Department Neuroimmunology, Medical University Vienna, Center for Brain Research, Spitalgasse 4, A-1090, Vienna, Austria.
Department Pathobiology of the Nervous System, Medical University Vienna, Center for Brain Research, Spitalgasse 4, A-1090, Vienna, Austria.
Acta Neuropathol Commun. 2020 Apr 15;8(1):49. doi: 10.1186/s40478-020-00920-x.
Most cases of neuromyelitis optica spectrum disorders (NMOSD) harbor pathogenic autoantibodies against the water channel aquaporin 4 (AQP4). Binding of these antibodies to AQP4 on astrocytes initiates damage to these cells, which culminates in the formation of large tissue destructive lesions in the central nervous system (CNS). Consequently, untreated patients may become permanently blind or paralyzed. Studies on the induction and breakage of tolerance to AQP4 could be of great benefit for NMOSD patients. So far, however, all attempts to create suitable animal models by active sensitization have failed. We addressed this challenge and identified peptides, which mimic the conformational AQP4 epitopes recognized by pathogenic antibodies of NMOSD patients. Here we show that these mimotopes can induce the production of AQP4-reactive antibodies in Lewis rats. Hence, our results provide a conceptual framework for the formation of such antibodies in NMOSD patients, and aid to improve immunization strategies for the creation of animal models suitable for tolerance studies in this devastating disease.
大多数视神经脊髓炎谱系疾病（NMOSD）病例都存在针对水通道蛋白 4（AQP4）的致病性自身抗体。这些抗体与星形胶质细胞上的 AQP4 结合，引发这些细胞的损伤，最终导致中枢神经系统（CNS）中形成大的组织破坏性病变。因此，未经治疗的患者可能会永久性失明或瘫痪。对 AQP4 的诱导和耐受的研究可能对 NMOSD 患者有很大的好处。然而，到目前为止，通过主动致敏来创建合适的动物模型的所有尝试都失败了。我们解决了这一挑战，并确定了模拟 NMOSD 患者致病性抗体识别的构象 AQP4 表位的肽。在这里，我们显示这些模拟表位可以在 Lewis 大鼠中诱导产生 AQP4 反应性抗体。因此，我们的结果为 NMOSD 患者中形成这种抗体提供了一个概念框架，并有助于改进免疫策略，以创建适合该破坏性疾病耐受研究的动物模型。
