The main immunogenic region (MIR) of the nicotinic acetylcholine receptor and the anti-MIR antibodies

Abstract

Myasthenia gravis (MG) is caused by autoantibodies against the nicotinic acetylcholine receptor (AChR) of the neuromuscular junction. The anti-AChR antibodies are heterogeneous. However, a small region on the extracellular part of the AChR alpha subunit, called the main immunogenic region (MIR), seems to be the major target of the anti-AChR antibodies, but not of the specific T-cells, in experimental animals and possibly in MG patients. The major loop of the overlapping epitopes for all testable anti-MIR monoclonal antibodies (MAbs) was localized within residues 67-76 (WNPADYGGIK for Torpedo and WNPDDYGGVK for human AChR) of the alpha subunit. The N-terminal half of alpha 67-76 is the most critical, Asn68 and Asp71 being indispensable for binding. Yet anti-MIR antibodies are functionally and structurally quite heterogeneous. Anti-MIR MAbs do not affect channel gating, but they are very potent in mediating acceleration of AChR degradation (antigenic modulation) in cell cultures and in transferring experimental MG in animals. Fab fragments of anti-MIR MAbs bound to the AChR prevent the majority of the MG patients' antibodies from binding to and causing loss of the AChR. Whether this inhibition means that most MG antibodies bind on the same small region or is a result of broad steric/allosteric effects is under current investigation.

Identification of Residues at the α and ε Subunit Interfaces Mediating Species Selectivity of Waglerin-1 for Nicotinic Acetylcholine Receptors

“…The intermediate affinities indicate at least two determinants of Wtx-1 selectivity, one N-terminal and one C-terminal to the junction at position 83. Of the four N-terminal residue differences, only positions 59 and 61 are near the ligand recognition site (1), whereas positions 67 and 76 are in or near the main immunogenic region removed from the binding site (30). Of the six C-terminal residues, positions 168 and 115 are near the ligand recognition site.…”

A pathogenetic role for the thymoma in myasthenia gravis. Autosensitization of IL-4- producing T cell clones recognizing extracellular acetylcholine receptor epitopes presented by minority class II isotypes.

“…Although both T cells were selected against the whole AChR ␣ subunit, their epitopes, ␣75-90 and ␣149-158, derive from the extracellular domain of the native protein that is also recognized by the patients' B cells and serum anti-AChR antibodies (12,36,37). The intact conformation of this domain has never been detected in thymomas (13).…”

Characterisation, crystallisation and preliminary X‐ray diffraction analysis of a Fab fragment of a rat monoclonal antibody with very high affinity for the human muscle acetylcholine receptor

“…Anti-AChR autoantibodies cause AChR loss and blockage of the function of AChR molecules, resulting in failure of the neuromuscular transmission [2]. The majority of the anti-AChR antibodies in sera of MG patients compete for binding to a region in the extracellular suJ.face of the a-subunit of the AChR, called the main immunogenic region (MIR) [3,4]. Anti-MIR monoclonal antibodies (n:Abs) induce experimental MG when injected into rats [4,5] and when added to cell cultures cause AChR loss via antigenic modulation [6,7].…”

“…The majority of the anti-AChR antibodies in sera of MG patients compete for binding to a region in the extracellular suJ.face of the a-subunit of the AChR, called the main immunogenic region (MIR) [3,4]. Anti-MIR monoclonal antibodies (n:Abs) induce experimental MG when injected into rats [4,5] and when added to cell cultures cause AChR loss via antigenic modulation [6,7]. Contrary to the intact antibodies, their Fab frz gments, being univalent, do not crosslink the AChR molecules, and thus they do not cause antigenic modulation.…”