Laranjeira Simão, Symmonds Mkael, Palace Jacqueline, Payne Stephen J, Orlowski Piotr
Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Old Road Campus Research Building, OX3 7DQ, Oxford, United Kingdom.
Department of Clinical Neurology, University of Oxford, United Kingdom.
J Theor Biol. 2017 Nov 21;433:39-48. doi: 10.1016/j.jtbi.2017.08.020. Epub 2017 Aug 23.
Neuromyelitis Optica (NMO) is a severe neuro-inflammatory disease of the central nervous system characterized by predominant damage to the optic nerve and of the spinal cord. The pathogenic antibody found in the majority of patients targets the AQP4 channels on astrocytic endfeet and causes the cells to swell. Although, the pathophysiology of the disease is broadly known, there are no specific targeted treatments for this process clinically available nor accurate prognostic markers both during attacks and for predicting long term neuronal damage. This lack is, in part, due to the rarity of the disease and its relatively recent pathogenic clarity. Hence, the ability to mathematically model the progress of the condition to test prospective therapies in silico would be a step forward. This paper combines state of the art models of cellular metabolism and cytotoxic oedema in neurons and astrocytes and augments it with a detailed characterization of water transport across the cellular membrane. In particular, we capture the process of perforation of the cell through the human complement cascade and resulting water and ionic fluxes. Simulating NMO by injecting its antibody and human complement into the extracellular space showed a 25% increase of the astrocytic volume after 12 h from onset. Most of the volume change occurred during the first 30 min of simulation with a peak volume change of 38%. The model was further adapted to simulate the therapeutic potential of CD59. It was found that there is a threshold of CD59 concentration that can prevent the swelling of astrocytes. Since the astrocyte volume changes mostly during the first hour, further experimental work should focus on this time scale to provide data for further model refinement and validation.
视神经脊髓炎（NMO）是一种严重的中枢神经系统神经炎性疾病，其特征是视神经和脊髓受到主要损害。大多数患者体内发现的致病抗体靶向星形胶质细胞终足上的水通道蛋白4（AQP4）通道，导致细胞肿胀。尽管该疾病的病理生理学已广为人知，但临床上尚无针对此过程的特异性靶向治疗方法，在发作期间以及预测长期神经元损伤方面也没有准确的预后标志物。这种缺乏部分归因于该疾病的罕见性及其相对较新的致病机制明确性。因此，能够通过数学模型模拟病情进展以在计算机上测试前瞻性疗法将是向前迈出的一步。本文结合了神经元和星形胶质细胞中细胞代谢和细胞毒性水肿的最新模型，并通过对跨细胞膜水转运的详细表征对其进行了扩充。特别是，我们捕捉了通过人类补体级联反应导致细胞穿孔以及由此产生的水和离子通量的过程。通过将NMO抗体和人类补体注入细胞外空间来模拟NMO，结果显示从发病起12小时后星形胶质细胞体积增加了25%。大部分体积变化发生在模拟的前30分钟内，体积变化峰值为38%。该模型进一步经过调整以模拟CD59的治疗潜力。结果发现存在一个CD59浓度阈值，可以防止星形胶质细胞肿胀。由于星形胶质细胞体积变化大多发生在最初的一小时内，进一步的实验工作应聚焦于这个时间尺度，以提供数据用于进一步完善和验证模型。
