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A Dual Altered Peptide Ligand Inhibits Myasthenia Gravis Associated Responses by Inducing Phosphorylated Extracellular‐regulated Kinase 1,2 that Upregulates CD4 + CD25 + Foxp3 + Cells
Author(s) -
BenDavid H.,
Venkata Aruna B.,
Sela M.,
Mozes E.
Publication year - 2007
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1111/j.1365-3083.2007.01940.x
Subject(s) - myasthenia gravis , extracellular , peptide , phosphorylation , kinase , ligand (biochemistry) , chemistry , foxp3 , microbiology and biotechnology , biology , biochemistry , immunology , receptor , immune system
Myasthenia gravis (MG) and its animal model experimental autoimmune MG (EAMG), are T‐cell dependent, antibody‐mediated autoimmune disorders. A dual altered peptide ligand (APL) composed of the tandemly arranged two single amino acids analogs of two myasthenogenic peptides, p195–212 and p259–271, was demonstrated to downregulate, in vitro and in vivo , MG‐associated autoimmune responses. Upregulation of regulatory CD4 + CD25 + cells plays a key role in the mechanism of action of the dual APL. The objectives of the present study were to address the involvement of extracellular‐regulated kinase (ERK)1,2 in the mechanisms by which the dual APL‐induced CD4 + CD25 + cells suppress MG‐associated autoimmune responses. We demonstrate here that administration of the dual APL increased activated ERK1,2 in the CD4 + CD25 + ‐enriched population. Further, inhibition of ERK1,2 by its inhibitor, U0126, in dual APL‐induced CD4 + CD25 + cells, abrogated their ability to suppress interferon (IFN)‐ γ secretion by lymph node (LN) cells of mice that were immunized with the myasthenogenic peptide. Moreover, inhibition of ERK1,2 in the dual APL‐induced regulatory CD4 + CD25 + cells, resulted in downregulation of the forkhead box p3 (Foxp3) gene and protein expression levels, as well as in the downregulation of CD4 + CD25 + development, suggesting that the active suppression exerted by the dual APL via CD4 + CD25 + cells depends on ERK1,2 activity.