Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
J Autoimmun. 2014 Nov;54:8-14. doi: 10.1016/j.jaut.2014.08.002. Epub 2014 Sep 8.
Immune cell infiltration to the brain's territory was considered for decades to reflect a pathological process in which immune cells attack the central nervous system (CNS); such a process is observed in the inflammatory autoimmune disease, multiple sclerosis (MS). As neuroinflammatory processes within the CNS parenchyma are also common to other CNS pathologies, regardless of their etiology, including neurodegenerative disorders such as Alzheimer's disease (AD) and Amyotrophic lateral sclerosis (ALS), these pathologies have often been compared to MS, a disease that benefits from immunosuppressive therapy. Yet, over the last decade, it became clear that autoimmunity has a bright side, and that it plays a pivotal role in CNS repair following damage. Specifically, autoimmune T cells were found to facilitate CNS healing processes, such as in the case of sterile mechanical injuries to the brain or the spinal cord, mental stress, or biochemical insults. Even more intriguingly, autoimmune T cells were found to be involved in supporting fundamental processes of brain functional integrity, such as in the maintenance of life-long brain plasticity, including spatial learning and memory, and neurogenesis. Importantly, autoimmune T cells are part of a cellular network which, to operate efficiently and safely, requires tight regulation by other immune cell populations, such as regulatory T cells, which are indispensable for maintenance of immunological self-tolerance and homeostasis. Here, we suggest that dysregulation of the balance between peripheral immune suppression, on one hand, and protective autoimmunity, on the other, is an underlying mechanism in the emergence and progression of the neuroinflammatory response associated with chronic neurodegenerative diseases and brain aging. Mitigating chronic neuroinflammation under these conditions necessitates activation, rather than suppression, of the peripheral immune response directed against self. Accordingly, we propose that fighting off acute and chronic neurodegenerative conditions requires breaking peripheral immune tolerance to CNS self-antigens, in order to boost protective autoimmunity. Nevertheless, the optimal approach to fine tune such immune response must be individually explored for each condition.
几十年来，人们一直认为免疫细胞浸润大脑区域反映了一种免疫细胞攻击中枢神经系统（CNS）的病理过程；这种过程发生在炎症性自身免疫性疾病多发性硬化症（MS）中。由于神经炎症过程在中枢神经系统实质中也很常见于其他中枢神经系统疾病，无论其病因如何，包括神经退行性疾病如阿尔茨海默病（AD）和肌萎缩侧索硬化症（ALS），这些疾病经常与多发性硬化症相比较，多发性硬化症受益于免疫抑制治疗。然而，在过去十年中，很明显自身免疫有其积极的一面，它在中枢神经系统损伤后的修复中起着关键作用。具体来说，自身免疫性 T 细胞被发现促进中枢神经系统的愈合过程，例如在大脑或脊髓的无菌机械损伤、精神压力或生化损伤的情况下。更有趣的是，自身免疫性 T 细胞被发现参与支持大脑功能完整性的基本过程，例如维持终身大脑可塑性，包括空间学习和记忆以及神经发生。重要的是，自身免疫性 T 细胞是细胞网络的一部分，为了有效地和安全地运作，它需要其他免疫细胞群的紧密调节，如调节性 T 细胞，它们对于维持免疫自我耐受和体内平衡是不可或缺的。在这里，我们提出，外周免疫抑制与保护性自身免疫之间平衡的失调是与慢性神经退行性疾病和大脑衰老相关的神经炎症反应出现和进展的潜在机制。在这些情况下，减轻慢性神经炎症需要激活针对自身的外周免疫反应，而不是抑制它。因此，我们提出，击退急性和慢性神经退行性疾病需要打破针对中枢神经系统自身抗原的外周免疫耐受，以增强保护性自身免疫。然而，必须针对每种情况单独探索微调这种免疫反应的最佳方法。
