Basic Research for Regenerative Therapy of Multiple Sclerosis

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Objectives and Backgrounds : Multiple sclerosis(MS) is an immune-mediated disease affecting the central nervous system(CNS) white matter, regulated by a complex interplay between genetic and environmental factors, characterized by multifocal inflammatory demyelination and axonal degeneration that cause permanent neurological deficits. MS shows remarkable clinicopathological heterogeneity, categorized into relapsing-remitting MS(RRMS), secondary progressive MS(SPMS), and primary progressive MS(PPMS) based on the disease course, conventional MS(CMS) and opticospinal MS(OSMS) by lesion distribution, interferon-beta(IFNB) responder and nonresponder from the therapeutic response, and lymphocyte-mediated, antibody-mediated, and oligodendrocyte apoptosis-mediated demyelination from the pathological aspect. Because of its variability, the accurate clinical diagnosis of MS is often difficult due to lack of a reliable diagnostic marker. Recent studies showed that glial scar produced by reactive … More astrocytes, myelin-associated neurite outgrowth inhibitor Nogo expressed on oligodendrocytes, and proihflammatory cytokines released from activated microglia, play an inhibitory role in efficient remyelination and axonal regeneration. IFNB has been utilized as one of the most effective medications against acute relapse in MS, although the underlying mechanism remains unknown and IFNB is ineffective for induction of remyelination and axonal regeneration. Until present, no regenerative therapy is available for MS. The aim of this work is (1)to identify a novel molecular marker of MS by analyzing gene expression profile specific for MS on a DNA microarray, (2)to establish a method to distinguish IFNB responder and nonresponder before treatment, (3)to clarify the molecular mechanism of reactive gliosis, and (4)to investigate a pathological role of Nogo in the failure of axonal regeneration, in MS. Methods, Results, and Conclusions : We found that (1)by DNA microarray analysis, a family of genes involved in regulation of apoptosis are aberrantly expressed in peripheral blood lymphocytes in MS. (2)by hierarchial clustering analysis, a set of genes differentially expressed between untreated MS patients and control subjects separated four distinct subgroups of MS patients where IFNβ responders were clustered in two of these subgroups. (3)by immunohistochemical and proteome analysis, 14-3-3 epsilon isoform binds to vimentin and GFAP in cultured human astrocytes and reactive astrocytes in MS lesions. (4)by immunohistochemistry, Nogo-A is upregulated on surviving oligodendrocytes, while Nogo receptor expression is enhanced in reactive astrocytes and microglia in demyelinating lesions of MS. These results suggest a possible approach to develop regenerative therapy for MS, such as a targeted inhibition of 14-3-3 function in reactive astrocytes that might be useful for prevention of gliosis, and an application of humanized antibodies blocking Nogo-A/NgR interaction that might be helpful for supporting axonal regeneration in MS. Less