Immune dysregulation in long covid may contribute to the development of neurological disorders through the effects of cytokines
https://doi.org/10.22328/2077-9828-2024-16-4-7-16
Abstract
Aim of the study: to investigate the role of proinflammatory markers and some immune cells in neural and cognitive disorders in long COVID patients.
Materials and methods. The study included 81 patients diagnosed with long COVID, the presence of which was determined by the persistence of a complex of multidirectional symptoms for more than 12 weeks that developed during or after COVID-19. Flow cytometry was used to assess lymphocyte subsets. The main lymphocyte subpopulations were analyzed: T cells, cytotoxic T cells, B cells, NK and NKT cells in blood plasma via multiplex xMAP analysis. Also concentrations of GM-CSF, IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12, IL-13, IL-17, MCP-1, MIP-1b, TNF were measured. The content of proinflammatory cytokines and some immune system cells was characterized in respondents with long COVID. A comparative analysis of data was conducted with individuals without a history of COVID-19, as well as between patients with different numbers of SARS-CoV-2 cases.
Results and discussion. The study identified characteristic features of long COVID that affect both the nervous and immune systems.
Analysis of the blood cells revealed absolute and relative lymphopenia due to a decrease in NK cells. We also noticed an increased number of NKT cells in patients who suffered multiple COVID-19, when compared to those who only were infected with SARS-CoV-2 once. Cytokine analysis revealed increase in concentrations of IL-5, IL-8, IL-13, IL-17 and CCL2/MCP1 in blood plasma of long COVID patients.
Conclusion. The data provides additional support to the theory of immune dysregulation in neurological symptoms of long COVID.
About the Authors
V. V. RassokhinRussian Federation
St. Pеtеrsburg
N. A. Arsentieva
Russian Federation
St. Pеtеrsburg
Z. R. Korobova
Russian Federation
St. Pеtеrsburg
N. E. Lyubimova
Russian Federation
St. Pеtеrsburg
O. K. Batsunov
Russian Federation
St. Pеtеrsburg
E. V. Boeva
Russian Federation
St. Pеtеrsburg
A. A. Knizhnikova
Russian Federation
St. Pеtеrsburg
A. O. Norka
Russian Federation
St. Pеtеrsburg
N. B. Khalezova
Russian Federation
St. Pеtеrsburg
N. A. Belyakov
Russian Federation
St. Pеtеrsburg
References
1. Consequences of the COVID-19 pandemic / edited by N. A. Belyakov and S. F. Bagnenko. St. Petersburg: Baltic Medical Educational Center, 2023. 464 p.: ill. (In Russ.)]
2. Desforges M., Le Coupanec A., Dubeau P. et al. Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System? // Viruses. 2019. Vol. 12, No. 1. Р. 14. Published 2019 Dec 20. doi: 10.3390/v12010014.
3. Matyushkina D., Shokina V., Tikhonova P. et al. Autoimmune Effect of Antibodies against the SARS-CoV-2 Nucleoprotein // Viruses. 2022. Vol. 14, No. 6. Р. 1141. Published 2022 May 25. doi: 10.3390/v14061141.
4. Lee M.H., Perl D.P., Steiner J. et al. Neurovascular injury with complement activation and inflammation in COVID-19 // Brain. 2022. Vol. 145, No. 7. Р. 2555–2568. doi: 10.1093/brain/awac151.
5. DeMaio A., Mehrotra S., Sambamurti K., Husain S. The role of the adaptive immune system and T cell dysfunction in neurodegenerative diseases // J. Neuroinflammation. 2022. Vol. 19, No. 1. Р. 251. Published 2022 Oct 8. doi: 10.1186/s12974-022-02605-9.
6. Chen J., Liu X., Zhong Y. Interleukin-17A: The key cytokine in neurodegenerative diseases // Front Aging. Neurosci. 2020. Vol. 12. Р. 566922. doi: 10.3389/fnagi.2020.566922.
7. Belyakov N.A., Rassokhin V.V., Totolyan N.A. et al. Delayed mental, neurological and somatic disorders associated with COVID-19. HIV Infection and Immunosuppressive Disorders, 2023, Vol. 15, No. 4, рр. 53–62 (In Russ.)]. https://doi.org/10.22328/2077-9828-2023-15-4-53-62.
8. Belyakov N.A., Bagnenko S.F., Rassokhin V.V., Trofimova T.N. et al. Evolution of the COVID-19 pandemic / еd. by N. A. Belyakov and S. F. Bagnenko. St. Petersburg: Baltic Medical Educational Center, 2021. 410 p. (In Russ.)].
9. Varghese J., Sandmann S., Ochs K. et al. Persistent symptoms and lab abnormalities in patients who recovered from COVID-19 // Sci. Rep. 2021. Vol. 11. Р. 12775. https://doi.org/10.1038/s41598-021-91270-8,
10. Shouman S., El-Kholy N., Hussien A.E. et al. SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147 // Cell Commun Signal. 2024. Vol. 22. Р. 349. https://doi.org/10.1186/s12964-024-01718-3.
11. Dobrynina M.A., Zurochka A.V., Komelkova M.V., Luo S. Impairment of natural killer populations in the patients recovered from COVID-19. Russian Journal of Immunology, 2022, Vol. 25, Nо. 2, рр. 161–166 (In Russ.)]. doi: 10.46235/1028-7221-1132-ION.
12. Lee M.J., Blish C.A. Defining the role of natural killer cells in COVID-19 // Nat. Immunol. 2023. Vol. 24, No. 10. Р. 1628–1638. doi: 10.1038/s41590-023-01560-8.
13. Wu L., Van Kaer L. Natural killer T cells in health and disease // Front. Biosci (Schol Ed). 2011. Vol. 3, No. 1. Р. 236–251. Published 2011 Jan 1. doi: 10.2741/s148.
14. Nikolouli E., Mommert S., Dawodu D.M. et al. The stimulation of TH2 cells results in increased IL-5 and IL-13 production via the H4 receptor // Allergy. 2024. Vol. 79, No. 8. Р. 2186–2196. doi: 10.1111/all.16182.
15. Greenfeder S., Umland S.P., Cuss F.M. et al. Th2 cytokines and asthma. The role of interleukin-5 in allergic eosinophilic disease // Respir Res. 2001. Vol. 2, No. 2. Р. 71–79. doi: 10.1186/rr41.
16. Ju X., Son K., Jamil R. et al. Eosinophil-independent IL-5 levels are increased in critically ill COVID-19 patients who survive // Allergy Asthma Clin. Immunol. 2023. Vol. 19, No. 1. Р. 58. Published 2023. Jul 4. doi: 10.1186/s13223-023-00810-6.
17. Pala D., Pistis M. Anti-IL5 Drugs in COVID-19 Patients: Role of Eosinophils in SARS-CoV-2-Induced Immunopathology // Front Pharmacol. 2021. Vol. 12. Р. 622554. Published 2021 Mar 9. doi: 10.3389/fphar.2021.622554.
18. Lins C., Borojevic R. Interleukin-5 receptor alpha chain expression and splicing during brain development in mice // Growth Factors. 2001. Vol. 19, No. Р. 145–152. doi: 10.3109/08977190109001082.
19. Elomaa A.P., Niskanen L., Herzig K.H. et al. Elevated levels of serum IL-5 are associated with an increased likelihood of major depressive disorder // BMC Psychiatry. 2012. Vol. 12. Р. 2. Published 2012 Jan 9. doi: 10.1186/1471-244X-12-2.
20. Li S., Olde Heuvel F., Rehman R. et al. Interleukin-13 and its receptor are synaptic proteins involved in plasticity and neuroprotection // Nat. Commun. 2023. Vol. 14, No. 1. Р. 200. Published 2023 Jan 13. doi: 10.1038/s41467-023-35806-8.
21. Mori S., Maher P., Conti B. Neuroimmunology of the Interleukins 13 and 4 // Brain Sci. 2016. Vol. 6, No. 2. Р. 18. Published 2016. Jun 13. doi: 10.3390/brainsci6020018.
22. Maione F., Casillo G.M., Raucci F. et al. Interleukin-17A (IL-17A): A silent amplifier of COVID-19 // Biomed Pharmacother. 2021. Vol. 142. Р. 111980. doi: 10.1016/j.biopha.2021.111980.
23. Queiroz M.A.F., Neves P.F.M.D., Lima S.S. et al. Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome // Front Cell Infect Microbiol. 2022. Vol. 12. Р. 922422. Published 2022 Jun 30. doi: 10.3389/fcimb.2022.922422.
24. Sie C., Korn T., Mitsdoerffer M. Th17 cells in central nervous system autoimmunity // Exp. Neurol. 2014. Vol. 262, Pt A. Р. 18–27. doi: 10.1016/j.expneurol.2014.03.009.
25. Yang L., Guo C., Zhu J. et al. Increased Levels of Pro-Inflammatory and Anti-Inflammatory Cellular Responses in Parkinson’s Disease Patients: Search for a Disease Indicator // Med. Sci. Monit. 2017. Vol. 23. Р. 2972–2978. Published 2017. Jun 18. doi: 10.12659/msm.904240.
26. Mamun-or-Rashid, Roknuzzaman A.S.M., Sarker R. et al. Altered serum interleukin-17A and interleukin-23A levels may be associated with the patho-physiology and development of generalized anxiety disorder // Sci. Rep. 2024. Vol. 14. Р. 15097. https://doi.org/10.1038/s41598-024-66131-9.
27. Korobova Z.R., Arsentieva N.A., Liubimova N.E. et al. A Comparative Study of the Plasma Chemokine Profile in COVID-19 Patients Infected with Different SARS-CoV-2 Variants // Int. J. Mol. Sci. 2022. Vol. 23, No. 16. Р. 9058. Published 2022 Aug 13. doi: 10.3390/ijms23169058.
28. Cesta M.C., Zippoli M., Marsiglia C. et al. The Role of Interleukin-8 in Lung Inflammation and Injury: Implications for the Management of COVID-19 and Hyperinflammatory Acute Respiratory Distress Syndrome // Front Pharmacol. 2022. Vol. 12. Р. 808797. Published 2022 Jan 12. doi: 10.3389/fphar.2021.808797.
29. Giron S.E., Bjurstrom M.F., Griffis Ch.A. et al. Increased Central Nervous System Interleukin-8 in a Majority Postlaminectomy Syndrome Chronic Pain Population // Pain Medicine. 2018. Vol. 19, Issue 5. P. 1033–1043.
30. Tsai S.-J. Role of interleukin 8 in depression and other psychiatric disorders // Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2020. Р. 110173.
31. Shan L.L., Wang Y.L., Qiao T.C et al. Association of Serum Interleukin-8 and Serum Amyloid A With Anxiety Symptoms in Patients With Cerebral Small Vessel Disease // Front Neurol. 2022. Jul 8. Vol. 13. Р. 938655. doi: 10.3389/fneur.2022.938655. PMID: 35923828; PMCID: PMC9341200.
32. Kolotov K.A., Rasputin P.G. Monocytic chemotactic protein-1 in physiology and medicine (review of literature). Perm Medical Journal, 2018, Vol. 35, Nо. 3, рр. 99–105 (In Russ.)]. doi: 10.17816/pmj35399-105.
33. Berentschot J.C., Drexhage H.A., Aynekulu Mersha D.G. et al. Immunological profiling in long COVID: overall low grade inflammation and T-lymphocyte senescence and increased monocyte activation correlating with increasing fatigue severity // Front Immunol. 2023. Oct 10. Vol. 14. Р. 1254899. doi: 10.3389/fimmu.2023.1254899. PMID: 37881427; PMCID: PMC10597688.
34. Zhang K., Wang H., Xu M. et al. Role of MCP-1 and CCR2 in ethanol-induced neuroinflammation and neurodegeneration in the developing brain // J. Neuroinflammation. 2018. Vol. 15, No. 197. https://doi.org/10.1186/s12974-018-1241-2.
Review
For citations:
Rassokhin V.V., Arsentieva N.A., Korobova Z.R., Lyubimova N.E., Batsunov O.K., Boeva E.V., Knizhnikova A.A., Norka A.O., Khalezova N.B., Belyakov N.A. Immune dysregulation in long covid may contribute to the development of neurological disorders through the effects of cytokines. HIV Infection and Immunosuppressive Disorders. 2024;16(4):7-16. (In Russ.) https://doi.org/10.22328/2077-9828-2024-16-4-7-16