Suppression of experimental myasthenia gravis by a B-cell epitope-free recombinant acetylcholine receptor.

Abstract

Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are antibody-mediated autoimmune diseases in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. Previously we have revealed that oral treatment with the less native recombinant fragment of the extracellular domain of the human AChR (Halpha1-205) suppressed ongoing EAMG, whereas the more native recombinant Trx-Halpha1-210 exacerbated EAMG. In this study, we speculated on the role of B-cell epitopes in oral tolerogens for the induction of oral tolerance in EAMG. We developed a B-cell epitope-free AChR fragment (BF-AChR) by removing two major B-cell epitopes (67-76 and 129-145) from Trx-Halpha1-210. BF-AChR exhibited a poor response to EAMG sera and to AChR-specific B- and T-cells while its parent fragment, Trx-Halpha1-210, showed much higher reactivity. Oral administration of BF-AChR ameliorated the symptoms in ongoing myasthenic rats accompanied by a significant decrease in AChR-specific humoral and Th1 cellular responses. The underlying mechanism for BF-AChR-induced oral tolerance was mediated by a shift from Th1 to regulatory T-cell (IL-10(+), CD4(+) TGF-beta(+) or Foxp3(+)) responses. This shift was assessed by changes in the cytokine profile and a deviation in the anti-AChR IgG isotypes from IgG2a/IgG2b to IgG1. Our results suggest that the removal of pathogenic B-cell epitopes from AChR fragments increases tolerogenicity by reducing the activation and proliferation of autoreactive B- and T-cells. Collectively, careful consideration of the immunogenicity of a tolerogen is necessary to induce successful oral tolerance in autoimmune disorders.

• Authors: Hwa-Jung Yi, Chang-Suk Chae, Jae-Seon So, Socrates J Tzartos, Miriam C Souroujon, Sara Fuchs, Sin-Hyeog Im
• Journal: Molecular immunology (Mol Immunol) Vol. 46 Issue 1 Pg. 192-201 (Nov 2008) ISSN: 0161-5890 [Print] England
• PMID: 18799218 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Cytokines
• Epitopes, B-Lymphocyte
• Immunoglobulin G
• Inflammation Mediators
• Receptors, Cholinergic
• Recombinant Proteins

Topics

• Administration, Oral
• Animals
• Autoantibodies (immunology)
• B-Lymphocytes (drug effects, immunology)
• Cytokines (immunology)
• Down-Regulation (drug effects)
• Epitopes, B-Lymphocyte (immunology)
• Female
• Immunoglobulin G (immunology)
• Immunohistochemistry
• Inflammation Mediators (immunology)
• Myasthenia Gravis, Autoimmune, Experimental (blood, drug therapy, immunology)
• Rats
• Rats, Inbred Lew
• Receptors, Cholinergic (administration & dosage, immunology)
• Recombinant Proteins (pharmacology, therapeutic use)
• Sequence Deletion
• T-Lymphocytes (drug effects, immunology)
• Th1 Cells (drug effects, immunology)