Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
Mol Immunol. 2011 Aug;48(14):1592-603. doi: 10.1016/j.molimm.2011.04.003. Epub 2011 May 4.
The brain is considered to be an immune privileged site, because the blood-brain barrier limits entry of blood borne cells and proteins into the central nervous system (CNS). As a result, the detection and clearance of invading microorganisms and senescent cells as well as surplus neurotransmitters, aged and glycated proteins, in order to maintain a healthy environment for neuronal and glial cells, is largely confined to the innate immune system. In recent years it has become clear that many factors of innate immunity are expressed throughout the brain. Neuronal and glial cells express Toll like receptors as well as complement receptors, and virtually all complement components can be locally produced in the brain, often in response to injury or developmental cues. However, as inflammatory reactions could interfere with proper functioning of the brain, tight and fine tuned regulatory mechanisms are warranted. In age related diseases, such as Alzheimer's disease (AD), accumulating amyloid proteins elicit complement activation and a local, chronic inflammatory response that leads to attraction and activation of glial cells that, under such activation conditions, can produce neurotoxic substances, including pro-inflammatory cytokines and oxygen radicals. This process may be exacerbated by a disturbed balance between complement activators and complement regulatory proteins such as occurs in AD, as the local synthesis of these proteins is differentially regulated by pro-inflammatory cytokines. Much knowledge about the role of complement in neurodegenerative diseases has been derived from animal studies with transgenic overexpressing or knockout mice for specific complement factors or receptors. These studies have provided insight into the potential therapeutic use of complement regulators and complement receptor antagonists in chronic neurodegenerative diseases as well as in acute conditions, such as stroke. Interestingly, recent animal studies have also indicated that complement activation products are involved in brain development and synapse formation. Not only are these findings important for the understanding of how brain development and neural network formation is organized, it may also give insights into the role of complement in processes of neurodegeneration and neuroprotection in the injured or aged and diseased adult central nervous system, and thus aid in identifying novel and specific targets for therapeutic intervention.
大脑被认为是一个免疫特惠部位，因为血脑屏障限制了血液来源的细胞和蛋白质进入中枢神经系统 (CNS)。因此，为了维持神经元和神经胶质细胞的健康环境，检测和清除入侵的微生物和衰老细胞以及多余的神经递质、老化和糖化蛋白，主要依赖于先天免疫系统。近年来，人们清楚地认识到许多先天免疫因素在大脑中都有表达。神经元和神经胶质细胞表达 Toll 样受体和补体受体，实际上所有的补体成分都可以在大脑中局部产生，通常是对损伤或发育信号的反应。然而，由于炎症反应可能干扰大脑的正常功能，因此需要严格和精细的调节机制。在与年龄相关的疾病中，如阿尔茨海默病 (AD)，积累的淀粉样蛋白会引发补体激活和局部慢性炎症反应，导致神经胶质细胞的吸引和激活，在这种激活条件下，神经胶质细胞可以产生神经毒性物质，包括促炎细胞因子和氧自由基。这种过程可能会因补体激活物和补体调节蛋白之间的平衡失调而加剧，这种失调在 AD 中发生，因为这些蛋白质的局部合成受到促炎细胞因子的差异调节。关于补体在神经退行性疾病中的作用的许多知识是从转基因过表达或敲除特定补体因子或受体的动物研究中获得的。这些研究为慢性神经退行性疾病以及急性疾病（如中风）中补体调节剂和补体受体拮抗剂的潜在治疗用途提供了深入了解。有趣的是，最近的动物研究还表明，补体激活产物参与大脑发育和突触形成。这些发现不仅对理解大脑发育和神经网络形成的组织方式很重要，还可能为补体在损伤、衰老和患病的成年中枢神经系统中的神经退行性和神经保护过程中的作用提供深入了解，并有助于确定治疗干预的新的和特定的靶点。
