Mechanisms and suppression of inflammatory demyelination.
Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system commonly used as a model for multiple sclerosis. In both of these diseases demyelination occurs association with perivascular infiltrates of T-cells and macrophages. The similarities in immunopathology suggest that these two diseases share common mechanisms of tissue destruction. We have proposed a general mechanism to explain the clinical and histopathological features of EAE. T-cells sensitized to the inducing antigen, myelin basic protein (MBP), react with antigen-presenting cells (possibly endothelial cells, microglia or astrocytes) in the central nervous system. As a consequence of this reaction, T-cells release lymphokines which activate macrophages, stimulate an augmenting inflammatory response, and, through the action of vasoactive amines, induce vasospasm and breakdown of the blood-brain barrier. The activated macrophages secrete inflammatory mediators, including plasminogen activator and other proteinases, which, in concert with serum plasminogen and complement, initiate myelin destruction. The macrophage products also serve to enhance the inflammatory response and vascular permeability. In support of this hypothesis we find that: (1) macrophage-secreted proteinases can degrade MBP in lyophilized myelin and that proteolysis is amplified in the presence of plasminogen; (2) proteolysis of proteins in fresh myelin by macrophage proteinases and plasminogen or by plasmin is potentiated by complement; (3) removal of macrophages from the circulation suppresses EAE; (4) proteinase inhibitors suppress EAE; and (5) prazosin, an alpha 1-adrenergic receptor antagonist, suppresses the clinical signs of EAE and the increased vascular permeability but only delays the inflammatory response. We believe that prazosin acts on the vascular alpha 1-adrenergic receptor to inhibit vasospasm and prevent opening of the blood-brain barrier. Thus it is possible to suppress both clinical signs and pathology by interceding at several steps of the cell-mediated immune reaction.
Norton
W T
WT
Department of Neurology, Albert Einstein College of Medicine, Bronx, New York 10461.
Brosnan
C F
CF
Cammer
W
W
Goldmuntz
E A
EA
D000818:Animals; D001812:Blood-Brain Barrier; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D007249:Inflammation; D009103:Multiple Sclerosis / Q000503:physiopathology