Chronic Sleep Restriction Increases Immunity to Autoantigen: Role of the SNS

描述（由申请人提供）：本申请涉及广泛的挑战领域：（01）“行为、行为改变和预防”和特定挑战主题：01- ar -101“关节炎和肌肉骨骼疾病的行为和生物医学研究方法的整合”患有类风湿关节炎（RA）、其他慢性关节炎和其他自身免疫性疾病的患者，无论是否炎症，都有部分慢性睡眠中断。目前尚不清楚这种部分慢性睡眠中断对新的自身抗原对RA关节炎过程和相关关节炎的免疫介导的耀斑有何影响。对动物和人类的研究表明，睡眠剥夺会导致激素的变化和交感神经系统（SNS）功能的增强以及其他影响。我们基本上对用于研究大鼠睡眠的Rechtschaffen-Bergmann disk over water （DOW）装置进行了改造，以适应小鼠。利用该装置和计算机程序控制磁盘旋转并产生慢性睡眠中断，我们一直在研究慢性（14-30天）睡眠限制对DBA/1LacJ小鼠II型胶原（CII）诱导的关节炎（CIA）的影响。我们的研究表明，与没有睡眠限制的对照组相比，长期睡眠限制的小鼠关节炎的严重程度和发病率都显著增加。我们在慢性睡眠受限关节炎小鼠中发现，对CII的免疫反应随着干扰素3和其他Th1细胞因子的产生增加、血清抗CII抗体水平增加、CD8+ T细胞减少、CD11b+细胞增加、血浆炎症细胞因子水平和脾脏SNS衍生神经肽Y水平的变化而增强。促肾上腺皮质激素释放激素（CRH）和褪黑激素可加速关节炎，尽管SNS可增加CRH和褪黑激素，但其在慢性睡眠限制中的作用尚不清楚。我们假设慢性睡眠中断导致对自身抗原（CII）的初级免疫反应增强，导致小鼠CIA模式RA关节炎和严重程度增加，这是由于SNS的激活导致免疫系统对CII的启动。具体目的1：在CIA模型中，评估慢性睡眠限制和SNS在增强对自身抗原CII的免疫和关节炎严重程度恶化方面的关系。目的1A：交感神经切除术对睡眠受限小鼠CIA临床来源的影响。Subaim 1B：交感神经切除术对睡眠受限小鼠CII免疫反应的影响。亚目标1C：慢性睡眠限制对CRH和褪黑激素免疫增强的作用。拟议的研究与RA相关，RA的特征是睡眠中断，关节炎的慢性加重/缓解临床过程和对多种自身抗原的免疫，并与其他自主神经疾病相关。慢性睡眠障碍存在于许多类风湿关节炎（RA）患者中，与交感神经系统释放去甲肾上腺素激活免疫系统、硬皮病、狼疮和其他自身免疫性疾病有关。长期睡眠不足可能会影响人体免疫系统的工作方式，我们对人类风湿性关节炎小鼠模型的研究表明，长期睡眠不足会加重关节炎，使其更加严重。这项拨款提案将研究人类风湿性关节炎小鼠模型中由慢性睡眠不足引起的几种潜在免疫系统异常，以及交感神经系统如何导致严重关节炎。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area: (01) "Behavior, Behavior Change, and Prevention" and Specific Challenge Topic: 01-AR-101 "Integrating Behavioral and Biomedical Research Approaches in Arthritis and Musculoskeletal Diseases" Patients with rheumatoid arthritis (RA), other chronic arthritides and other autoimmune diseases inflammatory or not, have partial chronic disrupted sleep. It is unknown what effect this partial chronic sleep disruption has on the immune mediated flares from new autoantigens on the arthritic processes of RA and related arthritides. Studies in animals and humans suggest that sleep deprivation leads to changes in hormones and increased sympathetic nervous system (SNS) function amongst other effects. We have basically adapted the Rechtschaffen-Bergmann disk over water (DOW) apparatus used to study sleep in rats to accommodate mice. Using this apparatus with a computer program to control disk rotation and produce chronic disrupted sleep, we have been studying the effect of chronic (14-30 day) sleep restriction on type II collagen (CII)-induced arthritis (CIA) in DBA/1LacJ mice. Our studies show that both the severity and the incidence of arthritis are significantly increased in mice chronically sleep-restricted compared to control litter mates not sleep restricted. We present evidence in the chronic sleep restricted arthritic mice that the immune response to CII is enhanced with increased production of interferon3 and other Th1 cytokines, increased serum levels of anti-CII antibodies, decreased CD8+ T cells, increased CD11b+ cells and changes in plasma levels of inflammatory cytokines and levels of SNS derived neuropeptide Y in spleen. Corticotrophin releasing hormone (CRH) and melatonin can accelerate arthritis, and although the SNS can increase CRH and melatonin or their role is unknown in chronic sleep restriction. We hypothesize that chronic disrupted sleep results in enhancement of the primary immune response to autoantigen (CII) resulting in increased arthritis and severity in the murine CIA mode of RA due to activation of the SNS which results in priming of the immune system to CII. The following Specific Aim will address these hypotheses: Specific Aim 1: Assess the relationships between chronic sleep restriction and the SNS in enhancing immunity to the autoantigen CII and worsening of arthritis severity in the CIA model. Subaim 1A: Effect of sympathectomy on clinical source of CIA in sleep restricted mice. Subaim 1B: Effect of sympathectomy on immune response to CII in sleep restricted mice. Subaim 1C: Role of CRH and melatonin in immune enhancement by chronic sleep restriction. The proposed studies have relevance to RA which is characterized by disrupted sleep, chronic exacerbating/remitting clinical course of arthritis and immunity to multiple autoantigens and have relevance to other autonomic diseases. Chronic sleep disturbance is present in many human patients with rheumatoid arthritis (RA) and is associated with activation of the sympathetic nervous system releasing norepinephrine which activates the immune system, scleroderma, lupus and other autoimmune diseases. The chronic loss of sleep may affect the way in which the body's immune system works, and our research in a mouse model of human RA has shown that chronic interruption of sleep aggravates the arthritis making it more severe. This grant proposal will study several potential abnormalities of the immune system caused by chronic loss of sleep in the mouse model of human RA and how the sympathetic nervous system contributes to the severe arthritis.