Multiple Sclerosis

Research Leaders: Professor David Nolan and Dr Monika Tschochner

Contact Dr Monika Tschochner

This research is generously supported by funding from the McCusker Charitable Research Foundation.

Multiple Sclerosis (MS) is a complex, multifactorial disease that usually affects young adults. The disease process can cause acute inflammation in the central nervous system including the brain, spinal cord and optic nerves. To date there is no way of effectively preventing multiple sclerosis, and while current treatments are often effective in keeping MS inactive, these approaches are limited because although they modify the immune system (thus inhibiting inflammation), they do not target the fundamental cause of the illness.

This research examines the interactions between the three major risk factors contributing to Multiple Sclerosis: genetic risk factors including human leukocyte antigen (HLA)-DRB1*1501 and other genetic variants in immune related genes, environmental factors such as low sunlight exposure and hence low vitamin D activation, as well as infection associated risk factors in MS disease. In this regard, we are particularly interested in the role of Epstein-Barr virus (EBV) infection and the possibility that immunological responses directed against the EBV latent protein EBNA-1 may be directly relevant to the development of MS. Our investigations in particular aim to identify, understand and link different risk factors for MS and subsequently utilising these findings to improve diagnosis and development of novel therapeutic strategies that can be applied in clinical practice in order to improve patient outcome.

This research effort is collaborative, closely involving neurologists with expertise in MS (Drs Allan Kermode, William Carroll and Jason Burton) as well as researchers from the Australian Neuromuscular Research Institute (ANRI) and from the University of Western Australia.

Role of Epstein-Barr virus in Multiple Sclerosis

The role of genetic variation within the Epstein-Barr virus gene sequence in shaping the immune response in patients with MS as well as healthy control subjects. We have developed novel methods that allow direct viral sequencing from patient samples, without having to go through prolonged culture systems that could influence genetic characteristics, and have additionally utilized ‘next-generation’ sequencing methods to detect low level sequence variation.

Understanding genetic risk factors that contribute to MS risk

Refining the understanding of genetic risk factors that contribute to MS risk, particularly genes within the HLA system. This project has already allowed for a more comprehensive understanding of HLA alleles that are associated with increased disease risk (HLA-DRB1*15, *16 and *08) as well as those that are protective (HLA-DRB1*04, *07 and *09), and has proposed common traits among risk-associated as well as protection-associated HLA genotypes that point towards antigen specificity of the immune response relevant to MS disease. This study also examined a genetic region associated with responsiveness to vitamin D stimulus, indicating that it was not a defining aspect of HLA-associated disease risk.

Nolan D, Castley A, Tschochner M, James I, Qiu W, Sayer D, Christiansen FT, Witt C, Mastaglia F, Carroll W, Kermode A. Contributions of vitamin D response elements and HLA promoters to multiple sclerosis risk. Neurology. 2012;79:538-46.

Role of B cells in MS disease pathogenesis

Further understanding the role of B cells in MS disease pathogenesis, particularly as this immune cell population is the long-term ‘home’ of Epstein-Barr virus as it persists through life. We have examined antibodies specifically directed against EBNA-1, as well as a specific sub-region of this protein, within a population of 426 MS patients and 186 healthy controls, showing that MS patients had significantly higher levels of antibodies compared with controls (all p<10–15). Combining these results with our previous knowledge of HLA alleles and disease risk, we were able to show that EBV antibody responses and HLA genes contributed independently to a model that classified cases and controls with an odds ratio >20 (sensitivity 92%, specificity 64%), strongly supporting the relevance of EBV-specific immunity in MS pathogenesis.

Strautins K, Tschochner M, James I, Choo L, Dunn D, Pedrini M, Kermode A, Carroll W, Nolan D. Combining HLA-DR risk alleles and anti-Epstein-Barr virus antibody profiles to stratify multiple sclerosis risk.Mult Scler. 2014 Mar;20(3):286-94

We now plan to characterise these antibodies further and investigate their potential role(s) in contributing directly to neurological inflammation, or in contributing to a ‘mis-directed’ immune response in which EBV infection leads to aberrant inflammatory responses directed against proteins in the central nervous system that appear to the immune system as similar to EBV. This project has received funding from Multiple Sclerosis Research Australia with assistance from the Trish Foundation.