nihr-sheffield-biomedical-research-centre-training-positions/
 

Funding Notes

Home/EU PhD students will be fully funded through the Sheffield NIHR Biomedical Research Centre for 3 years.

Salary/stipend rate:

PhD stipend will be paid in line with current RCUK rates.

Entry Requirements:

Candidates must have a first or upper second class honors degree or significant research experience to be eligible for the PhD positions.

Enquiries:

Interested candidates should in the first instance contact Professor Marios Hadjivassiliou on Marios.hadjivassiliou@sth.nhs.uk

How to apply:

Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select Neurosicence as the department.

Proposed start date: PhD positions are for a January or April 2018 start.