Mechanisms of demyelination and neurodegeneration in the cortical grey matter in multiple sclerosis

多发性硬化症(MS)是英国年轻人最常见的神经系统疾病。这种疾病的时间进程和严重程度极不稳定，无法预测它将遵循温和还是猛烈的过程。目前的治疗方法只成功地减少了发作的次数，但对疾病的进展没有影响。对大脑的损害被认为是由免疫系统对覆盖神经纤维的绝缘髓鞘的攻击造成的。这表现为纤维束的多个区域发炎。我们实验室最近对尸检大脑的研究发现了一组多发性硬化症病例(在目前的研究中占40%)，其中大脑表层也有广泛的损害。这些病例的特点是脑膜发炎，脑膜是构成大脑外层的组织。我们发现产生抗体的细胞，B淋巴细胞，正在脑膜中增殖。这表明，对脑细胞有毒的物质正在扩散到大脑皮层的底层，并在这一亚型多发性硬化症病例中造成损害。这些病例还遵循了更具侵袭性的病程，导致轮椅依赖的时间更短，死亡更早。该项目旨在了解神经元损伤的机制，以便为开发新的治疗方法确定药物靶点。我们将使用两组可以获得尸检组织的多发性硬化症病例，一组脑膜中有B淋巴细胞，并遵循更具侵袭性的病程，另一组没有。首先，我们将研究组织损伤区域神经元数量的变化，然后调查哪些基因被神经元开启和关闭，这可能解释其中一些正在死亡的原因。这将通过使用基因芯片同时研究这些细胞中的所有30,000多个基因来实现。将分析已知对神经元有毒的蛋白质在脑组织中的存在，这些蛋白质可能已经从大脑表面扩散。患者病史将被用来将这些信息与疾病发作和复发频率等变量相关联。确定这一亚组的MS患者具有不良预后的高风险，有助于在发生广泛和不可逆转的损害之前进行早期治疗。

Multiple Sclerosis (MS) is the commonest neurological disorder of young adults in the UK. The time course and severity of the disease is extremely variable and there is no way to predict whether it will follow a mild or aggressive course. Current treatments are only successful at decreasing the number of attacks but have no effect on the progression of the disease. Damage to the brain is thought to be caused by an attack by the immune system on the insulating myelin sheath that covers nerve fibres. This appears as multiple areas of inflammation in the fibre tracts. Recent research in our laboratories on post-mortem brains has identified a subgroup of MS cases (40% in the current study) in which there is also extensive damage to the surface layers of the brain. These cases are characterised by inflammation in the meninges, the tissue that forms the outside lining of the brain. We have found that antibody producing cells, B-lymphocytes, are proliferating in the meninges. This suggests that substances toxic to the cells of the brain are diffusing into the underlying layers of the cerebral cortex and causing the damage in this subset of MS cases. These cases also followed a more aggressive disease course, resulting in a shorter time to wheelchair dependence and earlier death. This project is designed to gain an understanding of the mechanisms of damage to neurons in order to identify drug targets for the development of novel treatments. We will use two groups of MS cases for which post-mortem tissue is available, one group that has B-lymphocytes in the meninges and which followed the more aggressive disease course and a group that does not. Firstly, we will study the changes in the number of neurons in areas of tissue damage and then investigate which genes are being turned on and off by the neurons that might explain why some of them are dying. This will be achieved by studying all 30,000+ genes in these cells simultaneously using gene chips. The presence within the brain tissue of proteins known to be toxic to neurons, which may have diffused from the brain surface, will be analysed. Patient histories will be used to correlate this information with variables such as disease onset and relapse frequency. Identification of this sub-group of MS patients at high risk of a poor outcome could facilitate early treatment before extensive and irreversible damage occurs.