1. Department of Neurology and Neurological Sciences,
2. Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California 94305, USA
3. Department of Cell Biology, Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA
4. Northridge Neurological Center, Northridge, California 91325, USA
5. Department of Neurology, University of California at San Francisco School of Medicine, California 94143, USA
6. Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
7. Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
8. Department of Pathology (Neuropathology), Stanford, California 94305, USA
9. These authors contributed equally to this work.

Correspondence to: Lawrence Steinman¹ Correspondence and requests for materials should be addressed to L.S. (Email: steinman@stanford.edu).

Abstract

Understanding the neuropathology of multiple sclerosis (MS) is essential for improved therapies. Therefore, identification of targets specific to pathological types of MS may have therapeutic benefits. Here we identify, by laser-capture microdissection and proteomics, proteins unique to three major types of MS lesions: acute plaque, chronic active plaque and chronic plaque. Comparative proteomic profiles identified tissue factor and protein C inhibitor within chronic active plaque samples, suggesting dysregulation of molecules associated with coagulation. In vivo administration of hirudin or recombinant activated protein C reduced disease severity in experimental autoimmune encephalomyelitis and suppressed Th1 and Th17 cytokines in astrocytes and immune cells. Administration of mutant forms of recombinant activated protein C showed that both its anticoagulant and its signalling functions were essential for optimal amelioration of experimental autoimmune encephalomyelitis. A proteomic approach illuminated potential therapeutic targets selective for specific pathological stages of MS and implicated participation of the coagulation cascade.

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