Main immunogenic region structure promotes binding of conformation-dependent myasthenia gravis autoantibodies, nicotinic acetylcholine receptor conformation maturation, and agonist sensitivity.
Main immunogenic region structure promotes binding of conformation-dependent myasthenia gravis autoantibodies, nicotinic acetylcholine receptor conformation maturation, and agonist sensitivity.
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主要的免疫原性结构促进了依赖构象肌无力自身抗体，烟碱乙酰胆碱受体构象成熟和激动剂敏感性的结合。
DOI：
10.1523/jneurosci.2833-09.2009
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发表时间：
2009-11-04
期刊：
影响因子：
--
通讯作者：
Lindstrom J
中科院分区：
文献类型：
--
作者：
Luo J;Taylor P;Losen M;de Baets MH;Shelton GD;Lindstrom J
主要免疫原性区域（MIR）是肌肉烟碱乙酰胆碱受体（AChR）α1亚单位胞外顶端的构象依赖性区域，是人重症肌无力和大鼠实验性自身免疫性重症肌无力中半数或半数以上抗肌肉AChR自身抗体的靶点。通过制备人α1亚基与α7亚基的嵌合体，确定大鼠mAb和患者源性人mAb 637识别的MIR表位均由两个不连续序列组成，仅在天然构象中相邻。MIR，包括环α1 67-76与N-末端α螺旋α 11 -14的组合，赋予大多数大鼠mAb与MIR的高亲和力结合。然而，人mAb 637的高亲和力结合需要对应于α 115 -32的额外序列。具有相同α1 MIR序列取代的ASAB乙酰胆碱结合蛋白的水溶性嵌合体被大多数人、猫和犬MG血清识别。α1/α7嵌合体中α1 MIR序列的存在极大地促进了AChR的表达，并显著改变了对激活的敏感性。这揭示了MIR的结构和功能以及抗原意义。
The main immunogenic region (MIR) is a conformation-dependent region at the extracellular apex of α1 subunits of muscle nicotinic acetylcholine receptor (AChR) that is the target of half or more of the autoantibodies to muscle AChRs in human myasthenia gravis and rat experimental autoimmune myasthenia gravis. By making chimeras of human α1 subunits with α7 subunits, both MIR epitopes recognized by rat mAbs and by the patient-derived human mAb 637 to the MIR were determined to consist of two discontiguous sequences, which are adjacent only in the native conformation. The MIR, including loop α1 67–76 in combination with the N-terminal α helix α1 1–14, conferred high-affinity binding for most rat mAbs to the MIR. However, an additional sequence corresponding to α1 15–32 was required for high-affinity binding of human mAb 637. A water soluble chimera of Aplysia acetylcholine binding protein with the same α1 MIR sequences substituted was recognized by a majority of human, feline, and canine MG sera. The presence of the α1 MIR sequences in α1/α7 chimeras greatly promoted AChR expression and significantly altered the sensitivity to activation. This reveals a structural and functional, as well as antigenic, significance of the MIR.