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）：本申请涉及广泛的挑战领域：(01)“行为、行为改变和预防”和具体挑战主题：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”患有类风湿性关节炎（RA）、其他慢性关节炎和其他炎症或非炎症性自身免疫性疾病的患者患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自身抗原对 RA 和相关关节炎的关节炎过程的免疫介导的发作有何影响。对动物和人类的研究表明，睡眠不足会导致激素变化、交感神经系统 (SNS) 功能增强以及其他影响。我们基本上已经将用于研究大鼠睡眠的 Rechtschaffen-Bergmann 水上圆盘 (DOW) 装置改造为适应小鼠。使用该装置和计算机程序来控制椎间盘旋转并产生慢性睡眠中断，我们一直在研究长期（14-30 天）睡眠限制对 DBA/1LacJ 小鼠中 II 型胶原 (CII) 诱导的关节炎 (CIA) 的影响。我们的研究表明，与未限制睡眠的对照同窝小鼠相比，长期睡眠限制的小鼠关节炎的严重程度和发病率均显着增加。我们在慢性睡眠受限关节炎小鼠中提供了证据，表明对 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、抗 CII 抗体血清水平增加、CD8+ T 细胞减少、CD11b+ 细胞增加以及炎症细胞因子血浆水平和脾脏中 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 可以增加 CRH 和褪黑激素，但它们在慢性睡眠限制中的作用尚不清楚。我们假设，长期睡眠中断会导致对自身抗原（CII）的初级免疫反应增强，从而导致小鼠 CIA RA 模式中关节炎和严重程度的增加，这是由于 SNS 的激活导致免疫系统对 CII 的启动。以下具体目标将解决这些假设： 具体目标 1：评估慢性睡眠限制和 SNS 在增强对自身抗原 CII 的免疫力和 CIA 模型中关节炎严重程度恶化方面的关系。 Subaim 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对 CII 免疫反应的影响。 Subaim 1C：CRH 和褪黑激素在慢性睡眠限制增强免疫中的作用。拟议的研究与 RA 相关，其特征是睡眠中断、关节炎的慢性恶化/缓解临床病程和对多种自身抗原的免疫，并且与其他自主神经疾病相关。许多类风湿性关节炎 (RA) 患者都存在慢性睡眠障碍，并且与交感神经系统激活释放去甲肾上腺素有关，去甲肾上腺素会激活免疫系统、硬皮病、狼疮和其他自身免疫性疾病。长期睡眠不足可能会影响人体免疫系统的工作方式，我们对人类类风湿性关节炎小鼠模型的研究表明，长期睡眠中断会加剧关节炎，使其变得更加严重。该拨款提案将研究人类类风湿性关节炎小鼠模型中因长期睡眠不足引起的几种潜在的免疫系统异常，以及交感神经系统如何导致严重关节炎。