Tissue plasminogen activator involvement in experimental autoimmune myasthenia gravis: aggravation and therapeutic potential.

Abstract

Tissue plasminogen activator (tPA), a component of the PA/plasmin system, is elevated in inflammatory areas and plays a role in inflammatory neurological disorders. In the present study we explored the involvement of tPA and the potential immunomodulatory activity of tPA in experimental autoimmune myasthenia gravis (EAMG). Mice deficient in tPA (tPA(-/-)) present with a markedly more severe disease than wild type EAMG mice. In an attempt to treat EAMG with an 18aa peptide derived from the PA system inhibitor (PAI-1), designed to tether out the endogenous inhibitor, a significant suppression of disease severity was demonstrated. The more severe disease in tPA(-/-) mice was accompanied by a higher level of anti-AChR antibodies and increased expression of B-cell markers. In view of the essential role of B-cell activating factor (BAFF) in B-cell maturation, the expression of BAFF family components was tested. An increase in BAFF and BAFF receptor was observed in EAMG tPA(-/-) mice, whereas BCMA expression was reduced, consistent with the increased level of pathogenic antibodies and the more severe disease. Given the importance of T regulatory cells (Tregs) in EAMG, they were evaluated and their number was reduced in tPA(-/-) mice, in which EAMG was aggravated, whereas following PAI-1dp treatment, Tregs were replenished and the disease was ameliorated. The results show the involvement of tPA in EAMG, implying a protective role for tPA in EAMG pathogenesis. The amelioration of EAMG by PAI-1dp treatment suggests that the PA system may be considered a potential site for therapeutic intervention in neuroimmune diseases.

• Authors: Devorah Gur-Wahnon, Tehila Mizrachi, Shane Wald-Altman, Abd Al-Roof Higazi, Talma Brenner
• Journal: Journal of autoimmunity (J Autoimmun) Vol. 52 Pg. 36-43 (Aug 2014) ISSN: 1095-9157 [Electronic] England
• PMID: 24423642 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Autoantibodies
• B-Cell Activating Factor
• Peptide Fragments
• Plasminogen Activator Inhibitor 1
• Receptors, Cholinergic
• Tnfsf13b protein, mouse
• Tissue Plasminogen Activator

Topics

• Animals
• Autoantibodies (blood)
• B-Cell Activating Factor (genetics, metabolism)
• Disease Progression
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myasthenia Gravis, Autoimmune, Experimental (blood, drug therapy, immunology)
• Peptide Fragments (administration & dosage)
• Plasminogen Activator Inhibitor 1 (administration & dosage)
• Receptors, Cholinergic (immunology)
• T-Lymphocytes, Regulatory (drug effects, immunology)
• Tissue Plasminogen Activator (genetics, metabolism)
• Up-Regulation