A dual altered peptide ligand down-regulates myasthenogenic T cell responses and reverses experimental autoimmune myasthenia gravis via up-regulation of Fas-FasL-mediated apoptosis.

Abstract

Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-dependent, antibody-mediated autoimmune diseases. A dual altered peptide ligand (APL) that is composed of the tandemly arranged two single amino acid analogues of two myasthenogenic peptides, p195-212 and p259-271, was demonstrated to down-regulate in vitro and in vivo MG-associated autoreactive responses. The aims of this study were to investigate the possible role of Fas-FasL-mediated apoptosis in the down-regulatory mechanism of the dual APL. We demonstrate here the effect of the dual APL on expression of key molecules involved in the Fas-FasL pathway, in a p195-212-specific T cell line, in mice immunized with Torpedo acetylcholine receptor and in mice afflicted with EAMG (induced with the latter). In vitro and in vivo results show that the dual APL up-regulated expression of Fas and FasL on the CD4 cells. Expression of the pro-apoptotic molecules, caspase 8 and caspase 3, was significantly up-regulated, while anti-apoptotic cFLIP and Bcl-2 were down-regulated upon treatment with the dual APL. The dual APL also increased phosphorylation of the mitogen-activated protein kinases, c-Jun-NH2-terminal kinase and p-38, known to play a role in the regulation of FasL expression. Further, in the T cell line incubated with the dual APL as well as in mice of the SJL inbred strain immunized with the myasthenogenic peptide and treated concomitantly with the dual APL, the percentage of apoptotic cells increased. Results strongly indicate that up-regulation of apoptosis via the Fas-FasL pathway is one of the mechanisms by which the dual APL reverses EAMG manifestations in C57BL/6 mice.

• Authors: Badiga Venkata Aruna, Hava Ben-David, Michael Sela, Edna Mozes
• Journal: Immunology (Immunology) Vol. 118 Issue 3 Pg. 413-24 (Jul 2006) ISSN: 0019-2805 [Print] England
• PMID: 16827902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Annexin A5
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Cflar protein, mouse
• Fas Ligand Protein
• Fasl protein, mouse
• Intracellular Signaling Peptides and Proteins
• Ligands
• Membrane Glycoproteins
• Peptide Fragments
• Receptors, Cholinergic
• Receptors, Interleukin-2
• Tumor Necrosis Factors
• fas Receptor
• Casp8 protein, mouse
• Caspase 8
• Caspases

Topics

• Animals
• Annexin A5 (metabolism)
• Apoptosis (immunology)
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CD4-Positive T-Lymphocytes (immunology)
• Caspase 8
• Caspases (biosynthesis)
• Cell Line
• Down-Regulation (immunology)
• Fas Ligand Protein
• Female
• Immunization
• Immunotherapy (methods)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Ligands
• Membrane Glycoproteins (immunology)
• Mice
• Mice, Inbred C57BL
• Myasthenia Gravis, Autoimmune, Experimental (immunology, pathology, therapy)
• Peptide Fragments (immunology)
• Receptors, Cholinergic (immunology)
• Receptors, Interleukin-2 (analysis)
• T-Lymphocyte Subsets (immunology)
• Tumor Necrosis Factors (immunology)
• Up-Regulation (immunology)
• fas Receptor (immunology)