Autoimmunity: MS microarrays
Microarray analysis of human multiple sclerosis lesions has revealed marked differences in gene expression between autopsy tissue from MS patients compared with similar tissue from individuals without MS. Microarray analysis of human multiple sclerosis (MS) lesions has revealed marked differences in gene expression between autopsy tissue from MS patients compared with similar tissue from individuals without MS. The authors validated two of the differentially expressed genes as potential therapeutic targets in a mouse model of MS, which established the power of the microarray approach. MS is an autoimmune disease of the central nervous system (CNS) that results from immune-cell infiltration of the CNS white matter. Inflammation and the subsequent destruction of myelin cause the well-known symptoms of progressive paralysis. Environmental factors and genetic susceptibility are both implicated in the aberrant immune response against myelin. Histologically, two types of lesions are seen: acute lesions, which are characterized by inflammation, and chronic lesions, which show scarring and demyelination. A comparison of messenger RNA transcripts from the two types of lesions uncovered several genes that were not thought previously to be important in MS, such as those that encode granulocyte colony-stimulating factor (G-CSF) and the Fc receptor. The analysis also revealed differential expression of genes in the different lesions. In all of the MS samples, the expression of thirty-nine genes was increased and the expression of 49 genes was decreased, relative to non-MS samples. Genes that had increased expression levels included those that encode the immune-response molecules G-CSF, MHC class II and immunoglobulin G; the adhesion molecules integrin- 4 and P-selectin; the complement components C1r and C3; B-cell- and macrophage-specific molecules; and several pro-inflammatory cytokines. However, comparison of the two types of lesion indicated that there is a molecular difference between acute and chronic lesions; this involves the selective upregulation of expression of 22 and 32 genes, respectively. The authors tested the value of the microarray approach using the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Expression of the Fc receptor was upregulated in chronic lesions. Fc-receptor-deficient EAE mice had less-severe acute disease and no chronic disease compared with wild-type mice. The expression of G-CSF was upregulated in acute lesions. The ability of G-CSF to alter the course of EAE was tested by treating the mice with G-CSF before and during the onset of disease. Early treatment decreased the severity of the disease, but later treatment had no effect, which indicates that G-CSF might be a regulatory molecule that naturally suppresses acute attacks. Although EAE is a useful model for MS, clinical trials have shown that many efficacious therapies in mice have not translated well into humans. So, caution must be exercised in spite of the animal-model validation of two MS targets. However, this study provides proof of principle for the power of microarray technology to identify new therapeutic targets. An enormous amount of data is included in these types of reports. Databanks that contain the raw gene-array data will allow more-meaningful comparisons across datasets to make the most of the increasing number of these analyses. Melanie Brazil References- Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalitis. Nature Med. 8, 500–507 (2002) | Article | PubMed |
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