Role of the clotting system in the pathogenesis of neuroimmunologic disease.
Experimental allergic encephalomyelitis (EAE) is a prototypic neuroautoimmune disease involving sensitization to central nervous system myelin basic protein (MBP). Our studies of the clotting system and ensuing fibrinolysis implicate coagulation and cleavage of fibrin within or on the luminal surface of the cerebrovasculature as events initiating the inflammation characterizing EAE. Among recipient rats injected with MPB-primed, cultured-activated lymph node cells, opening of the blood-brain barrier (BBB) and deposition of perivascular fibrin within the spinal cord occur in parallel 1 day before onset of clinical signs of EAE. Daily treatment of recipient rats with trans-4-(aminomethyl)cyclohexanecarboxylic acid, a synthetic product that specifically inhibits plasminogen activator derived from endothelial cells, results in marked reduction of increased permeability of the BBB and suppression of clinical signs of EAE. We postulate that the critical event precipitating EAE is binding of circulating MBP-reactive immune effector cells to MBP immunodeterminants on the surface of cerebrovascular endothelial cells. Coagulation and ensuing fibrinolysis occur at sites of binding of effector cells to cerebrovascular endothelium. Release of biologically active peptides cleaved from fibrin open the BBB, thereby setting the stage for the cascade of inflammatory events culminating in clinical manifestations of EAE.
D000818:Animals; D001777:Blood Coagulation; D001812:Blood-Brain Barrier / Q000187:drug effects; D002560:Cerebrovascular Circulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D005342:Fibrinolysis; D007249:Inflammation; D009103:Multiple Sclerosis / Q000503:physiopathology; D004676:Myelin Basic Protein / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology; D014148:Tranexamic Acid / Q000494:pharmacology
D004676:Myelin Basic Protein; D014148:Tranexamic Acid