美国加州大学Ryan E. Hibbs研究组开发出通过肌肉乙酰胆碱受体结构阐明自身免疫机制。该研究于2025年4月8日发表于国际一流学术期刊《细胞》杂志上。

小组展示了不同功能状态下成人AChR的高分辨率冷冻电镜（cryo-EM）结构。使用6种MG患者来源的单克隆抗体，该研究组绘制了不同的表位，涉及不同的致病机制，包括受体阻断、内化和补体激活。电生理和结合试验揭示了这些自身抗体如何直接抑制AChR通道的激活。这些发现为MG免疫发病机制提供了重要的见解，揭示了未被识别的抗体表位多样性和受体抑制模式，并为开发针对抗体介导的自身免疫性疾病的个性化治疗提供了框架。

据介绍，骨骼肌收缩是由乙酰胆碱（ACh）在神经细胞连接处与其嗜离子受体（achr）结合而引发的。在重症肌无力（MG）中，自身抗体靶向AChR，破坏神经传递并引导肌无力。虽然有治疗方法，但不同的患者反应表明致病异质性。由于缺乏完整的人细胞achr结构，了解MG分子基础的进展受到限制。

附：英文原文

Title: Autoimmune mechanisms elucidated through muscle acetylcholine receptor structures

Author: Huanhuan Li, Minh C. Pham, Jinfeng Teng, Kevin C. O’Connor, Colleen M. Noviello, Ryan E. Hibbs

Issue&Volume: 2025-04-08

Abstract: Skeletal muscle contraction is triggered by acetylcholine (ACh) binding to its ionotropic receptors (AChRs) at neuromuscular junctions. In myasthenia gravis (MG), autoantibodies target AChRs, disrupting neurotransmission and causing muscle weakness. While treatments exist, variable patient responses suggest pathogenic heterogeneity. Progress in understanding the molecular basis of MG has been limited by the absence of structures of intact human muscle AChRs. Here, we present high-resolution cryoelectron microscopy (cryo-EM) structures of the human adult AChR in different functional states. Using six MG patient-derived monoclonal antibodies, we mapped distinct epitopes involved in diverse pathogenic mechanisms, including receptor blockade, internalization, and complement activation. Electrophysiological and binding assays revealed how these autoantibodies directly inhibit AChR channel activation. These findings provide critical insights into MG immunopathogenesis, uncovering unrecognized antibody epitope diversity and modes of receptor inhibition, and provide a framework for developing personalized therapies targeting antibody-mediated autoimmune disorders.

DOI: 10.1016/j.cell.2025.03.004

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00277-6