Aberrant T regulatory cell responses to candidate viral and auto-antigens in the pathogenesis of multiple sclerosis

Lead Research Organisation: University of Aberdeen
Department Name: Unlisted

Abstract

Multiple sclerosis (MS) affects over 80,000 people in the UK and may cause paralysis, blindness and problems with sensation. It is a disease that seems to be caused by attacks of the immune system on parts of the brain. Many researchers think it may be caused by an unusual response to an infection, as it occurs in clusters, especially in colder climates. The leading candidate infectious agent is Epstein-Barr virus, the cause of glandular fever, which has infected almost all patients with MS. After initial infection, the virus lives on in people as a latent form. We have shown that latent EBV fools the immune system into thinking it is not a problem by stimulating a special sort of immune cell called a regulatory T cell. Knowing that the immune response to EBV may be important in MS, we recently looked at the regulatory T cell response to EBV in patients with MS and found that it was strikingly different to that of healthy people. We now propose to look at these differences in more detail to establish the way in which infection with such a virus might lead to the disease.

Technical Summary

Several epidemiological features of multiple sclerosis (MS), especially geographical and temporal clustering, have suggested the importance of exposure to an infectious agent during childhood or adolescence in its pathogenesis. The best of these associations is with Epstein-Barr virus (EBV). A meta-analysis of case control studies, as well as subsequent data, has shown that over 99% of patients with MS have been infected, with a summary odds ratio of over 13 compared to controls. Other case-control studies have shown that infectious mononucleosis and high anti-EBV antibody titres are risk factors for the subsequent development of MS. If EBV is causal, it would be predicted that the immune response to latent infection is pathological. We have previously shown that the immune responses to at least two EBV latent antigens are dominated by regulatory T cells. Furthermore, we now have pilot data showing that the regulatory T cell response to EBV latent and antigens differ substantially from healthy donors. We therefore propose to study regulatory immune responses to an EBV latent antigen (LMP1) and an auto-antigen (MOG) in cross-sectional and longitudinal case control studies of patients with MS. We will also study these responses in healthy subjects before and after EBV infection, apparently EBV seronegative MS patients and monozygotic twin pairs both concordant and discordant for MS. In this way, we will test the hypotheses that either EBV infection is an important factor in the immunopathogenesis of MS or the aberrant immune responses we have observed and MS share common causation.

Publications

10 25 50
 
Title MS serum bank 
Description Stored plasma/serum samples of patients with MS. Database of patients with MS now being developed into full survey. This database being used to collect genetic samples. 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2008 
Provided To Others? Yes  
Impact Database being used to collect DNA samples for genetic studies in Cambridge and Edinburgh 
 
Description EBV meta-analyses 
Organisation University of Aberdeen
Department Institute of Applied Health Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Jointly performed meta-analyses
Collaborator Contribution Jointly performed meta-analyses
Impact Almohmeed YH, Avenell A, Aucott L, Vickers MA. Systematic review and meta-analysis of the sero-epidemiological association between Epstein Barr virus and Multiple Sclerosis. PLoS One. 2013 Apr 9;8(4):e61110. doi: 10.1371/journal.pone.0061110. Print 2013. Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and systemic lupus erythematosus. Hanlon P, Avenell A, Aucott L, Vickers MA. Arthritis Res Ther. 2014 Jan 6;16(1):R3. doi: 10.1186/ar4429. BMC Infect Dis. 2014 Mar 20;14:151. doi: 10.1186/1471-2334-14-151. The epidemiology of infectious mononucleosis in Northern Scotland: a decreasing incidence and winter peak. Visser E1, Milne D, Collacott I, McLernon D, Counsell C, Vickers M.
Start Year 2011
 
Description The effects of vitamin D or UV light on Treg function in patients with MS 
Organisation University of Dundee
Department Section of Ageing & Health
Country United Kingdom 
Sector Academic/University 
PI Contribution I instigated a partnership between several internal collaborators (specialists in clinical trials, UV phototherapy)
Collaborator Contribution Development of clinical trial protocolDevelopment of protocol to test Treg function
Impact Grant Application to Chief Scientist's Office submitted but now rejected Project completed and paper written "The effect of ultraviolet light on systemic immune function and 25-hydroxyvitamin D". About to be submitted to Journal of Allergy and Clinical Immunology. After submission, we will apply again to the Chief Scientist's Office.
Start Year 2010
 
Description The effects of vitamin D or UV light on Treg function in patients with MS 
Organisation University of Edinburgh
Department Centre for Multiple Sclerosis Research
Country United Kingdom 
Sector Academic/University 
PI Contribution I instigated a partnership between several internal collaborators (specialists in clinical trials, UV phototherapy)
Collaborator Contribution Development of clinical trial protocolDevelopment of protocol to test Treg function
Impact Grant Application to Chief Scientist's Office submitted but now rejected Project completed and paper written "The effect of ultraviolet light on systemic immune function and 25-hydroxyvitamin D". About to be submitted to Journal of Allergy and Clinical Immunology. After submission, we will apply again to the Chief Scientist's Office.
Start Year 2010
 
Description Interview on BBC Scotland news 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Interviewed about vitamin D on BBC Scotland 6pm news

Difficult to quantify.
Year(s) Of Engagement Activity 2009
 
Description Interview with Herald newspaper 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact Was interviewed by reporter from 'The Herald' concerning MS, particularly its links with vitamin D deficiency

Difficult to quantify.
Year(s) Of Engagement Activity 2009
 
Description Lecture Stuart Centre 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact Lecture to MS group

None quantifiable
Year(s) Of Engagement Activity 2006
 
Description Poster session Stuart Centre 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact Prepared and manned a poster at a patient/relative open day

Patients seeemed interested but difficult to quantify impact
Year(s) Of Engagement Activity 2008
 
Description School visit, Aberdeen 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Gave talk and asked questions on MS

Pupils seemed interested and asked numerous questions. Difficult to quantify impact.
Year(s) Of Engagement Activity 2009
 
Description Session on Radio Scotland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Took part in phone-in on vitamin D

Difficult to quantify impact on listening audience.
Year(s) Of Engagement Activity 2009