Gene expression pattern characterises development of Multiple Sclerosis

Extract:

Introduction:
Multiple sclerosis (MS) is a serious neurological disorder affecting young Caucasian individuals, usually with an age of onset at 18 to 40 years old. Females account for approximately 60% of MS cases and the manifestation and course of the disease is highly variable from patient to patient. The disorder is characterised by the development of plaques within the central nervous system (CNS). MS remains the most frequent cause of neurological disability, with the exception of trauma, for young adults. Investigations on twins show higher concordance rates of MS in monozygotic compared to dizygotic twins. In addition, familial susceptibility studies show that around 15% of MS patients have an affected relative. Familial risk for MS is thus very high compared to the lifetime prevalence in the general population of approximately 0.2%. Genome wide screens for MS have provided potential data for finding specific chromosomal loci involved in MS susceptibility. A series of whole genome screens for linkage to MS have been undertaken and resulted in the discovery of significant chromosomal susceptibility loci in the genome. These data have triggered a lot of interest in the regions found associated with MS and interestingly there are a number of genes that may plausibly be involved in the aetiology and pathophysiology of MS. These candidate genes have been implicated in a variety of approaches but usually involve immunological and/or genetic studies. One of the most consistent findings has been an association of specific major histocompatibility molecules which genes are located in the chromosome 6p21. However, other significant Non HLA regions pinpoint the involvement of several candidate genes that are currently under investigation at the sequencing and proteomic levels. Many gene expression studies have been undertaken to look at the specific patterns of gene transcript levels in MS. Human tissues and experimental mice were used in these gene-profiling studies and a very valuable and interesting set of data has resulted from these various expression studies. In general, genes showing variable expression include mainly immunological and inflammatory genes, stress and antioxidant genes, as well as metabolic and central nervous system markers. Of particular interest are a number of genes localised to susceptible loci previously shown to be in linkage with MS. However due to the clinical complexity of the disease, the heterogeneity of the tissues used in expression studies, as well as the variable DNA chips/membranes used for the gene profiling, it is difficult to interpret the available information. Although this information is essential for the understanding of the pathogenesis of MS, it is difficult to decipher and define the gene pathways involved in the disorder. Experiments in gene expression profiling in MS have been numerous and lists of candidates are now available for analysis. Researchers have investigated gene expression in peripheral mononuclear white blood cells (PBMCs), in MS animal models (EAE) and post mortem MS brain tissues. The genetic hallmarks of MS genetics, found to date, will be discussed in this chapter and particular conclusion on gene pathways and interactions proposed to possibly unravel the unknown aetiology of MS. Discussions on the effect of some MS medication and their effect in both cellular and molecular levels will be discussed.