insights

Read Time: 7 Minutes

Sleep is widely considered an important variable in immune health as increasing evidence suggests that poor sleep quality and quantity may be a driver for the development and progression of inflammatory diseases.^1-5 The bidirectional nature of sleep and immunity suggests that, in the absence of an infection, sleep may promote inflammatory homeostasis through effects on several inflammatory mediators, such as cytokines.^1-4 (In the case of homeostatic inflammation, there is a spontaneous activation of innate immune sensors induced by endogenous ligands).⁶ Research suggests that prolonged sleep deficiency may lead to chronic, systemic, low-grade inflammation and may be associated with some autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjögren’s syndrome, systemic lupus erythematosus, systemic sclerosis, and osteoarthritis.^1,3-4

A 2016 Taiwanese nationwide longitudinal study found that chronic insomnia requiring sleep-inducing medications was associated with a 70% increased risk for developing an autoimmune disease.⁷ Likewise, individuals with autoimmune disease frequently report disturbed sleep, suggesting a bidirectional relationship.^4,8-9 What are the mechanisms behind this intricate connection, and what evidence-based approaches can be used to mitigate the effects of poor sleep quality and quantity in autoimmune disease patients?

Circadian Clocks

The body’s circadian rhythms and sleep hygiene play a critical role in immune system homeostasis; both innate and adaptive immune responses—ranging from leukocyte mobilization to cytokine release and T-cell differentiation—are mediated in a time-of-day-dependent manner.² A 2020 review exploring the connection between biological rhythms, sleep, and immune regulation explains that molecular clocks operate in almost all nucleated cells throughout the body, thereby allowing cells to factor time-of-day information into the control of metabolism and other important pathways. Clock proteins and clock genes are subject to numerous forms of biochemical regulation like methylation, acetylation, and phosphorylation, among others. These modifications impact clock protein levels and activity, thereby allowing ambient biochemical cues, such as temperature, nutrient status, and hormone levels, to synchronize internal cellular time with the external world.²

The most researched connection between circadian clocks and immune function is in the regulation of proinflammatory cytokine secretion; this involves the ability of clock proteins to directly transactivate or repress gene expression of key cytokines and chemokines, including CCL2, TNF, IL-6, and CXCL5.² Recent studies in mice suggest that fragmented sleep increases the production of inflammatory monocytes by the bone marrow and may lead to atherosclerosis.^2,10 In experimental studies, inadequate sleep seems to impair immune effector cell functions such as NK cell activity.^1,2

Sleep & Autoimmunity: A Focus on Multiple Sclerosis and Rheumatoid Arthritis

Scientists hypothesize that altered sleep habits, specifically sleep deprivation, may be a consequence and a marker of neurodegenerative diseases like multiple sclerosis (MS) and rheumatoid arthritis (RA).^5,11-12 Fatigue can be a major early finding in individuals with autoimmune disease, and inflammation is often a contributing factor to this impairment.⁴ However, the association between autoimmune diseases and sleep is complex and multifactorial, making it difficult for researchers to decipher the direct cause.⁴

Disease development may be accelerated by sleep deprivation through a variety of mechanisms, including the production of several proinflammatory cytokines, such as IL-6 and IL-17, and the related TH17-cell response.⁵ Additionally, studies of experimentally sleep-deprived healthy humans showed impaired suppressive activity of CD4 regulatory T cells (Treg), which normally is highest at night and lowest in the morning. Writing in Communications Biology in 2021, Garbinaro et al explain that the suppressive function of Treg toward excessive immune response is an important homeostatic mechanism whose impairment is implicated in autoimmune disease pathogenesis. Hence, the authors conclude that sleep deprivation may not be solely a symptom or consequence of autoimmune disease but may directly contribute to its pathogenesis, increasing a patient’s susceptibility to developing an autoimmune disease.⁵

Multiple Sclerosis

Multiple sclerosis (MS), a common chronic inflammatory autoimmune disease of the central nervous system, is believed to be a consequence of infiltrating T lymphocytes that are reactive to myelin proteins and induce an inflammatory response that destroys the myelin and the axons. The pathology of MS consists of demyelination, axonal loss, inflammation, and gliosis.³ Insomnia occurs in approximately 40% of patients with MS,³ and sleep disturbance in individuals with MS is approximately four times higher than in the general population.¹³

MS has also been associated with an increased risk of rapid eye movement (REM) sleep behavior disorder, which is also associated with enhanced levels of inflammatory molecules,^4,14 as well as sleep-disordered breathing like obstructive sleep apnea and restless leg syndrome.^15,16 Some researchers speculate that since inflammation can induce fatigue, it is plausible that neuroinflammation occurring with disturbed sleep or sleep loss could exacerbate fatigue in individuals with autoimmune disease.⁴

Another major driver of sleep or circadian disruption arises from chronic stress resulting from physiological and/or psychological factors,¹⁷ as the hypothalamic-pituitary-adrenal (HPA) axis is involved in hormonal responses to stress that modulate fatigue.⁴ Data suggests that individuals with autoimmune diseases have increased stress levels compared to the general population, and some research suggests that stress can modulate brain inflammation in MS.^4,17

Rheumatoid Arthritis

Sleep disturbance also presents challenges for patients with rheumatoid arthritis (RA)—a chronic autoimmune disease characterized by changes in the synovium followed by joint swelling, pain, cartilage and bone destruction, and subsequent systemic inflammation.^9,11,18 The immunopathology of RA is characterized by inappropriate production of various cytokines, in particular TNF, among several other immunological abnormalities.¹ In a recent study, cellular inflammation was higher in RA patients, compared with matched, healthy controls, and showed a complex time-of-day-dependent association with sleep efficiency and slow-wave-sleep (the deepest form of sleep) amount. For example, higher sleep efficiency was associated with lower stimulated monocytic TNF production in the morning, though with higher production when assessed in the evening. As stated by the authors, these findings may suggest a feedback loop between sleep parameters and cellular production of pro-inflammatory cytokines.¹

Several other studies have also found that higher RA disease activity is associated with sleep problems, including a Korean study that found decreasing subjective sleep quality as RA disease activity was increasing.^9,19 More than half of all RA patients report sleep problems, including difficulty falling asleep, nocturnal awakenings, nonrestorative sleep, and fatigue, at a frequency that is up to three times higher than that of the general population.^11,18,20,21 However, the directionality of this association is not clear.¹⁸

Many sleep issues experienced in patients with RA may stem from pain,⁹ and some studies suggest that impaired sleep in RA is mainly secondary to joint pain, disease activity, and altered mood.¹¹ Interestingly, pain has also been found to predict sleep disturbance over time, even without sleep issues affecting pain.⁹ Chronic pain and associated sleep issues are also a risk for developing depressive symptoms in patients with RA, which may in turn have an additional influence as depression may be a predictive factor for poor quality sleep.⁹ In a 2021 study of female patients with a previous diagnosis of RA, poor sleep was associated with a greater frequency and severity of depressive symptoms.¹¹ These are important findings, though the exact mechanisms of RA disease activity and sleep issues are not known.

Interventions

Since inflammation may play a role in inducing fatigue, some researchers speculate that inflammatory pathways and the subsequent physiological alterations modulated by the inflammation are treatable targets for fatigue in patients with autoimmune disease.⁴ The question remains, however, whether immune and inflammatory consequences of dysfunctional sleep will return to normal once recovery sleep has been attained.¹ That said, the following items may help with sleep recovery:

• Recovery sleep following experimentally induced sleep deficiency¹
• Daytime napping¹
• Cognitive behavioral therapy^1,5
• Physical activity^22-24
• Sleep hygiene education²⁵
• Environmental modifications, such as changes to a bedroom, including modifying noise, light, temperature, bedding, and technology²⁵

Russell G. Foster, writing in “Sleep, circadian rhythms and health” in Interface Focus, outlines evidence-based actions individuals can undertake to help improve insomnia:¹⁷

• Get as much morning natural light as possible; timed light exposure using a light box has also been shown to be helpful for some sleep/wake timing problems.
• Minimize light exposure prior to bedtime to reduce levels of alertness, specifically blue light, as it suppresses the body’s release of melatonin.
• Create a quiet and dark sleeping space.
• Keep a good bedtime routine of getting up and going to bed at the same time.¹⁷

It is abundantly clear that environmental factors, like sleep, have an important part to play in the underlying etiology of autoimmune disease. In rheumatoid arthritis, for instance, genetic factors have been shown to be responsible for less than 50% of the risk.²⁶ This means that environmental factors—and gene-environment interactions—must play a significant role. Learn more about chronic inflammation, systemic influences on the immune system, and the consequent dysfunction that may ensue in IFM’s Immune Advanced Practice Module. Also learn more about tools and strategies to help patients achieve sustainable lifestyle change and improve their well-being through IFM’s new course Lifestyle: The Foundations of Functional Medicine.

Related Articles

Barriers to Immune Resilience

The Microbiome and Immune-Related Diseases

Beneficial Effects of Meditation on Inflammation

References

1. Besedovsky L, Lange T, Haack M. The sleep-immune crosstalk in health and disease. Physiol Rev. 2019;99(3):1325-1380. doi:1152/physrev.00010.2018
2. Haspel JA, Anafi R, Brown MK, et al. Perfect timing: circadian rhythms, sleep, and immunity – an NIH workshop summary. JCI Insight. 2020;5(1):e131487. doi:1172/jci.insight.131487
3. Iranzo A. Sleep and neurological autoimmune diseases. Neuropsychopharmacology. 2020;45(1):129-140. doi:1038/s41386-019-0463-z
4. Zielinski MR, Systrom DM, Rose NR. Fatigue, sleep, and autoimmune and related disorders. Front Immunol. 2019;10:1827. doi:3389/fimmu.2019.01827
5. Garbarino S, Lanteri P, Bragazzi NL, Magnavita N, Scoditti E. Role of sleep deprivation in immune-related disease risk and outcomes. Commun Biol. 2021;4(1):1304. doi:1038/s42003-021-02825-4
6. Amadori M, ed. The Innate Immune Response to Noninfectious Stressors: Human and Animal Models. Academic Press; 2016.
7. Kok VC, Horng JT, Hung GD, et al. Risk of autoimmune disease in adults with chronic insomnia requiring sleep-inducing pills: a population-based longitudinal study. J Gen Intern Med. 2016;31(9):1019-1026. doi:1007/s11606-016-3717-z
8. Blattner MS, de Bruin GS, Bucelli RC, Day GS. Sleep disturbances are common in patients with autoimmune encephalitis. J Neurol. 2019;266(4):1007-1015. doi:1007/s00415-019-09230-2
9. Grabovac I, Haider S, Berner C, et al. Sleep quality in patients with rheumatoid arthritis and associations with pain, disability, disease duration, and activity. J Clin Med. 2018;7(10):336. doi:3390/jcm7100336
10.  McAlpine CS, Kiss MG, Rattik S, et al. Sleep modulates haematopoiesis and protects against atherosclerosis. 2019;566(7744):383-387. doi:10.1038/s41586-019-0948-2
11.  Lopes FHA, Freitas MVC, de Bruin VMS, de Bruin PFC. Depressive symptoms are associated with impaired sleep, fatigue, and disease activity in women with rheumatoid arthritis. Adv Rheumatol. 2021;61(1):18. doi:1186/s42358-021-00176-6
12.  Irwin MR, Olmstead R, Carroll JE. Sleep disturbance, sleep duration, and inflammation: a systematic review and meta-analysis of cohort studies and experimental sleep deprivation. Biol Psychiatry. 2016;80(1):40-52. doi:1016/j.biopsych.2015.05.014
13.  Garland SN, Scurrey SRM, Ploughman M; Health, Lifestyle and Aging with MS Canadian Consortium. Factors associated with poor sleep in older adults with multiple sclerosis. Int J Behav Med. 2017;24(6):937-945. doi:1007/s12529-017-9653-4
14.  Marrie RA, Reider N, Cohen J, et al. A systematic review of the incidence and prevalence of sleep disorders and seizure disorders in multiple sclerosis. Mult Scler. 2015;21(3):342-349. doi:1177/1352458514564486
15.  Foschi M, Rizzo G, Liguori R, et al. Sleep-related disorders and their relationship with MRI findings in multiple sclerosis. Sleep Med. 2019;56:90-97. doi:1016/j.sleep.2019.01.010
16.  Cederberg KLJ, Jeng B, Saski JE, Braley TJ, Walters AS, Motl RW. Restless legs syndrome and health-related quality of life in adults with multiple sclerosis. J Sleep Res. 2020;29(3):e12880. doi:1111/jsr.12880
17.  Foster RG. Sleep, circadian rhythms and health. Interface Focus. 2020;10(3):20190098. doi:1098/rsfs.2019.0098
18.  Becker B, Raymond K, Hawkes C, et al. Qualitative and psychometric approaches to evaluate the PROMIS pain interference and sleep disturbance item banks for use in patients with rheumatoid arthritis. J Patient Rep Outcomes. 2021;5(1):52. doi:1186/s41687-021-00318-w
19.  Son CN, Choi G, Lee SY, et al. Sleep quality in rheumatoid arthritis, and its association with disease activity in a Korean population. Korean J Intern Med.2015;30(30):384-390. doi:3904/kjim.2015.30.3.384
20.  Sariyildiz MA, Batmaz I, Bozkurt M, et al. Sleep quality in rheumatoid arthritis: relationship between the disease severity, depression, functional status and the quality of life. J Clin Med Res. 2014;6(1):44-52. doi:4021/jocmr1648w
21.  Zhang L, Shen B, Liu S. Rheumatoid arthritis is associated with negatively variable impacts on domains of sleep disturbances: evidence from a systematic review and meta-analysis. Psychol Health Med. 2021;26(3):267-277. doi:1080/13548506.2020.1764597
22.  Siengsukon C, Karahan AY, Strober L. Practical sleep information for people with multiple sclerosis. Arch Phys Med Rehabil. 2020;101(7):1271-1274. doi:1016/j.apmr.2020.03.009
23.  Karimi S, Jalilian M, Abdi A, Khazaie H, Sarbarzeh PA. Surveying sleep quality and fatigue in multiple sclerosis patients at a multiple sclerosis center in Kermanshah, Iran, in 2017. Neurobiol Sleep Circadian Rhythms. 2020;8:100050. doi:1016/j.nbscr.2020.100050
24.  Bahmani DS, Gonzenbach R, Motl RW, et al. Better objective sleep was associated with better subjective sleep and physical activity; results from an exploratory study under naturalistic conditions among persons with multiple sclerosis. Int J Environ Res Public Health. 2020;17(10):3522. doi:3390/ijerph17103522
25.  Akbarfahimi M, Nabavi SM, Kor B, Rezaie L, Paschall E. The effectiveness of occupational therapy-based sleep interventions on quality of life and fatigue in patients with multiple sclerosis: a pilot randomized clinical trial study. Neuropsychiatr Dis Treat. 2020;16:1369-1379. doi:2147/ndt.s249277
26.  Deane KD, Demoruelle MK, Kelmenson LB, Kuhn KA, Norris JM, Holers VM. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2017;31(1):3-18. doi:1016/j.berh.2017.08.003