Structural characterization of the main immunogenic region of the Torpedo acetylcholine receptor.
Structural characterization of the main immunogenic region of the Torpedo acetylcholine receptor.
复制标题
鱼雷乙酰胆碱受体主要免疫原性区域的结构特征。
DOI：
10.1016/j.molimm.2013.11.005
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发表时间：
2014
影响因子：
3.6
通讯作者：
Fairclough,RobertH
中科院分区：
文献类型：
--
作者：
Morell,StuartW;Trinh,VuB;Gudipati,Eswari;Friend,Alexander;Page,NelsonA;Agius,MarkA;Richman,DavidP;Fairclough,RobertH
为了开发用于自身免疫性疾病的抗原特异性免疫疗法，靶向免疫学热点的分子结构的知识将指导试剂的生产以抑制和停止抗原特异性攻击剂的产生。为此，我们鉴定了电鳐烟碱型乙酰胆碱受体（AChR）α亚基的三个非连续片段，它们构成AChR上构象敏感的免疫热点，称为主要免疫原性区（MIR）：α（1-12）、α（65-79）和α（110-115）。该区域是来自重症肌无力（MG）患者和实验性自身免疫性重症肌无力（EAMG）动物的血清中大于50%的抗AChR Ab的靶标。许多单克隆抗体（单克隆抗体）提出了一个物种的电器官AChR交叉反应的神经肌肉AChR MIR在几个物种。用抗电鳐AChR的抗MIR单克隆抗体132 A探测电鳐AChR的α亚基，我们确定了三个MIR片段中的两个，α（1-12）和α（65-79），形成一个复合物，提供了mAb 132 A识别的特征成分。这两个片段跨越第三个片段α（110-115），似乎不贡献132 A识别的特异性侧链，但对于最佳抗体结合是必需的。该第三区段似乎形成三维132 A表位锚定的基础。
To develop antigen-specific immunotherapies for autoimmune diseases, knowledge of the molecular structure of targeted immunological hotspots will guide the production of reagents to inhibit and halt production of antigen specific attack agents. To this end we have identified three noncontiguous segments of theTorpedonicotinic acetylcholine receptor (AChR) α-subunit that contribute to the conformationally sensitive immunological hotspot on the AChR termed the main immunogenic region (MIR): α(1–12), α(65–79), and α(110–115). This region is the target of greater than 50% of the anti-AChR Abs in serum from patients with myasthenia gravis (MG) and animals with experimental autoimmune myasthenia gravis (EAMG). Many monoclonal antibodies (mAbs) raised in one species against an electric organ AChR cross react with the neuromuscular AChR MIR in several species. Probing theTorpedoAChR α-subunit with mAb 132A, a disease inducing anti-MIR mAb raised against theTorpedoAChR, we have determined that two of the three MIR segments, α(1–12) and α(65–79), form a complex providing the signature components recognized by mAb 132A. These two segments straddle a third, α(110–115), that seems not to contribute specific side chains for 132A recognition, but is necessary for optimum antibody binding. This third segment appears to form a foundation upon which the three-dimensional 132A epitope is anchored.