A 17-Mer self-peptide of acetylcholine receptor binds to B cell MHC class II, activates helper T cells, and stimulates autoantibody production and electrophysiologic signs of myasthenia gravis.

Abstract

We have identified in an extracellular segment of the alpha1 subunit of nicotinic acetylcholine receptor (AChR) of homologous muscle a 17-residue autoantigen that, without conjugation to a carrier, activates Th lymphocytes and induces production of autoantibodies that cause electrophysiologic signs of experimental autoimmune myasthenia gravis. A panel of overlapping synthetic peptides revealed two T cell epitopes, one encompassed by residues 121-136 and the other by 129-145. Residues 129 (glutamic acid) and 130 (isoleucine) were implicated in a pathogenic B cell epitope. Peptide 129-145 (Glu-Ile-Ile-Val-Thr-His-Phe-Pro-Phe-Asp-Glu-Gln-Asn-Cys-Ser-Met-Lys, a conserved sequence in rat and human AChR) induced autoantibody production in 76% of rats. All seropositive rats had evidence of experimental autoimmune myasthenia gravis; five of five tested had electrophysiologic signs, and all had loss of immunochemically measured autologous muscle AChR. Analogues of 129-145, with single residues substituted by alanine, revealed phenylalanine 135, phenylalanine 137, and glutamic acid 139 as most important determinants of Ag/MHC-II/TCR interactions; phenylalanine 137 is critical for T cell activation. B cells were the major MHC-II-positive cell type to which the self-peptide 129-145 bound in a population of nonimmune splenic cells. More efficient processing and presentation of the Th cell epitope by an expanded population of immune B cells selected by specifically binding another epitope of the same peptide would greatly amplify the production of autoantibodies. Peptide autoantigens of this type could plausibly perpetuate the autoantibody response in myasthenia gravis, and are a rational target for strategies aimed at Ag-specific therapeutic intervention.

• Authors: H Yoshikawa, E H Lambert, D R Walser-Kuntz, Y Yasukawa, D J McCormick, V A Lennon
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 159 Issue 3 Pg. 1570-7 (Aug 01 1997) ISSN: 0022-1767 [Print] United States
• PMID: 9233656 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Autoantibodies
• Autoantigens
• Epitopes
• Histocompatibility Antigens Class II
• Peptide Fragments
• Receptors, Cholinergic

Topics

• Amino Acid Sequence
• Animals
• Autoantibodies (biosynthesis)
• Autoantigens (chemistry, immunology, metabolism)
• B-Lymphocytes (immunology, metabolism)
• Electrophysiology
• Epitopes (chemistry, pharmacology)
• Female
• Histocompatibility Antigens Class II (metabolism)
• Humans
• Lymphocyte Activation (drug effects)
• Molecular Sequence Data
• Myasthenia Gravis (etiology, immunology, physiopathology)
• Peptide Fragments (chemical synthesis, immunology, metabolism)
• Protein Binding (immunology)
• Rats
• Rats, Inbred Lew
• Receptors, Cholinergic (immunology, metabolism, physiology)
• T-Lymphocytes, Helper-Inducer (immunology)