Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets.
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.
Han
May H
MH
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
Hwang
Sun-Il
SI
Roy
Dolly B
DB
Lundgren
Deborah H
DH
Price
Jordan V
JV
Ousman
Shalina S
SS
Fernald
Guy Haskin
GH
Gerlitz
Bruce
B
Robinson
William H
WH
Baranzini
Sergio E
SE
Grinnell
Brian W
BW
Raine
Cedric S
CS
Sobel
Raymond A
RA
Han
David K
DK
Steinman
Lawrence
L
D000328:Adult; D000818:Animals; D001777:Blood Coagulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000145:classification / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011486:Protein C / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D040901:Proteomics; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism
D011486:Protein C; D013917:Thrombin