Tzartos S J, Cung M T, Demange P, Loutrari H, Mamalaki A, Marraud M, Papadouli I, Sakarellos C, Tsikaris V
Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece.
Mol Neurobiol. 1991 Spring;5(1):1-29. doi: 10.1007/BF02935610.
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.
重症肌无力（MG）由针对神经肌肉接头处烟碱型乙酰胆碱受体（AChR）的自身抗体引起。抗AChR抗体具有异质性。然而，在实验动物以及可能在MG患者中，AChRα亚基细胞外部分的一个小区域，即主要免疫原性区域（MIR），似乎是抗AChR抗体的主要靶点，但不是特异性T细胞的主要靶点。所有可检测的抗MIR单克隆抗体（MAb）重叠表位的主要环位于α亚基的67 - 76位残基内（电鳐的为WNPADYGGIK，人AChR的为WNPDDYGGVK）。α67 - 76的N端一半最为关键，Asn68和Asp71对于结合不可或缺。然而，抗MIR抗体在功能和结构上相当异质。抗MIR MAb不影响通道门控，但它们在介导细胞培养中AChR降解加速（抗原调制）以及在动物中传递实验性MG方面非常有效。与AChR结合的抗MIR MAb的Fab片段可阻止大多数MG患者的抗体与AChR结合并导致其丢失。这种抑制是意味着大多数MG抗体结合在同一小区域，还是广泛的空间/变构效应的结果，目前正在研究中。
