Immune-based nutrient deprivation and neurodegenerative disease

描述（由申请人提供）：免疫系统在慢性神经退行性疾病中神经元死亡中的作用仍然是一个关键的未解决问题。一种常见的观点是，慢性神经退行性变是一种免疫病理学形式，其中过度产生炎症介质，如TNF α、IL-1 β和活性氮或氧，导致神经元细胞死亡。在诸如急性病毒或细菌感染的疾病中存在这种免疫病理学的强有力的先例。然而，来自多个来源的新证据认为，促炎性免疫病理学并不是慢性脑疾病中神经元损失的原因。在这里，我们提出，一种不同类型的免疫病理学，一个最常见的与免疫抑制，是负责慢性神经退行性疾病，如阿尔茨海默氏病的神经元细胞死亡。免疫抑制是获得性免疫豁免的一个特征，其保护关键细胞，但降低组织产生有效毒性反应的能力，该毒性反应将“清除”包括Abeta在内的免疫原。无效清除导致“持续性感染”，从而导致慢性炎症性疾病。我们对AD小鼠模型（CVN小鼠）的数据显示完全AD样病理学，强烈表明阿尔茨海默病可能代表一种不适当的免疫抑制状态，由Abeta产生引发或促进。来自该小鼠的初步数据显示在细胞Abeta产生和实质沉积开始时抗炎/修复基因和蛋白质的表达增加。促炎基因表达随着年龄的增长而发生，但伴随着抗炎和致耐受性基因和蛋白质的表达增加。因此，我们认为免疫抑制环境在整个神经退行性变过程中得到维持。营养缺乏是免疫细胞诱导免疫抑制的主要机制。通过增加精氨酸和色氨酸的摄取，免疫细胞降低了微环境中这些必需氨基酸的水平。周围细胞可能经历氨基酸饥饿和增加的自噬，导致细胞死亡。我们的初步数据表明氨基酸饥饿发生在CVN小鼠脑。两种酶的活性增加是免疫抑制的特征;即精氨酸酶（Arg）和吲哚胺双加氧酶（IDO），精氨酸酶使用精氨酸来制造用于多胺和脯氨酸生产的鸟氨酸，吲哚胺双加氧酶使用色氨酸来生产犬脑氨酸。AD的CVN小鼠模型显示精氨酸的脑水平降低和精氨酸酶和IDO表达增加。这项建议将集中在营养剥夺的作用，作为一个关键因素，诱导自噬和神经元的损失在AD。目的是确定：1）CVN小鼠中营养缺乏与AD样病理学进展之间的关系; 2）免疫抑制性免疫细胞是否通过局部营养缺乏直接促进疾病进展; 3）免疫介导的营养缺乏是否在神经元死亡和AD病理学中起因果作用。这些研究为理解慢性神经退行性疾病中免疫介导疾病的基本机制提供了一种新的方法。

DESCRIPTION (provided by applicant): The role of the immune system in neuronal death in chronic neurodegenerative diseases remains a critical unsolved question. One common view is that chronic neurodegeneration represents a form of immune pathology, in which the excessive production of inflammatory mediators such as TNFalpha, IL-1beta, and reactive nitrogen or oxygen species leads to neuronal cell death. There is a strong precedent for such immune pathology in diseases such as acute viral or bacterial infection. However new evidence from multiple sources argues that pro- inflammatory immune pathology is not the cause of neuronal loss in chronic brain disease. Here we propose that a different type of immune pathology, one most commonly associated with immune suppression, is responsible for neuronal cell death in chronic neurodegenerative diseases such as Alzheimer's disease. Immunosuppression is a feature of acquired immune privilege that protects critical cells but reduces the ability of the tissue to mount an effective toxic response that would "clear" immunogens including Abeta. Ineffectual clearance leads to "persistent infection" and hence to a chronic inflammatory disease. Our data on a mouse model of AD that shows full AD-like pathology (the CVN mouse) strongly suggest that Alzheimer's disease may represent an inappropriate immunosuppressive state, initiated or facilitated by Abeta production. Preliminary data from this mouse show increased expression of anti- inflammatory/repair genes and proteins at the onset of cellular Abeta production and parenchymal deposition. Pro-inflammatory gene expression occurs with age but is accompanied by increased expression of anti-inflammatory and tolerogenic genes and proteins. Thus, we believe that an immunosuppressive environment is maintained throughout the neurodegenerative process. Nutrient deprivation is a principal mechanism by which immune cells induce immune- suppression. By increasing arginine and tryptophan uptake, immune cells reduce the levels of these essential amino acids in the microenvironment. Surrounding cells may undergo amino acid starvation and increased autophagy leading to cell death. Our preliminary data suggest that amino acid starvation occurs in CVN mice brain. Increased activity of two enzymes are featured in immunosuppression; namely arginase (Arg) that uses arginine to make ornithine for polyamine and proline production and Indoleamine dioxygenase (IDO) that uses tryptophan to produce kyneurine. The CVN mouse model of AD demonstrates both decreased brain levels of arginine and increased arginase and IDO expression. This proposal will focus on the role of nutrient deprivation as a key factor in the induction of autophagy and neuronal loss in AD. The aims will establish, 1) the relationship between nutrient deprivation and the progression of AD- like pathology in the CVN mouse 2) if immunosuppressive immune cells contribute directly to disease progression through regional nutrient deprivation and 3) if immune-mediated nutrient deprivation plays a causal role in neuronal death and AD pathology. These proposed studies represent a novel approach to understanding the basic mechanisms of immune mediated disease in chronic neurodegenerative disease.