Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The myasthenogenic peptides p195-212 and p259-271 are sequences of the human acetylcholine receptor and were shown to induce myasthenia gravis-associated immune responses in mice. A dual altered peptide ligand (APL) composed of the two APLs of the myasthenogenic peptides inhibited, in vitro and in vivo, those responses. The aims of this study were to elucidate the events that follow the in vivo treatment with the dual APL and to characterize the cell population that is induced by the latter. We demonstrate here that s.c. administration of the dual APL up-regulates CD4+CD25+ regulatory T cells that are characterized by up-regulated expression of cytotoxic T lymphocyte-associated antigen 4, intracellular and membranal TGF-beta, and Foxp3. Administration of the dual APL to mice concomitant with the immunization with either of the myasthenogenic peptides resulted also in the up-regulation of c-Jun-NH2-terminal kinase activity and of Fas signaling pathway molecules as determined by measuring Fas, Fas ligand, and caspase 8. Thus, our results suggest that the suppression of myasthenia gravis-associated T cell responses exerted by the dual APL is mediated by the CD4+CD25+ immunoregulatory T cell function via TGF-beta or cytotoxic T lymphocyte-associated antigen 4, which further stimulate a cascade of events that up-regulates apoptosis.
 ...
PMID:Down-regulation of myasthenogenic T cell responses by a dual altered peptide ligand via CD4+CD25+-regulated events leading to apoptosis. 1567 27

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.
 ...
PMID: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. 1682 2