Transcriptional analysis of multiple sclerosis brain lesions reveals a complex pattern of cytokine expression

Multiple sclerosis (MS) is a common and severe neurological disorder associ ated with an autoimmune response directed against myelin components within the CNS, Lymphocyte activation, extravasation, and recruitment, as well as effector function, involves the turning on and off of a number of genes, th us triggering specific transcriptional pathways. The characterization of th e transcriptome in MS lesions should provide a better understanding of the mechanisms that generate and sustain the pathogenic immune response in this disease. Here we performed transcriptional profiling of 56 relevant genes in brain specimens from eight MS patients and eight normal controls by kine tic RT-PCR, Results showed a high transcriptional activity for the gene cod ing for myelin basic protein (MBP); however, it was not differentially expr essed in MS samples, suggesting that remyelination is an active process als o in the noninflammatory brain. CD4 and HLA-DR alpha transcripts were drama tically increased in MS as compared with controls. This reveals a robust MH C class II up-regulation and suggests that Ag is being presented locally to activated T cells. Although analysis of cytokine and cytokine receptor gen es expression showed predominantly increased levels of several Th1 molecule s (TGF-beta, RANTES, and macrophage-inflammatory protein (MIP)-1 alpha) in MS samples, some Th2 genes (IL-3, IL-5, and IL-6/IL-6R) mere found to be up -regulated as well. Similarly, both proinflammatory type (CCR1, CCR5) and i mmunomodulatory type (CCR4, CCR8) chemokine receptors were differentially e xpressed in the MS brain. Overall, our data suggest a complex regulation of the inflammatory response in human autoimmune demyelination.