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神经元死亡中的作用仍然是一个关键的未解决的问题。一种常见的观点是，慢性神经退行性变代表了一种免疫病理形式，其中炎症介质如TNFalpha、il -1 β和活性氮或活性氧的过量产生导致神经元细胞死亡。这种免疫病理在急性病毒或细菌感染等疾病中有很强的先例。然而，来自多个来源的新证据表明，促炎免疫病理不是慢性脑疾病中神经元丧失的原因。在这里，我们提出一种不同类型的免疫病理，一种最常见的与免疫抑制相关的免疫病理，是慢性神经退行性疾病（如阿尔茨海默病）中神经元细胞死亡的原因。免疫抑制是获得性免疫特权的一个特征，它保护关键细胞，但降低了组织产生有效毒性反应的能力，这种反应将“清除”包括Abeta在内的免疫原。无效的清除导致“持续感染”，从而导致慢性炎症性疾病。我们在AD小鼠模型上的数据显示完全AD样病理（CVN小鼠）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β产生引发或促进。该小鼠的初步数据显示，抗炎/修复基因和蛋白的表达在细胞β生成和实质沉积开始时增加。促炎基因的表达随着年龄的增长而增加，但同时伴随着抗炎和耐受性基因和蛋白质的表达增加。因此，我们认为在整个神经退行性过程中维持免疫抑制环境。营养剥夺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。周围细胞可能发生氨基酸饥饿和自噬增加，导致细胞死亡。我们的初步数据表明，氨基酸饥饿发生在CVN小鼠的大脑中。两种酶的活性增加是免疫抑制的特征；即精氨酸酶（Arg），它利用精氨酸制造鸟氨酸，用于多胺和脯氨酸的生产，以及吲哚胺双加氧酶（IDO），它利用色氨酸生产kyneurine。AD的CVN小鼠模型显示大脑精氨酸水平降低，精氨酸酶和IDO表达增加。本提案将重点关注营养剥夺在AD自噬和神经元丢失诱导中的关键作用。研究的目的是确定：1)营养剥夺与CVN小鼠AD样病理进展之间的关系；2)免疫抑制性免疫细胞是否通过局部营养剥夺直接促进疾病进展；3)免疫介导的营养剥夺是否在神经元死亡和AD病理中起因果作用。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新的途径。

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.