Disease susceptibility Pathways in Multiple Sclerosis

My group is studying the genes involved in the pathogenesis of multiple sclerosis so that effective therapies may be developed. Several genes have been shown to contribute to MS susceptibility – for example the KIR receptors that are expressed on immune cells called NK cells, tumour necrosis factor-receptor 1, the interleukin-7 receptor alpha chain, and the (e) the T-box transcription factor eomesodermin (EOMES) gene region. These genes are very close to each other on the chromosomes, and so it has been difficult to work out their relative importance. We have developed methods that will allow us to study each of these genes in isolation, and determine how each contributes to the pathogenecity of MS. Data from our studies will be used in the development of new and more effective therapies for this debilitating disease.

Goals To provide a functional understanding of how MHC class I and class II genes confer risk to multiple sclerosis (MS). Our research has focussed predominantly on exploring the pathogenesis of a HLA-associated disease of the central nervous system – multiple sclerosis (MS). We have translated MS-associated genotypes to phenotypes and in doing so have shed light on disease mechanisms and provided therapeutic opportunities. We have shown that the DRB1*1501 allele is the primary risk gene in MS and that its disease-mediating effect can be modified by the linked DRB5*0101 (1). We have demonstrated functional interactions between MS associated genes and shown how protective genes can regulate risk genes, leading to less severe disease (1-4). Further, we have determined the functional and structural bases for interactions between MS-risk genes and environmental factors. Our studies in autoimmune encephalomyelitis (EAE) an animal model of MS, have shown that the acid sensitive ion channel ASIC1 is important in pathogenesis. Tissue acidosis in the spinal cord of EAE mice causes the ASIC1 channels to open, and as these are permeable to Na+ and Ca2+ ions (2) the clinical deficit and axonal degeneration caused by excessive accumulation of these two ions is reduced. Thus we have identified this acid sensing ion channel as a potential therapeutic target in MS. Future research plans Future work will focus on the study of several immune genes showing MS associated variations by using humanized and transgenic mouse models: (a) the KIR receptors that are expressed on NK cells, and their interaction with difference HLA-C alleles; (b) tumour necrosis factor-receptor 1; (c) the interleukin-7 receptor alpha chain; and the (e) the T-box transcription factor eomesodermin (EOMES) gene region. We will also carry out multiple MS family whole genome sequencing. References: (1) Gregersen et al 2006 Nature 443:574 (2) Friese et al 2007 Nature Med 12:1483 (3) Friese et al 2008 Nature Med 14: 1227 (4) Harkiolaki et al 2009 Immuity 30: 348 (5) Fugger et al 2009 Nature Rev Immunol 9: 408.