B-cell markers from the BAFF family as predictors for experimental autoimmune myasthenia gravis aggravation in mice lacking plasminogen activator components

Tissue plasminogen activator (tPA), a component of the extracellular proteases of the PA system, is elevated in an area of inflammation, and plays a role in inflammatory neurological disorders. Our study focuses on the involvement of tPA in the animal model for Multiple Sclerosis Experimental Autoimmune Encephalomyelitis (EAE), and in Experimental Autoimmune Myasthenia Gravis (EAMG). Our results show that mice lacking tPA developed markedly more severe diseases. To further understand the underlying mechanisms resulting in the severe disease in tPA−/− mice (in EAMG), a whole genome micro-array was performed. Differentially expressed genes were clustered in pathways connected to the immune system such as; NF kappa B and TNF family, antigen presentation pathway, complement and the BAFF pathway. Consistent with the higher level of pathogenic antibodies and the more severe disease manifestation, expression of BAFF and BAFF-receptor increased while B-cell maturation antigen (BCMA) expression reduced. Given the pivotal role of T regulatory (Treg) in maintaining self-tolerance, we tested the Treg population and found a significant reduction in Tregs in EAE and EAMG in tPA−/− mice quantitatively but not functionally. Furthermore, a correlation between tPA deficiency and a decrease in TGF-beta gene expression was found, which may explain the impairment in Tregs and the more severe diseases. Finally, using components derived from the plasminogen activator inhibitor (PAI-1), and mutant tPA proteins without catalytic activity, treatment of EAE and EAMG mice resulted in a marked suppression of both diseases. Cumulatively these results suggest a role for tPA in autoimmune pathogenesis and propose it as a potential site for therapeutic intervention.