Airways therapy of obstructive sleep apnea dramatically improves aberrant levels of soluble cytokines involved in autoimmune disease (original) (raw)
Section snippets
Protein abbreviations
APRIL, TNFSF13, Tumor Necrosis Factor Superfamily Member 13. BAFF, TNFSF13B, B-Cell Activating Factor. CD30, TNFRSF8, CD30L, Tumor Necrosis Factor Receptor Superfamily Member 8. CD163 CD163. Chitinase 3-like 1 CHI3L1. CXCR5 CXCR5. CXCL13, CXCL13. HIF1A, HIF1A, Hypoxia Inducible Factor 1 alpha. IL-2, IL2, IL2, T Cell Growth Factor Interleukin 2**.** IFN-Alpha-2, IFNA2, Interferon Alpha 2. Endothelin 1, EDN1, Preproendothelin-1. IFN-Gamma, IFNG. IL-6, IL6, Interleukin 6, B-Cell Stimulatory Factor.
Patient data
Nineteen OSA patients had formerly been diagnosed using polysomnography (PSG) based on their Apnea Hypopnea Index (AHI > 5), but were currently receiving nightly airways therapy and were designated airways treated OSA patients. Eighteen of these recorded using CPAP, while patient #31 reported using a dental airways device [8]. There were 19 OSA patients currently with apnea, but not receiving airways therapy. Also 8 Control individuals were recruited, but among these, patient #9 was borderline
Patients
Cytokine levels were examined in the serum of nineteen OSA patients receiving airways therapy (airways treated patients, Table 1) and compared to nineteen OSA patients not receiving airways therapy and a group of volunteers without OSA (control individuals). Table 1 summarizes important biometric, sleep and laboratory data for the three groups of subjects with details presented in Supplemental Data Files SD1.
Assaying changes in serum cytokine levels
We found the levels of four cytokines with previously reported rolls in autoimmunity
Discussion
Sleep apnea is highly associated with increased risk of various autoimmune diseases. Three cytokines, TNF-Alpha, IL-17, and IL-6, that are positively associated with autoimmune disorders are often elevated in OSA patients and decreased in response to airways therapy. Herein, and fitting this pattern, we find the levels of APRIL were relatively high in apneic patients, but were significantly reduced by airways therapy. Airways therapy did not reduce APRIL all the way to the very low levels
Conclusions
The low levels of CD30, IL-2 and IFN-Alpha-2 we observed in OSA patients contrasted with expectations of increase in their expression based on previous direct or indirect evidence linking their elevated expression with acute hypoxia. APRIL levels were higher in OSA patients than in airways treated OSA patients, but the link between APRIL expression and hypoxia experienced by OSA has not been suggested in previous literature. Perhaps the chronic intermittent hypoxia experienced for months and
Compliance with ethical standards
Yes.
Funding
This project, RBM, SA, and BGP were supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002378 and the University of Georgia's Clinical and Translational Research Unit. YW, HC, and PM were supported by NSF grants DMS 1925066, NSF grants DMS 1903226, and NIH grants R01 GM122080. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National
Author contributions
YW managed the data sets in Excel and prepared all the figures in R in collaboration with RBM and PM. RBM focused the project on cytokines involved in autoimmunity, managed the technical aspects of the project, and wrote the manuscript with input from the team. SA prepared all the serum samples and ran the BioPlex assays. PM directed YW in the statistical analysis of the data. BGP conceived of and initiated the study of OSA and airways treated OSA patients, defined the patient recruitment
Consent for publication
Yes.
Declaration of Competing Interest
The authors have no financial or ethical conflicts of interest that might influence the publication of this work.
Acknowledgements
The authors would like to thank David Hall of the University of Georgia and Nick Pervolarakis of UC Irvine for their help with the statistical data and Julie Nelson for her help running the BioPlex Instrument at UGA's Cytometry Shared Resource Laboratory and MaryAnne DellaFera for her careful reading of an early draft of the manuscript.
References (114)
- et al.
Quality of life consequences of sleep-disordered breathing
J. Allergy Clin. Immunol.
(1997)
- C.P. Ward et al.
Spatial learning and memory deficits following exposure to 24 h of sleep fragmentation or intermittent hypoxia in a rat model of obstructive sleep apnea
Brain Res.
(2009)
- J.H. Kang et al.
Obstructive sleep apnea and the risk of autoimmune diseases: a longitudinal population-based study
Sleep Med.
(2012)
- C.S. Masarsky
Hypoxic stress: a risk factor for post-concussive hypopituitarism?
Med. Hypotheses
(2018)
- Y.W. Yang et al.
Increased risk of psoriasis following obstructive sleep apnea: a longitudinal population-based study
Sleep Med.
(2012)
- B. Abrams
Long-term sleep apnea as a pathogenic factor for cell-mediated autoimmune disease
Med. Hypotheses
(2005)
- M. Vakil et al.
The complex associations between obstructive sleep apnea and auto-immune disorders: a review
Med. Hypotheses
(2018)
- E. Toubi et al.
Innate immune-responses and their role in driving autoimmunity
Autoimmun. Rev.
(2019)
- Z. Dorkova et al.
Effects of continuous positive airway pressure on cardiovascular risk profile in patients with severe obstructive sleep apnea and metabolic syndrome
Chest
(2008)
- M. Thangarajh et al.
Increased levels of APRIL (a proliferation-inducing ligand) mRNA in multiple sclerosis
J. Neuroimmunol.
(2005)
- E.Y. Kim et al.
Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines
Cytokine
(2017)
- L. Baert et al.
The role of APRIL - a proliferation inducing ligand - in autoimmune diseases and expectations from its targeting
J. Autoimmun.
(2018)
- F. Mackay et al.
The role of the BAFF/APRIL system on T cell function
Semin. Immunol.
(2006)
- K. Shinoda et al.
CD30 ligand is a new therapeutic target for central nervous system autoimmunity
J. Autoimmun.
(2015)
- H. Arai et al.
Changes in work performances in obstructive sleep apnea patients after dental appliance therapy
Psychiatry Clin. Neurosci.
(1998)
- T.A. Omachi et al.
Obstructive sleep apnea: a risk factor for work disability
Sleep
(2009)
- S.M. Rajaratnam et al.
Sleep disorders, health, and safety in police officers
JAMA
(2011)
- CDC
Sleep and Sleep Disorders: Data and Statistics
- J. Kostrzewa-Janicka et al.
Mandibular advancement appliance for obstructive sleep Apnea treatment
Adv. Exp. Med. Biol.
(2017)
- S. Cantore et al.
Evaluation of an oral appliance in patients with mild to moderate obstructive sleep apnea syndrome intolerant to continuous positive airway pressure use: preliminary results
Int. J. Immunopathol. Pharmacol.
(2016)
- C. Fava et al.
Obstructive sleep apnea syndrome and cardiovascular diseases
Semin. Thromb. Hemost.
(2011)
- Q.R. Huang et al.
Clinical patterns of obstructive sleep apnea and its comorbid conditions: a data mining approach
J. Clin. Sleep Med.
(2008)
- G. Jean-Louis et al.
Obstructive sleep apnea and cardiovascular disease: role of the metabolic syndrome and its components
J. Clin. Sleep Med.
(2008)
- B.G. Phillips et al.
Hypertension and obstructive sleep apnea
Curr. Hypertens. Rep.
(2003)
- P. Samson et al.
Clinical characteristics, comorbidities, and response to treatment of veterans with obstructive sleep apnea, Cincinnati veterans affairs medical Center, 2005-2007
Prev. Chronic Dis.
(2012)
- J.C. Yu et al.
Sleep Apnea and Obesity. S D Med Spec no:28–34
- M.S. Blattner et al.
Sleep disturbances are common in patients with autoimmune encephalitis
J. Neurol.
(2019)
- Y.H. Hsiao et al.
Sleep disorders and increased risk of autoimmune diseases in individuals without sleep apnea
Sleep
(2015)
- S.R. Sangle et al.
Autoimmune rheumatic disease and sleep: a review
Curr. Opin. Pulm. Med.
(2015)
- M. Purabdollah et al.
Relationship between sleep disorders, pain and quality of life in patients with rheumatoid arthritis
J. Caring Sci.
(2015)
- K.J. Tien et al.
Obstructive sleep apnea and the risk of atopic dermatitis: a population-based case control study
PLoS One
(2014)
- G. Shalom et al.
Psoriasis and obstructive sleep apnea
Int. J. Dermatol.
(2016)
- J.M. Cohen et al.
Sleep disordered breathing and the risk of psoriasis among US women
Arch. Dermatol. Res.
(2015)
- A.E. Mirrakhimov
Obstructive sleep apnea and autoimmune rheumatic disease: is there any link?
Inflamm. Allergy Drug Targets
(2013)
- T.V. Serebrovskaya et al.
Intermittent hypoxia in childhood: the harmful consequences versus potential benefits of therapeutic uses
Front. Pediatr.
(2015)
- P. Sadiku et al.
Hypoxia and the regulation of myeloid cell metabolic imprinting: consequences for the inflammatory response
EMBO Rep.
(2019)
- C. Jing et al.
Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis
Proc. Natl. Acad. Sci. U. S. A.
(2020)
- Z. Liu et al.
IFN-alpha confers resistance of systemic lupus erythematosus nephritis to therapy in NZB/W F1 mice
J. Immunol.
(2011)
- E. Andreakos
Targeting cytokines in autoimmunity: new approaches, new promise
Expert. Opin. Biol. Ther.
(2003)
- E.V. Loftus
Biologic therapy in Crohn’s disease: review of the evidence
Rev. Gastroenterol. Disord.
(2007)
- A. Ambrosi et al.
IL-17: a new actor in IFN-driven systemic autoimmune diseases
Eur. J. Immunol.
(2012)
- J. Tabarkiewicz et al.
The role of IL-17 and Th17 lymphocytes in autoimmune diseases
Arch. Immunol. Ther. Exp.
(2015)
- T. Kuwabara et al.
The role of IL-17 and related cytokines in inflammatory autoimmune diseases
Mediat. Inflamm.
(2017)
- T. Tanaka et al.
IL-6 in inflammation, immunity, and disease
Cold Spring Harb. Perspect. Biol.
(2014)
- C. Ding et al.
Targeting IL-6 in the treatment of inflammatory and autoimmune diseases
Expert Opin. Investig. Drugs
(2009)
- T. Kishimoto et al.
IL-6: A New Era for the treatment of autoimmune inflammatory diseases
- L. Kheirandish-Gozal et al.
Obstructive sleep Apnea and inflammation: proof of concept based on two illustrative cytokines
Int. J. Mol. Sci.
(2019)
- A. Hegglin et al.
Eight months of continuous positive airway pressure (CPAP) decrease tumor necrosis factor alpha (TNFA) in men with obstructive sleep apnea syndrome
Sleep Breath.
(2012)
- Y.Q. Jiang et al.
Efficacy of continuous positive airway pressure treatment in treating obstructive sleep apnea hypopnea syndrome associated with carotid arteriosclerosis
Exp. Ther. Med.
(2017)
- F. Jin et al.
Effect of continuous positive airway pressure therapy on inflammatory cytokines and atherosclerosis in patients with obstructive sleep apnea syndrome
Mol. Med. Rep.
(2017)
Cited by (5)
2024, Sleep Medicine Reviews
If the risks of these disorders are high, closer examination by a sleep specialist/physician must be undertaken and treatments considered if a firm diagnosis is established. We underline that in the case of OSA, a recent study found that airway therapy for obstructive sleep apnea was effective in decreasing levels of several cytokines involved in JIA (TNF-α, IL-6, IL-17), drawing interest in sleep disorder treatments as a key step toward the management of JIA [72]. However, in children with JIA, effects of OSA treatments, with continuous positive airway pressure (CPAP) or adenoidectomy and tonsillectomy, on underlying inflammatory pathogenesis are scarce.
2023, Cell Reports Methods
More broadly, t-SNE and UMAP use can be implemented in cases where the cell is not the individual unit. For example, using people as the individual unit, high-dimensional data such as immune response,24 genomic variation,25 or microbiome composition26 can drive the algorithm. The cross entropy test would then allow statistical comparison of disparate groups (e.g., based on disease state) to identify differences in the underlying data.
© 2021 Published by Elsevier Inc.