title: 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.affiliation: Laboratory of Neuroimmunology, Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, PO Box 12000, Jerusalem, Israel. Electronic address: devorah.gur-wahnon@mail.huji.ac.il.
authors.forename: Devorah
authors.initials: D
authors.lastname: Gur-Wahnon
authors.affiliation: Laboratory of Neuroimmunology, Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, PO Box 12000, Jerusalem, Israel. Electronic address: tehilati@gmail.com.
authors.forename: Tehila
authors.initials: T
authors.lastname: Mizrachi
authors.affiliation: Laboratory of Neuroimmunology, Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, PO Box 12000, Jerusalem, Israel. Electronic address: shane.wald@mail.huji.ac.il.
authors.forename: Shane
authors.initials: S
authors.lastname: Wald-Altman
authors.affiliation: Department of Biochemistry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Electronic address: abdh@ekmd.huji.ac.il.
authors.forename: Abd
authors.initials: A
authors.lastname: Al-Roof Higazi
authors.affiliation: Laboratory of Neuroimmunology, Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, PO Box 12000, Jerusalem, Israel. Electronic address: Brenner@cc.huji.ac.il.
authors.forename: Talma
authors.initials: T
authors.lastname: Brenner
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000097:blood* / Q000188:drug therapy / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage; D017395:Plasminogen Activator Inhibitor 1 / Q000008:administration & dosage; D011950:Receptors, Cholinergic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D001323:Autoantibodies; D053264:B-Cell Activating Factor; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; D011950:Receptors, Cholinergic; C505720:Tnfsf13b protein, mouse; D010959:Tissue Plasminogen Activator
keywords: B-cell activating factor; Experimental autoimmune myasthenia gravis; Myasthenia gravis; T-regulatory cells; Tissue plasminogen activator