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

长期睡眠限制会增加对自身抗原的免疫力：SNS 的作用

• 批准号: 7941787
• 负责人: ARNOLD E POSTLETHWAITE
• 金额: $ 41.84万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941787
• 关键词: Address; Affect; Aggravated Arthritis; American; Animals; Antibodies; Antigens; Applications Grants; Area; Arthritis; Arts; Autoantigens; Autoimmune Diseases; Autonomic nervous system disorders; Behavior; Behavioral; Biomedical Research; CD8B1 gene; Cells; Chemicals; Chronic; Clinical; Collagen Type II; Complement 3d Receptors; Corticotropin-Releasing Hormone; DBA/1LacJ Mouse; Data; Developed Countries; Development; Disease; Dopamine; Epidemic; Flare; Gland; Healthcare Systems; Hormones; Hour; Human; IL2RA gene; ITGAM gene; Immune; Immune response; Immune system; Immunity; Immunization; Incidence; Inflammatory; Interferon Type II; Interferons; Interruption; Lupus; Mediating; Melatonin; Methodology; Methods; Modeling; Mus; Musculoskeletal Diseases; Nerve; Nerve Fibers; Nervous System Physiology; Norepinephrine; Onset of illness; Output; Partner in relationship; Patients; Plasma; Prevention; Process; Production; Quality of life; Rattus; Research; Research Personnel; Rheumatoid Arthritis; Role; Rotation; Scleroderma; Serum; Severities; Sleep; Sleep Deprivation; Sleep disturbances; Source; Spleen; Sympathectomy; Sympathetic Nervous System; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Time; To autoantigen; Water; Work; antibody conjugate; behavior change; chemokine; computer program; cytokine; ds-DNA; mouse model; neuropeptide Y; response

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.

描述（由申请人提供）：此申请应解决广泛的挑战领域：（01）“行为，行为改变和预防”和特定的挑战主题：01-AR-101”将关节炎和肌肉骨骼疾病的行为和生物医学研究方法整合在一起”患者”患者（RANISERIDES和其他自动症状症状和其他自动化症状扰动型）患者（RA）患者（RA）和其他慢性疾病症状。尚不清楚这种部分慢性睡眠中断对新自身抗原的免疫介导的耀斑对RA和相关关节炎的关节炎过程的影响。对动物和人类的研究表明，睡眠剥夺会导致激素的变化和提高的交感神经系统（SNS）功能增加。我们基本上已经在水上（DOW）设备（用于研究大鼠睡眠以容纳小鼠的睡眠状态）的Rechtschaffen-Bergmann磁盘（DOW）。使用该设备与计算机程序控制磁盘旋转并产生慢性破坏睡眠，我们一直在研究慢性（14-30天）睡眠限制对DBA/1LACJ小鼠中II型胶原蛋白（CII）诱导的关节炎（CIA）的影响。我们的研究表明，与不受限制睡眠的对照组合相比，慢性睡眠限制的小鼠的严重程度和关节炎的发生率显着增加。 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.皮质营养素释放激素（CRH）和褪黑激素可以加速关节炎，尽管SNS可以增加CRH和CRH和褪黑激素，或者它们的作用在慢性睡眠限制中尚不清楚。我们假设慢性睡眠破坏导致对自身抗原（CII）的原发性免疫反应的增强，从而导致因SNS的激活而导致RA的鼠CIA模式下的关节炎和严重程度增加，从而导致免疫系统启动到CII。以下具体目的将解决以下假设：具体目标1：评估慢性睡眠限制与SNS之间的关系，以增强对自身抗原CII的免疫力，并在中央情报局模型中对关节炎的严重程度恶化。 Subaim 1a：交感神经切除术对睡眠限制小鼠CIA临床来源的影响。 Subaim 1B：交感神经对睡眠限制小鼠中CII的免疫反应的影响。 Subaim 1C：CRH和褪黑激素通过慢性睡眠限制在免疫增强中的作用。拟议的研究与RA相关，其特征是睡眠中断，慢性加剧/减轻关节炎的临床过程和对多种自身抗原的免疫力，并与其他自主疾病相关。许多类风湿关节炎（RA）的人类患者存在慢性睡眠障碍，并且与激活免疫系统，硬皮病，狼疮和其他自身免疫性疾病的交感神经系统的激活有关。慢性睡眠丧失可能会影响人体免疫系统的工作方式，我们在人类RA的小鼠模型中的研究表明，睡眠的慢性中断会加剧关节炎，从而更加严重。该赠款提案将研究由人类RA小鼠模型中的慢性睡眠丧失引起的免疫系统的几种潜在异常，以及交感神经系统如何促进严重关节炎。