01 June 2002
Lancet Neurology, Volume 1, Number 2
A large-scale microarray analysis has shown pronounced differences in gene expression in tissue obtained post-mortem from four women with multiple sclerosis (MS) compared with tissue from one man and one woman without MS. “Linkage analysis in MS has so far promised much, but has essentially revealed only that the major histocompatibility complex class II genes are associated with susceptibility to MS”, says Lawrence Steinman (Stanford University, CA, USA) the lead investigator of the study. “Transcriptional profiling of MS lesions has opened a rich mine, where many potential drug targets may be found.”
Steinman's group used microarray analysis to show that 39 genes had increased expression in all MS lesions and 49 genes had decreased expression. The researchers also compared gene expression in tissue from two poles of MS pathology: acute lesions, characterised by inflammation, and chronic “silent” lesions, which show extensive scarring and demyelination. Each type of lesion showed upregulation of a distinct set of genes. “Surprisingly, many of the inflammatory molecules considered important in MS and experimental autoimmune encephalomyelitis (for example, interferon-?, tumour necrosis factor-?, interleukin-12 and others) were not found in either acute or chronic lesions”, write Stephen M Tompkins and Stephen D Miller (Northwestern University Medical School, Chicago, IL, USA) in an accompanying commentary.
Steinman's group choose two products of these genes as therapeutic targets of experimental autoimmune encephalomyelitis (EAE) in mice. They found that acute disease was less severe, and chronic disease was absent, in immunoglobulin Fc-receptor deficient EAE mice; this protein was upregulated in the chronic lesions obtained from the patients with MS. The second protein—granulocyte-colony stimulating factor (G-CSF), which is upregulated in acute MS lesions—decreased the severity of the early stages of EAE in mice when given before the onset of the disease (Nat Med 2002; 8: 500–08).
“This is one of the first published papers to go from an initial study of gene expression using microarrays to candidate pathway validation, and in so doing, begin to realise the promise of pharmacogenomics”, comments Dan Geschwind (University of California, Los Angeles, CA, USA). “That they were able to do so using such a small number of patient samples to begin with is even more impressive. How the changes in gene expression identified relate to the larger universe of MS patients remains to be demonstrated, but this study, along with that of Whitney and colleagues [Ann Neurol 1999; 46: 425–28], provides a critical basic starting point for generating and testing specific hypotheses regarding new molecular therapies for MS.”