Predictive Significance of Interleukins 17A and 33 in Risk of Relapsing–Remitting Multiple Sclerosis

Main Article Content

Milad Abdul Salam Al-Naseri
Ali Hussein Ad’hiah
https://orcid.org/0000-0002-2445-2242
Ehab Dawood Salman
https://orcid.org/0000-0002-2997-4154

Abstract

Cytokines are signaling molecules between inflammatory cells that play a significant role in the pathogenesis of a disease. Among these cytokines are interleukins (ILs) 17A and 33, and accordingly, the current case-control study sought to investigate the role of each of the two cytokines in the risk of developing multiple sclerosis (MS). Sixty-eight relapsing-remitting MS (RRMS) Iraqi patients and twenty healthy individuals (control group) were enrolled. Enzyme linked immunosorbent assay (ELISA) kits were used to determine serum levels of IL-17A and IL-33. Results revealed that IL-17A and IL-33 levels were significantly higher in MS patients than in controls (14.1 ± 4.5 vs. 7.5 ± 3.8 pg/mL; p < 0.001 and 65.3 ± 16.3 vs. 49.3 ± 20.0 pg/mL; p < 0.001, respectively). Receiver operating characteristic (ROC) curve analysis demonstrated that IL-17A was a very good predictor of MS (area under curve [AUC] = 0.869; 95% CI = 0.779 - 0.960; p < 0.001; cut-off value = 10.2 pg/mL; sensitivity = 80.8%; specificity = 75.0%). A similar prediction was presented by IL-33, but the AUC value was lower (AUC = 0.762; 95% CI = 0.63 - 0.89; p < 0.001; cut-off value = 56.4 pg/mL; sensitivity = 70.6%; specificity = 70.0%). Multinomial logistic regression analysis confirmed the significance of IL-17A and IL-33 in MS risk, and under three models of analysis, the estimated odds ratios for IL-17A (1.50, 1.49 and 1.50, respectively) and IL-33 (1.05, 1.05 and 1.06) were above 1.0. Patients stratified by gender (male and female), expanded disability status scale (EDSS: < 3 and ≥ 3) or medication (pre- and post-medication) showed no significant differences in serum levels of IL-17A and IL-33 for each stratum. However, with regard to response to medication, it was found that responding patients showed significantly higher levels of IL-33 than non-responders (70.9 ± 12.2 vs. 57.2 ± 18.2 pg/mL; p = 0.018). This difference was not observed when considering IL-17A. Pearson correlation analysis between IL-17A and IL-33 revealed that both cytokines were not significantly correlated. In conclusion, the study indicated that IL-17A and IL-33 were up-regulated in serum of MS patients, and this up-regulation was not influenced by age, gender, EDSS or medication status, but the elevated level of IL-33 was more pronounced in patients who responded to medication.

Article Details

How to Cite
1.
Predictive Significance of Interleukins 17A and 33 in Risk of Relapsing–Remitting Multiple Sclerosis. Baghdad Sci.J [Internet]. 2022 Dec. 1 [cited 2024 Mar. 28];19(6):1191. Available from: https://bsj.uobaghdad.edu.iq/index.php/BSJ/article/view/6431
Section
article
Author Biography

Ali Hussein Ad’hiah, Tropical-Biological Research Unit, College of Science, University of Baghdad, Baghdad, Iraq

Tropical-Biological Research Unit, College of Science, University of
 Baghdad, Iraq

How to Cite

1.
Predictive Significance of Interleukins 17A and 33 in Risk of Relapsing–Remitting Multiple Sclerosis. Baghdad Sci.J [Internet]. 2022 Dec. 1 [cited 2024 Mar. 28];19(6):1191. Available from: https://bsj.uobaghdad.edu.iq/index.php/BSJ/article/view/6431

References

Vidal-Jordana A, Montalban X. Multiple Sclerosis: Epidemiologic, Clinical, and Therapeutic Aspects. Neuroimaging Clin N Am. 2017 May 1;27(2):195–204. [accessed 21 Aug 2021] Available from: https://pubmed.ncbi.nlm.nih.gov/28391781/

Yamout BI, Alroughani R. Multiple Sclerosis. Semin Neurol. 2018 Apr 1; 38(2): 212–25. [accessed 21 Aug 2021] Available from: https://pubmed.ncbi.nlm.nih.gov/29791948/

Wang K, Song F, Fernandez-Escobar A, Luo G, Wang JH, Sun Y. The Properties of Cytokines in Multiple Sclerosis: Pros and Cons. Am J Med Sci. 2018 Dec 1; 356(6): 552–60. [accessed 21 Aug 2021] Available from: https://pubmed.ncbi.nlm.nih.gov/30447707/

Zhang F, Tossberg JT, Spurlock CF, Yao SY, Aune TM, Sriram S. Expression of IL-33 and its epigenetic regulation in multiple sclerosis. Ann Clin Transl Neurol. 2014 May 1; 1(5): 307–18. [accessed 21 Aug 2021] Available from: https://pubmed.ncbi.nlm.nih.gov/25215310/

Kolbinger F, Huppertz C, Mir A, Padova F. IL-17A and Multiple Sclerosis: Signaling Pathways, Producing Cells and Target Cells in the Central Nervous System. Curr Drug Targets. 2016 Mar 8; 17(16): 1882–93. [accessed 21 Aug 2021] Available from: https://pubmed.ncbi.nlm.nih.gov/26953244/

Chen K, Kolls JK. Interluekin-17A (IL17A). Gene. 2017 May 30; 614: 8–14. [accessed 21 Aug 2021] Available from: /pmc/articles/PMC5394985/

Milovanovic J, Arsenijevic A, Stojanovic B, Kanjevac T, Arsenijevic D, Radosavljevic G, et al. Interleukin-17 in Chronic Inflammatory Neurological Diseases. Front Immunol. 2020 Jun 3; 11: 947. [accessed 21 Aug 2021] Available from: /pmc/articles/PMC7283538/

Barin JG, Baldeviano GC, Talor M V., Wu L, Ong S, Quader F, et al. Macrophages participate in IL-17-mediated inflammation. Eur J Immunol. 2012 Mar; 42(3): 726–36. [accessed 21 Aug 2021] Available from: /pmc/articles/PMC4292791/

Chen J, Liu X, Zhong Y. Interleukin-17A: The Key Cytokine in Neurodegenerative Diseases. Front Aging Neurosci. 2020 Sep 29; 12: 566922. [accessed 21 Aug 2021] Available from: /pmc/articles/PMC7550684/

Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, et al. Multiple sclerosis. Nat Rev Dis Prim. 2018 Nov 8; 4(1): 1–27. [accessed 21 Aug 2021] Available from: https://www.nature.com/articles/s41572-018-0041-4

Vasanthakumar A, Kallies A. Interleukin (Il)-33 and the il-1 family of cytokines—regulators of inflammation and tissue homeostasis. Cold Spring Harb Perspect Biol. 2019 Mar 1; 11(3): a028506. [accessed 21 Aug 2021] Available from: http://cshperspectives.cshlp.org/content/11/3/a028506.full

Cayrol C, Girard JP. Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family. Immunol Rev. 2018 Jan 1; 281(1): 154–68. [accessed 21 Aug 2021] Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/imr.12619

Pei C, Barbour M, Fairlie-Clarke KJ, Allan D, Mu R, Jiang HR. Emerging role of interleukin-33 in autoimmune diseases. Immunology. 2014 Jan; 141(1): 9–17. [accessed 21 Aug 2021] Available from: /pmc/articles/PMC3893845/

Gautier V, Cayrol C, Farache D, Roga S, Monsarrat B, Burlet-Schiltz O, et al. Extracellular IL-33 cytokine, but not endogenous nuclear IL-33, regulates protein expression in endothelial cells. Sci Rep. 2016 Oct 3; 6(1): 1–12. [accessed 21 Aug 2021] Available from: https://www.nature.com/articles/srep34255

Molofsky AB, Savage AK, Locksley RM. Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation. Immunity. NIH Public Access. 2015; 42: 1005–19. [accessed 21 Aug 2021] Available from: /pmc/articles/PMC4471869/

Liu X, Xiao Y, Pan Y, Li H, Zheng SG, Su W. The role of the IL-33/ST2 axis in autoimmune disorders: Friend or foe? Cytokine Growth Factor Rev. 2019 Dec 1; 50: 60–74. [accessed 21 Aug 2021] Available from: https://pubmed.ncbi.nlm.nih.gov/31085085/

Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 Revisions to the ‘McDonald Criteria’. Ann Neurol. 2005; 58(6): 840–6. [accessed 21 Aug 2021] Available from: https://pubmed.ncbi.nlm.nih.gov/16283615/

Kallaur AP, Oliveira SR, Simao ANC, De Almeida ERD, Morimoto HK, Lopes J, et al. Cytokine profile in relapsing-remitting Multiple sclerosis patients and the association between progression and activity of the disease. Mol Med Rep. 2013 Mar 1; 7(3): 1010–20. [accessed 21 Aug 2021] Available from: http://www.spandidos-publications.com/10.3892/mmr.2013.1256/abstract

Meyer-Moock S, Feng YS, Maeurer M, Dippel FW, Kohlmann T. Systematic literature review and validity evaluation of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) in patients with multiple sclerosis. BMC Neurol. 2014 Mar 25; 14(1): 58. [accessed 21 Aug 2021] Available from: https://pubmed.ncbi.nlm.nih.gov/24666846/

Fluss R, Faraggi D, Reiser B. Estimation of the Youden Index and its associated cutoff point. Biometrical J. 2005 Aug; 47(4): 458–72. [accessed 21 Aug 2021] Available from: https://pubmed.ncbi.nlm.nih.gov/16161804/

Babaloo Z, Aliparasti MR, Babaiea F, Almasi S, Baradaran B , Farhoudi F. The role of Th17 cells in patients with relapsing-remitting multiple sclerosis: interleukin-17A and interleukin-17F serum levels. Immunol Lett. 2015; 164(2): 76-80. doi: 10.1016/j.imlet.2015.01.001.

Schofield C, Fischer SK, Townsend MJ, Mosesova S, Peng K , Setiadi AF, et al. Characterization of IL-17AA and IL-17FF in rheumatoid arthritis and multiple sclerosis . Bioanalysis. 2016 Nov; 8: 22, 2317-27.

Ashtari F, Madanian R, Shaygannejad V, Zarkesh SH, Ghadimi K. Serum levels of IL-6 and IL-17 in multiple sclerosis, neuromyelitis optica patients and healthy subjects. Int J Physiol Pathophysiol Pharmacol. 2019 Dec; 11(6): 267-73.

Bălaşa R, Bajko Z, Huţanu A. Serum levels of IL-17A in patients with relapsing-remitting multiple sclerosis treated with interferon-β. Mult Scler. 2013; 19(7): 885-90. doi: 10.1177/1352458512468497.

Matusevicius D, Kivisäkk P, He B, Kostulas N, Ozenci V, Fredrikson S, et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mul Scler. 1999 Apr; 5(2): 101-4.doi: 10.1177/135245859900500206.

Setiadi AF, Abbas AR, Jeet S, Wong K, Bischof A, Peng I, et al. IL-17A is associated with the breakdown of the blood-brain barrier in relapsing-remitting multiple sclerosis. J Neuroimmunol. 2019 Jul; 15 (332): 147-54. doi: 10.1016/j.jneuroim.2019.04.011.

Durelli L, Conti L, Clerico M, Boselli D, Contessa G, Ripellino P, et al. T-Helper 17 Cells Expand in Multiple Sclerosis and Are Inhibited by Interferon-β. Ann Neurol. 2009 May; 65(5): 499–509. doi: 10.1002/ana.21652.

Jafarzadeh A, Mahdavi R, Jamali M, Hajghani H, Nemati M, Ebrahimi H-A. Increased Concentrations of Interleukin-33 in the Serum and Cerebrospinal Fluid of Patients with Multiple Sclerosis. Oman Med J. 2016 Jan; 31(1): 40–5. https://doi.org/10.5001/omj.2016.08

Kouchaki E, Tamtaji OR, Dadgostar E, Karami M, Nikoueinejad H, Akbari H. Correlation of Serum Levels of IL-33, IL-37, Soluble Form of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), and Circulatory Frequency of VEGFR2-expressing Cells with Multiple Sclerosis Severity. Iran J Allergy Asthma Immunol. 2017 Aug; 16(4): 329-37.

Ahmadi M, Fathi F, Fouladi S, Alsahebfosul F, Manian M, Eskandari N. Serum IL-33 Level and IL-33, IL1RL1 Gene Polymorphisms in Asthma and Multiple Sclerosis Patients. Curr Mol Med. 2019; 19(5): 357-63. doi: 10.2174/1566524019666190405120137.

Mado H, Adamczyk-Sowa M, Bartman W, Wierzbicki K, Tadeusiak B, Sowa P. Plasma Interleukin-33 level in relapsing-remitting multiple sclerosis. Is it negatively correlated with central nervous system lesions in patients with mild disability? Clin Neurol Neurosurg. 2021 Jul; 206: 106700. doi: 10.1016/j.clineuro.2021.106700.

Christophi GP, Gruber RC, Panos M, Christophi RL, Jubelt B, Massa PT. Interleukin-33 upregulation in peripheral leukocytes and CNS of multiple sclerosis patients. Clin Immunol. 2012 Mar; 142(3): 308-19. doi: 10.1016/j.clim.2011.11.007.

Alsahebfosoul F, Rahimmanesh I, Shajarian M, Etemadifar M, Sedaghat N, Hejazi Z, et al. Interleukin-33 plasma levels in patients with relapsing-remitting multiple sclerosis. Biomol Concepts. 2017 Mar; 8(1): 55-60. doi: 10.1515/bmc-2016-0026.

Similar Articles

You may also start an advanced similarity search for this article.