Patho-mechanisms of autoantibodies in CNS autoimmunity

中枢神经系统自身免疫中自身抗体的病理机制

• 批准号: 329044703
• 负责人: Professor Dr. Alexander Flügel
• 金额: --
• 依托单位: Abteilung Neuroimmunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/329044703?language=en
• 关键词: Patho; mechanisms; autoantibodies; CNS; autoimmunity

This project focuses on the question of what role CNS-specific autoantibodies play in the pathogenesis of CNS autoimmunity. B cells and autoantibodies are in the focus of research since an anti-CD20 antibody (rituximab) showed unexpected efficiency in the treatment of Multiple sclerosis (MS). How the B cells contribute to the disease pathogenesis is still incompletely understood. When following myelin oligodendrocyte glycoprotein (MOG)-reactive T and B cells during the course of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, we recently found that the presence of MOG-specific B cells significantly accelerated the entry of these pathogenic T cells into the CNS resulting in an earlier onset and increased severity of clinical disease in so-called regular EAE or a disease manifestation in subclinical EAE (Flach et al. PNAS 2016). Furthermore, we found that these effects were not mediated by the B cells per se but instead by B cell-derived autoantibodies. In the proposed research project we now aim to elucidate the mechanisms of how the autoantibodies exert their pathogenic function within the CNS. The following not mutually exclusive mechanisms might contribute to the observed clinical effects: 1) CNS-specific antibodies can enhance demyelination by opsonizing myelin for the destruction by myeloid effector cells or antibody-dependent cellular cytotoxicity (ADCC). 2) The immune complexes can bind to resident CNS cells (e.g. astrocytes or microglia), thereby triggering a release of pro-inflammatory factors that lead to an attraction of immune cells from the blood circulation. 3) Antibodies can target brain antigens in the CNS to local antigen-presenting phagocytes. The uptake of the antibody/antigen complexes can increase antigen presentation and consecutive T cell (re)activation. In our previous studies we found that in the presence of MOG-specific autoantibodies the T-cell activation levels within the CNS tissue were elevated (Flach et al. PNAS 2016). However, how exactly autoantibodies mediate T-cell activation in the CNS and which pathomechanism contributes to the tissue damage during the autoimmune process is still not clear. We therefore will address these questions by (i) following the autoantibodies and the autoimmune process in vivo using intravital 2-photon laser scanning microscopy; (ii) tracking T-cell activation in the context of local APCs using suitable biosensor-carrying animals; (iii) testing different autoantibody properties/specificities for their T-cell-activation-enhancing / demyelinating potential; (iv) evaluating the role of the different Fc receptors on distinct CNS cell populations; (v) creating transgenic mouse models with novel T- and B-cell reactivities; and (vi) testing the potential of human autoantibodies derived from patient sera / cerebrospinal fluids to accelerate and aggravate EAE.

本项目的重点是CNS特异性自身抗体在CNS自身免疫发病机制中的作用。B细胞和自身抗体是研究的焦点，因为抗CD 20抗体（利妥昔单抗）在多发性硬化症（MS）的治疗中显示出意想不到的效率。B细胞如何参与疾病的发病机制仍不完全清楚。当在实验性自身免疫性脑脊髓炎（EAE）（多发性硬化症的模型）过程中跟踪髓鞘少突胶质细胞糖蛋白（MOG）反应性T和B细胞时，我们最近发现MOG特异性B细胞的存在显著加速了这些致病性T细胞进入CNS，从而导致SO患者临床疾病的早期发作和严重程度增加。称为常规EAE或亚临床EAE的疾病表现（Flach et al. PNAS 2016）。此外，我们发现这些作用不是由B细胞本身介导的，而是由B细胞衍生的自身抗体介导的。在拟议的研究项目中，我们现在的目标是阐明自身抗体如何在中枢神经系统内发挥其致病功能的机制。以下不相互排斥的机制可能有助于观察到的临床效应：1）CNS特异性抗体可通过调理髓磷脂以破坏髓样效应细胞或抗体依赖性细胞毒性（ADCC）来增强脱髓鞘。2)免疫复合物可以结合驻留的CNS细胞（例如星形胶质细胞或小胶质细胞），从而触发促炎因子的释放，导致免疫细胞从血液循环中被吸引。3)抗体可以将CNS中的脑抗原靶向局部抗原呈递吞噬细胞。抗体/抗原复合物的摄取可以增加抗原呈递和连续的T细胞（再）活化。在我们之前的研究中，我们发现在存在MOG特异性自身抗体的情况下，CNS组织内的T细胞活化水平升高（Flach et al. PNAS 2016）。然而，在自身免疫过程中，自身抗体究竟如何介导CNS中的T细胞活化以及哪些病理机制导致组织损伤仍然不清楚。因此，我们将通过以下方式解决这些问题：（i）使用活体双光子激光扫描显微镜在体内跟踪自身抗体和自身免疫过程;（ii）使用合适的携带生物传感器的动物在局部APC的背景下跟踪T细胞活化;（iii）测试不同的自身抗体性质/特异性以增强T细胞活化/脱髓鞘潜力;（iv）检测不同的自身抗体性质/特异性以增强T细胞活化/脱髓鞘潜力。（iv）评估不同Fc受体对不同CNS细胞群的作用;（v）产生具有新的T-和B-细胞反应性的转基因小鼠模型;和（vi）测试源自患者血清/脑脊液的人自身抗体加速和加重EAE的潜力。