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

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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.