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Transcript
Obstructive Sleep Apnea and the Immune System By Mohammed Quadri, RPSGT Sleep disturbances affect practically every segPhysical barriers prevent pathogens such as ment of society permeating across all ethnic, sobacteria and viruses from entering the organism. cio-economic and age groups. Obstructive sleep If a pathogen breaches these barriers, the innate apnea is a process with gradual onset, many (natural) immune system provides an immeditimes starting with habitual snoring. Obstructive ate, but non-specific response. When diseaseapneas are characterized by partial or complete producing microorganisms overcome the natural airway obstruction during sleep, reductions in immune system, the adaptive immune system is blood oxygen levels, severe sleep fragmentation activated. and excessive daytime sleepiness. Left untreated, The immune system develops a specific sleep apnea leads to a progression in upper response to specific intruders. This specific MOHAMMED QUADRI, airway inflammation and may lead to various response is more effective and has a memory RPSGT other complications such as depression, fatigue, response that helps it quickly fight against simihypertension, sleep deprivation, drowsy driving, arrhythmias, lar infections in the future. Immunity results when antigens stroke and even sudden death.1 that are present on the surface of an invader stimulate the The obstructive sleep apnea syndrome is the clinical production of antibodies. There are two types of immune consequence of frequent episodes of apnea during sleep. response: antibody mediated, also know as humoral, which Obstructive apneas are pauses in breathing that last at least is regulated by B cells; and cell mediated, which is controlled 10 seconds and are accompanied by physical attempts to by T cells. breathe. Usually patients with 15 or more episodes of apnea T cells are lymphocytes that migrate to the thymus (i.e., a per hour of sleep are considered to have moderate to severe gland at the base of the neck) and are associated with lymph sleep apnea. Although prevalence estimates vary, obstructive nodes and spleen. B cells are in the bone marrow and are sleep apnea affects at least two percent to four percent of responsible for antibody response. Antibodies are a type of middle-aged adults in the general population.2 protein molecule known as an “immunoglobulin”; there are five classes of immunoglobulins: A,G,E,D and M. The Immune System Inflammation is one of the first responses of the immune The immune system protects organisms from infection and system to infection.3 The symptoms of inflammation are redinjury with specific defenses that are known as host defense ness and swelling, which are caused by increased blood flow mechanisms. These host defense mechanisms can be categoto the tissue. Inflammation is produced by eicosanoids (sigrized in the following groups: naling molecules) and cytokines (regulatory proteins), which are released by injured or infected cells. Eicosanoids include Physical and Chemical Barriers prostaglandins that produce fever and the dilation of blood Morphologic integrity of skin vessels associated with inflammation, and leukotrienes that Sphincters (muscles that open and close a body attract certain white blood cells (leukocytes).4,5 Common cyopening) tokines include interleukins that are responsible for commu Epiglottis (cartilage that covers the windpipe while nication between white blood cells; chemokines that promote swallowing) chemotaxis (movement toward or away from a stimulus); and Normal secretory and excretory flow interferons that have anti-viral effects, such as shutting down Endogenous microbial flora (“normal” bacteria) protein synthesis in the host cell.6 Growth factors and cyto Gastric acidity toxic factors also may be released. These cytokines and other Inflammatory Response chemicals recruit immune cells to the site of infection and Circulating phagocytes (white blood cells that break promote healing of any damaged tissue following the removal down bacteria) of pathogens.7 Complement (a system of proteins that helps destroy Sleep Apnea & the Immune System bacteria) Some research suggests that inflammation, particularly Other humoral (body fluid) mediators mucosal inflammation, could partially underlie sleep apnea. (e.g., bradykinin) Supporting this claim is the fact that when sleep apnea is Reticuloendothelial System treated with continuous positive airway pressure (CPAP), Tissue phagocytes inflammation is reduced. In addition, inflammatory mediators appear to play a role in both leading to injury of sensory Immune Response motor nerves in the upper airway and impairing muscle T lymphocytes (cells that promote cellular immunity) contraction, contributing to upper airway muscle dysfunction and their soluble products in sleep apnea. Moreover, surrogate biomarkers such as nitric B lymphocytes (cells that promote oxide have established that nasal and oropharyngeal mucosal humoral immunity) and immunoglobulins inflammation is present in patients with sleep apnea.8,9 Obstructive sleep apnea holds promise as a model for 18 A2Zzz 2008 • volume 17 • number 4 studying sleep and cytokines because of its many relevant characteristics, including neuroimmune interactions, mood changes and behaviors that directly affect the course of the disorder.10 Main features of pulmonary pathologies (e.g., interstitial lung disease, pulmonary hypertension) appear to be immune activation and vascular endothelial cell injury. Also interstitial and alveolar inflammation appear to be associated with these pathologies.11 It is important to note that cytokine-mediated upregulation of the inducible isoform of nitric oxide snythase, leading to the production of large quantities of nitric oxide, accompanies the immune-inflammatory processes. Excess nitric oxide generation appears to apply strong proinflammatory and cytotoxic properties and may be related to the pathogenesis of autoimmune diseases.12 In a study conducted in Turkey it has been shown that the levels of circulating inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are increased in patients with sleep apnea; this increases mortality in patients with cardiovascular risk factors.13 Findings from several studies have provided evidence for a link between sleep and immune-related factors, particularly with regard to the regulation of sleep. For example, experimental challenge tests have shown that bacterial products and particular immunomodulators may alter the amount of sleep and its stages.14,15 Detection of immune cell signaling factors in the circulation, such as IL-1 beta, TNF-alpha or its receptor, and/or IL-6, have been reported in patients with narcolepsy and sleep apnea who are affected by excessive daytime sleepiness.16 It is still speculative how sleep deprivation may perpetuate disease processes in humans. Sleep deprivation leads to activation of the immune system, but there is not enough response to eradicate invading bacteria and toxins, suggesting competing anti-inflammatory processes.17 Conclusion Evidence continues to mount that sleep disorders lead to various metabolic disorders; some studies have even shown that the response to vaccination is much diminished in sleepdeprived people. Sleep disorders may be related to changes in immune response, suggesting that sleep hygiene and treatment of sleep disorders could improve the body’s response in fighting infection. Further research is required to find the genetic link between sleep disorders and immune disorders, which could lead to the development of novel treatment options for some commonly prevailing, chronic conditions. The author thanks Susan Zafarlotfi, PhD, and Hormoz Ashtyani, MD, for their assistance in developing this article. References 1. 2. Svanborg E. Upper airway nerve lesions in obstructive sleep apnea. Am J Respir Crit Care Med 2001;164:187-189. Kushida CA, Littner MR, Hirshkowitz M et al. Practice parameters for the use of continuous and bilevel positive airway pressure devices to treat adult patients with sleeprelated breathing disorders. Sleep 2006;29(3):375-380. 3. Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol 2006;7(2):131–137. 4. Miller, SB. Prostaglandins in health and disease: an overview. Semin Arthritis Rheum 2006;36(1):37–49. 5. Ogawa Y, Calhoun WJ. The role of leukotrienes in airway inflammation. J Allergy Clin Immunol 2006;118(4):789–798. 6. Le Y, Zhou Y, Iribarren P, Wang J. Chemokines and chemokine receptors: their manifold roles in homeostasis and disease. Cell Mol Immunol 2004;1(2):95–104. 7. Martin P, Leibovich S. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol 2005;15(11):599–607. 8. Rubinstein I. Upper airway inflammation in obstructive sleep apnea. Am J Respir Crit Care Med 2002;165(7):1023-24. 9. Kimoff RJ, Sforza E, Champagne V, Ofiara L, Gendron D. Upper airway sensation in snoring and obstructive sleep apnea. Am J Respir Crit Care Med 2001;164:250-255. 10. Mills PJ, Dimsdale JE. Sleep apnea: a model for studying cytokines, sleep, and sleep disruption. Brain Behav Immun 2004;18(4):298-303. 11. Cool CD, Kennedy D, Voelkel NF, Tuder RM. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol 1997;28:434-442. 12. Vladutiu AO. Role of nitric oxide in autoimmunity. Clin Immunol Immunopathol 1995;76(1 Pt 1):1-11. Review. 13. Ciftci TU, Kokturk O, Bukan N, Bilgihan A. The relationship between serum cytokine levels with obesity and obstructive sleep apnea syndrome. Cytokine 2004;28(2):87-91. 14. Krueger JM, Obal FJ, Fang J, Kubota T, Taishi P. The role of cytokines in physiological sleep regulation. Ann N Y Acad Sci 2001;933:211–221. 15. Mullington JM, Hinze-Selch D, Pollmacher T. Mediators of inflammation and their interaction with sleep: relevance for chronic fatigue syndrome and related conditions. Ann N Y Acad Sci 2001;933:201–210. 16. Vgontzas AN, Papanicolaou DA, Bixler EO, Kales A, Tyson K, Chrousos GP. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab 1997;82:1313–16. 17. Everson CA. Clinical assessment of blood leukocytes, serum cytokines, and serum immunoglobulins as responses to sleep deprivation in laboratory rats. Am J Physiol Regul Integr Comp Physiol 2005;289:R1054-R1063. Mohammed Quadri, RPSGT, is a foreign medical graduate who has been in the sleep field for three years. He is Project Coordinator Clinical Trials at Hackensack University Medical Center in Hackensack, N.J. A2Zzz 2008 • volume 17 • number 4 19