Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets

May H. Han, Sun-Il Hwang, Dolly B. Roy, Deborah H. Lundgren, Jordan V. Price, Shalina S. Ousman, Guy Haskin Fernald, Bruce Gerlitz, William H. Robinson, Sergio E. Baranzini, Brian W. Grinnell, Cedric S. Raine, Raymond A. Sobel, David K. Han and Lawrence Steinman ()
Additional contact information
May H. Han: Department of Neurology and Neurological Sciences,
Sun-Il Hwang: Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA
Dolly B. Roy: Northridge Neurological Center, Northridge, California 91325, USA
Deborah H. Lundgren: Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA
Jordan V. Price: Department of Neurology and Neurological Sciences,
Shalina S. Ousman: Department of Neurology and Neurological Sciences,
Guy Haskin Fernald: University of California at San Francisco School of Medicine
Bruce Gerlitz: Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
William H. Robinson: Stanford University School of Medicine, Stanford, California 94305, USA
Sergio E. Baranzini: University of California at San Francisco School of Medicine
Brian W. Grinnell: Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
Cedric S. Raine: Albert Einstein College of Medicine, Bronx, New York 10461, USA
Raymond A. Sobel: Stanford, California 94305, USA
David K. Han: Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA
Lawrence Steinman: Department of Neurology and Neurological Sciences,

Nature, 2008, vol. 451, issue 7182, 1076-1081

Abstract: 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.

Date: 2008
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DOI: 10.1038/nature06559

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