Cruz-Herranz Andrés, Sagan Sharon A, Sobel Raymond A, Green Ari J, Zamvil Scott S
Department of Neurology, University of California, San Francisco, CA 94143, USA.
Program in Immunology, University of California, San Francisco, CA 94143, USA.
J Nat Sci. 2017 May;3(5).
Aquaporin-4 (AQP4)-specific antibodies are instrumental in promoting central nervous system (CNS) tissue injury in neuromyelitis optica (NMO), yet evidence indicates that AQP4-specific T cells also have a pivotal role in NMO pathogenesis. Although considerable effort has been devoted to creation of animal models to study how AQP4-specific T cells and antibodies may cooperate in development of both clinical and histologic opticospinal inflammatory disease, the initial attempts were unsuccessful. Recently, it was discovered that T cells from AQP4-deficient (AQP4) mice recognize distinct AQP4 epitopes that were not identified previously in wild-type (WT) mice, and that donor Th17 cells from AQP4 mice that target those novel epitopes could cause paralysis and visual system injury associated with opticospinal inflammation in WT recipient mice. These observations indicate that the pathogenic AQP4-specific T cell repertoire is normally controlled by negative selection. Here, we describe the advances leading to development of an animal model for aquaporin-targeted CNS autoimmunity (ATCA). This new model provides a foundation to investigate immune mechanisms that may participate in NMO pathogenesis. It should also permit preclinical testing of agents considered for treatment of NMO.
水通道蛋白4（AQP4）特异性抗体在视神经脊髓炎（NMO）中对促进中枢神经系统（CNS）组织损伤起重要作用，但有证据表明，AQP4特异性T细胞在NMO发病机制中也起关键作用。尽管已经投入了大量精力来创建动物模型，以研究AQP4特异性T细胞和抗体如何在临床和组织学视神经脊髓炎性疾病的发展中协同作用，但最初的尝试并不成功。最近，人们发现来自AQP4缺陷（AQP4-/-）小鼠的T细胞识别出以前在野生型（WT）小鼠中未发现的独特AQP4表位，并且来自AQP4-/-小鼠的靶向那些新表位的供体Th17细胞可导致WT受体小鼠出现与视神经脊髓炎相关的麻痹和视觉系统损伤。这些观察结果表明，致病性AQP4特异性T细胞库通常受阴性选择的控制。在此，我们描述了导致开发水通道蛋白靶向中枢神经系统自身免疫（ATCA）动物模型的进展。这个新模型为研究可能参与NMO发病机制的免疫机制提供了基础。它还应该允许对考虑用于治疗NMO的药物进行临床前测试。
