ANATOMY OF THE ANTIGENIC STRUCTURE OF A LARGE MEMBRANE AUTOANTIGEN, THE MUSCLE-TYPE NICOTINIC ACETYLCHOLINE-RECEPTOR

The neuromuscular junction nicotinic acetylcholine receptor (AChR), a pentameric membrane glycoprotein, is the autoantigen involved in the a utoimmune disease myasthenia gravis (MG).In animals immunized with int act AChR and in human MG, the anti-AChR antibody response is polyclona l. However, a small extracellular region of the AChR alpha-subunit, th e main immunogenic region (MIR), seems to be a major target for anti-A ChR antibodies. A major loop containing overlapping epitopes for sever al anti-MIR monoclonal antibodies (mAbs) lies within residues alpha 67 -76 at the extreme synaptic end of each alpha-subunit; however, anti-M IR mAbs are functionally and structurally quite heterogeneous. Anti-MI R mAbs do not affect channel gating, but are very effective in the pas sive transfer of MG to animals; in contrast, their Fab or Fv fragments protect the AChR from the pathogenic effects of the intact antibodies . Antibodies against the cytoplasmic region of the AChR can be elicite d by immunization with denatured AChR and the precise epitopes of many such mAbs have been identified; however, it is unlikely that such ant ibodies are present in significant amounts in human MG. Antibodies to other extracellular epitopes on all AChR subunits are present in both experimental and human MG; these include antibodies to the acetylcholi ne-binding site which affect AChR function in various ways and also in duce acute experimental MG. Finally, anti-AChR antibodies cross-reacti ve with non-AChR antigens exist, suggesting that MG may result from mo lecular mimicry. Despite extensive studies, many gaps remain in our un derstanding of the antigenic structure of the AChR, especially in rela tion to human MG. A thorough understanding of the antigenic structure of the AChR is required for an in-depth understanding, and for possibl e specific immunotherapy, of MG.