A dual altered peptide ligand inhibits myasthenia gravis associated responses by inducing phosphorylated extracellular-regulated kinase 1,2 that upregulates CD4+CD25+Foxp3+ cells.

Abstract

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.

• Authors: H Ben-David, B Venkata Aruna, M Sela, E Mozes
• Journal: Scandinavian journal of immunology (Scand J Immunol) Vol. 65 Issue 6 Pg. 567-76 (Jun 2007) ISSN: 0300-9475 [Print] England
• PMID: 17523950 (Publication Type: Journal Article)

Chemical References

• CD4 Antigens
• Forkhead Transcription Factors
• Interleukin-2 Receptor alpha Subunit
• Peptides
• dual altered peptide ligand
• Extracellular Signal-Regulated MAP Kinases

Topics

• Amino Acid Sequence
• Animals
• Autoimmunity (drug effects, immunology)
• CD4 Antigens (immunology)
• CD4-Positive T-Lymphocytes (cytology, drug effects, immunology, metabolism)
• Disease Models, Animal
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Forkhead Transcription Factors (immunology)
• Immunosuppression Therapy (methods)
• Interleukin-2 Receptor alpha Subunit (immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Myasthenia Gravis, Autoimmune, Experimental (drug therapy, enzymology, immunology, pathology)
• Peptides (immunology, therapeutic use)
• Phosphorylation (drug effects)
• Treatment Outcome
• Up-Regulation (drug effects, immunology)