A dual altered peptide ligand inhibits myasthenia gravis associated responses by inducing phosphorylated extracellular-regulated kinase 1,2 that upregulates CD4+CD25+Foxp3+ cells.
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)-gamma 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.
Ben-David
H
H
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Venkata Aruna
B
B
Sela
M
M
Mozes
E
E
D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000276:immunology; D007165:Immunosuppression Therapy / Q000379:methods; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D010455:Peptides / Q000276:immunology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D010455:Peptides; C514281:dual altered peptide ligand; D048049:Extracellular Signal-Regulated MAP Kinases