The Coagulation Factors, Activated Protein C And Thrombin, Modulate The Pathogenesis Of Experimental Autoimmune Encephalomyelitis

The immune and coagulation systems are closely linked. Components of the coagulation system, notably activated protein C (APC) and thrombin, have potent effects on the immune response. APC, beyond its traditional function as an anti-coagulant, has broad anti-inflammatory effects, mediated through modulation of leukocyte functions and conferring vascular barrier protection. Conversely, thrombin, the central enzyme in coagulation, induces pro-inflammatory responses and promotes vascular barrier disruption. We examined the influences of APC and thrombin on the pathogenic components of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis (MS), an autoimmune disease characterized by infiltration of encephalotogenic CD4+ T-cells in the CNS resulting in immunopathology. We investigated the influence of APC on EAE pathogenesis by inhibiting APC in the circulation of mice induced with EAE. Interestingly, we observed that APC inhibition alleviated EAE despite increased blood brain barrier (BBB) permeability and pronounced leukocyte infiltration in the brain. We additionally observed that the encephalotogenic CD4+ T-cells in the CNS is decreased, and, consistently, the CNS pathology is minimal. Moreover, inhibition of APC modulated the functional responses of peripheral leukocytes, resulting in increased and more activated CD11b+ myeloid population, including the CD11b+ regulatory subset referred to as myeloid-derived suppressor cells (MDSC) and characterized to be potent T-cell suppressors. We demonstrated that the increase in MDSCs resulted in the suppression of functional responses of CD4+ T-cells required for EAE progression. Thus, the net effect of APC inhibition during EAE is attenuated disease. We additionally examined the inflammatory effects of the coagulation factor, thrombin, on an in vitro BBB. Overall, thrombin effectively modified the BBB, resulting in a BBB phenotype that is conducive to leukocyte recruitment, firm adhesion and extravasation. The permissiveness of the BBB to leukocyte transendothelial migration is one the major pathological components of EAE and MS. These findings, therefore, are indicative of thrombin's potential influence on the progression of these diseases. Collectively, the results described in this dissertation strongly demonstrate the capacity of APC and thrombin in modulating the pathogenic components of EAE and further affirms that the dynamic interactions between the coagulation and immune systems in disease settings can affect disease progression