Myasthenogenicity of the main immunogenic region

Abstract

In myasthenia gravis (MG) and experimental autoimmune MG (EAMG), many pathologically significant autoantibodies are directed to the main immunogenic region (MIR) of muscle nicotinic acetylcholine receptors (AChRs), a conformation-dependent region at the extracellular tip of α1 subunits of AChRs. Human muscle AChR α1 MIR sequences were integrated into Aplesia ACh-binding protein (AChBP). The chimera potently induced EAMG, while AChBP induced EAMG much less potently. AChBP is a water-soluble protein resembling the extracellular domain of AChRs; yet, rats immunized with chimeras developed autoantibodies to both extracellular and cytoplasmic domains of muscle AChRs. We propose that an initial autoimmune response directed at the MIR leads to an autoimmune response sustained by muscle AChRs. Autoimmune stimulation sustained by endogenous muscle AChR may be a target for specific immunosuppression. These studies show that the α1 MIR is highly myasthenogenic, and that AChR-like proteins distantly related to muscle AChR can induce EAMG and, potentially, MG.

Figure 1

A model of the MIR α1(1–32, 60–81)/AChBP chimera and its interaction with an antibody to the MIR is shown. (A) MIR components are highlighted on a top view of the crystal structure of an Aplysia AChBP subunit. Below, a front view ribbon diagram shows a single chimeric subunit. (B) The crystal structure of Fab 192 is accompanied by the structure of the mouse α1 extracellular domain. Small differences in the sequences and conformation of the epitopes within the MIR profoundly influence the affinity with which antibodies are bound. The large size of bivalent IgG molecules with respect to the size of the MIR can result in competitive binding between different closely spaced epitopes within the MIR. The six hypervariable loops of the Fab, which form its antigen binding site are highlighted in cyan. This unusual mAb to the MIR does not appear to bind to the MIR loop per se, but competes for binding with mAbs, which do. The Fab is angled to suggest this, but not actually docked on the subunit model. This is part of Figure 1 from Luoet et al.