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*
Department of Neurology, University of California, San Francisco, CA 94143;
Roche Molecular Systems, Alameda, CA 94501; and
Rocky Mountain Multiple Sclerosis Center, Englewood, CO 80110-2790
Multiple sclerosis (MS) is a common and severe neurological
disorder associated 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, thus triggering specific transcriptional
pathways. The characterization of the 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 kinetic
RT-PCR. Results showed a high transcriptional activity for the gene
coding for myelin basic protein (MBP); however, it was not
differentially expressed in MS samples, suggesting that remyelination
is an active process also in the noninflammatory brain. CD4 and
HLA-DR
transcripts were dramatically increased in MS as compared
with controls. This reveals a robust MHC class II up-regulation and
suggests that Ag is being presented locally to activated T cells.
Although analysis of cytokine and cytokine receptor genes
expression showed predominantly increased levels of several Th1
molecules (TGF-
, RANTES, and macrophage-inflammatory protein
(MIP)-1) in MS samples, some Th2 genes (IL-3, IL-5, and IL-6/IL-6R)
were found to be up-regulated as well. Similarly, both proinflammatory
type (CCR1, CCR5) and immunomodulatory type (CCR4, CCR8) chemokine
receptors were differentially expressed in the MS brain. Overall, our
data suggest a complex regulation of the inflammatory response in human
autoimmune demyelination.
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