Biological determinants of the disease course - ErasMS
03 / 2007 - 03 / 2009
Stichting MS Research
An integrative approach is presented with the overall aim to identify factors that play a role in cause and course of MS. Five interconnected research lines are planned. A strategic choice has been made to execute this research program fully at the patient level. Animal models are operational, funded by projects grants and external sources, and can be applied where mechanistic studies are needed. The five research lines will generate data on their own but there are numerous interconnections between the different studies. First, a national multicentre study on the progression from clinically isolated syndrome (CIS) to MS will be initiated aiming to validate current diagnostic criteria in normal neurological practice. This will also generate data and biological material (serum, DNA, CSF) to identify clinical and biological determinants of the disease course. We have also started and aim to further expand a nationwide effort to study CIS and acute disseminated encephalomyelitis in children and possible progression to MS. For this study in patients below age 17, analyses will be performed at a national level and within a European consortium on pediatric MS (Prof. Marc Tardieu, Paris). Results will be compared between adults and children. Second will be a research line on genetic determinants of susceptibility for MS. During recent years we have strongly invested in constructing a national database on families with multiple affected members. This material will be analysed in depth by genome wide screens to identify novel gene loci. In addition we continue to collect DNA from sporadic MS patients. In parallel, we will study associations between candidate gene polymorphisms and MS. Also the association between these gene polymorphisms and disease course will be assessed. There will be special attention to candidate genes encoding molecules of the innate immune system. In the third line we will investigate two of the most promising candidate environmental factors, smoking and history of EBV infection. The Dutch multiplex MS families will also be valuable for research on environmental factors that affect MS, as we will be able to better match patients and controls (enhanced sharing of genes and environment in families). The immune system is probably the prime mediator via which certain environmental factors (e.g. infections) and genetic factors influence MS disease activity. Research in this area will improve understanding pathways involved in the pathophysiology of MS and could very well deliver clinically useful markers. Hense, in research line four, we will test the diagnostic and predictive value of a set of anti myelin antibodies, with special attention for the role of glycosylation of autoantigens. A high technology search for novel auto-antibodies and corresponding autoantigens, as well as state of the art proteomic analysis of CSF for MS specific markers is included in this line. Immune mechanisms will be studied at the level of dendritic cell interaction with microbial components and at the level of EBV specific immunity. Useful markers for clinical follow up of MS patients are scarce, especially at the level of neurodegeneration. Therefore, we aim in the fifth research line to validate the clinical use of a novel easily applicable surrogate tool to measure axonal loss in the eye, scanning laser polarimetry. This tool may be useful for future clinical trials.