Circulating AQP4-specific auto-antibodies alone can induce neuromyelitis optica spectrum disorder in the rat
Circulating AQP4-specific auto-antibodies alone can induce neuromyelitis optica spectrum disorder in the rat
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DOI：
10.1007/s00401-018-1950-8
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发表时间：
2019-03-01
影响因子：
12.7
通讯作者：
Bradl, Monika
中科院分区：
文献类型：
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作者：
Hillebrand, Sophie;Schanda, Kathrin;Bradl, Monika
已经确定，致病性水通道蛋白-4（AQP 4）特异性自身抗体与星形胶质细胞的结合可能会引发一系列事件，最终导致这些细胞的破坏，并形成视神经肌萎缩性疾病（NMOSD）患者典型的大组织破坏性病变。到目前为止，没有一项实验研究表明，抗体的全身存在可以单独诱导中枢神经系统（CNS）的任何损害，而对NMOSD患者大脑的病理学研究表明，可能存在抗体进入和随后的组织损伤的途径。在这里，我们系统性地应用了一种高致病性的单克隆抗体，该抗体对大鼠具有高亲和力，并显示AQP 4-abs可以通过脑室周围器官和脑膜或实质血管自行进入CNS，这些抗体根据其进入的模式和部位启动了具有AQP 4损失的完全不同的病变的形成，并且在致脑炎性T细胞应答存在的情况下，损伤形成更有效。我们进一步证明，已建立的组织破坏性病变通过对血管及其分支的短期和长期影响触发了额外病变的形成，并且AQP 4-abs对外周组织中的AQP 4表达具有深远的影响，其抵消了由CNS外的抗体吸收引起的可能的滴度损失。累积起来，这些数据表明，由CNS内外的AQP 4-abs引起的直接诱导的病理变化是血清阳性生物体中疾病演变的有效驱动因素。
It is well established that the binding of pathogenic aquaporin-4 (AQP4)-specific autoantibodies to astrocytes may initiate a cascade of events culminating in the destruction of these cells and in the formation of large tissue-destructive lesions typical for patients with neuromyelitis optica spectrum disorders (NMOSD). To date, not a single experimental study has shown that the systemic presence of the antibody alone can induce any damage to the central nervous system (CNS), while pathological studies on brains of NMOSD patients suggested that there might be ways for antibody entry and subsequent tissue damage. Here, we systemically applied a highly pathogenic, monoclonal antibody with high affinity to AQP4 over prolonged period of time to rats, and show that AQP4-abs can enter the CNS on their own, via circumventricular organs and meningeal or parenchymal blood vessels, that these antibodies initiate the formation of radically different lesions with AQP4 loss, depending on their mode and site of entry, and that lesion formation is much more efficient in the presence of encephalitogenic T-cell responses. We further demonstrate that the established tissue-destructive lesions trigger the formation of additional lesions by short and far reaching effects on blood vessels and their branches, and that AQP4-abs have profound effects on the AQP4 expression in peripheral tissues which counter-act possible titer loss by antibody absorption outside the CNS. Cumulatively, these data indicate that directly induced pathological changes caused by AQP4-abs inside and outside the CNS are efficient drivers of disease evolution in seropositive organisms.