Comparison of Expression Levels of miR-29b-3p and miR-326 in T Helper-1 and T Helper-17 Cells Isolated from Responsive and Non-responsive Relapsing-remitting Multiple Sclerosis Patients Treated with Interferon-beta
T helper type 1 (Th1) and Th17 Cells with distinct cytokine profiles including interferon-gamma (IFN-γ) and interleukin 17 (IL-17) have a pivotal role in neuroinflammation and myelin destruction in the central nervous system (CNS) in MS. MicroRNA-29b (MiR-29b) and miR-326 contribute to regulating Th1 and Th17 differentiation and altered expression of the miRNAs could be associated with response to treatment in multiple sclerosis (MS). Therefore, our study aimed to evaluate the percentage of Th1 and Th17 and determining the expression levels of miR-29b-3p and miR-326 in these lymphocyte subpopulations between responsive and non-responsive to interferon beta (IFN-β) therapy in relapsing-remitting multiple sclerosis (RRMS) patients.
The present study was performed on 40 RRMS patients following treatment with IFN-β. The percentage of Th1 cells and Th17 cells were determined by flow cytometry in responsive and non-responsive patients. The expression levels of miR-29b-3p and miR-326 were assessed in Th1 and Th17 cells by quantitative polymerase chain reaction (PCR). Enzyme-linked immunosorbent assay (ELISA) was applied to evaluate the plasma levels of IFN-γ and IL-17A.
No significant difference was observed in the percentage of Th1 and Th17 cells as well as the expression levels of miR-29b-3p and miR-326 (in Th1 and Th17, respectively) in treated patients. Also, we did not find any significant difference in IFN-γ and IL-17A plasma concentration between responsive or non-responsive to IFN-β therapy in patients with RRMS.
IFN-β may regulate other miRNAs in Th1 and Th17 cells than miR29b-3p and miR-326 in MS patients.
2. Frohmann E RM, Raine CS. Multiple sclerosisthe plaque and its pathogenesis. N Engl J Med. 2006;354:14.
3. Lassmann H, Bruck W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol. 2007;17(2):210-8.
4. Confavreux C, Vukusic S. The clinical course of multiple sclerosis. Handb Clin Neurol. 2014;122:343-69.
5. Lovett-Racke AE, Yang Y, Racke MK. Th1 versus Th17: are T cell cytokines relevant in multiple sclerosis? Biochim Biophys Acta. 2011;1812(2):246-51.
6. Du C, Liu C, Kang J, Zhao G, Ye Z, Huang S, et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol. 2009;10(12):1252-9.
7. Smith KM, Guerau-de-Arellano M, Costinean S, Williams JL, Bottoni A, Mavrikis Cox G, et al. miR-29ab1 deficiency identifies a negative feedback loop controlling Th1 bias that is dysregulated in multiple sclerosis. J Immunol. 2012;189(4):1567-76.
8. Chen C, Zhou Y, Wang J, Yan Y, Peng L, Qiu W. Dysregulated MicroRNA Involvement in Multiple Sclerosis by Induction of T Helper 17 Cell Differentiation. FrontImmunol. (2018);9:1256.
9. Honardoost MA, Kiani-Esfahani A, Ghaedi K, Etemadifar M, Salehi M. miR-326 and miR-26a, two potential markers for diagnosis of relapse and remission phases in patient with relapsing-remitting multiple sclerosis. Gene. 2014;544(2):128-33.
10. Azimi M, Ghabaee M, Naser Moghadasi A, Izad M. Altered Expression of miR-326 in T Cell-derived Exosomes of Patients with Relapsing-remitting Multiple Sclerosis. Iran J Allergy Asthma Immunol. 2018;(1):108-113.
11. Axtell RC, Raman C, Steinman L. Interferon-beta exacerbates Th17-mediated inflammatory disease. Trends Immunol. 2011;32(6):272-7.
12. Axtell RC, Raman C, Steinman L. Type I interferons: beneficial in Th1 and detrimental in Th17 autoimmunity. Clin Rev Allergy Immunol. 2013;44(2):114-20.
13. Martin-Saavedra FM, Gonzalez-Garcia C, Bravo B, Ballester S. Beta interferon restricts the inflammatory potential of CD4+ cells through the boost of the Th2 phenotype, the inhibition of Th17 response and the prevalence of naturally occurring T regulatory cells. Mol Immunol. 2008;45(15):4008-19.
14. Arellano G, Acuna E, Reyes LI, Ottum PA, De Sarno P, Villarroel L, et al. Th1 and Th17 Cells and Associated Cytokines Discriminate among Clinically Isolated Syndrome and Multiple Sclerosis Phenotypes. Front Immunol. 2017;8:753.
15. Patel N, Rao VA, Heilman-Espinoza ER, Lai R, Quesada RA, Flint AC. Simple and reliable determination of the modified Rankin Scale in neurosurgical and neurological patients: The mRS-9Q.Neurosurgery.2012; 71 (5): 971–5.
16. Hyun, JW, Kim, SH, Jeong, IH,et al.Utility of the Rio score and modified Rio score in Korean patients with multiple sclerosis. PLoS ONE 2015; 10(5).
17. Otaegui, D., Baranzini, S. E., Armañanzas, R., Calvo, B., et al. Differential micro RNA expression in PBMC from multiple sclerosis patients.PloS one.2009; 4(7): 6309.
18. Fattahi M, Sotoodehnejadnematalahi F, Shaygannejad V, Kazemi M. Comparison of The Expression of miR-326 between Interferon beta Responders and Non-Responders in Relapsing-Remitting Multiple Sclerosis. Cell. 2020;22(1):4.
19. Axtell RC, de Jong BA, Boniface K, van der Voort LF, Bhat R, De Sarno P, et al. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med. 2010;16(4):406-12.
20. Galligan CL ea. Interferon-beta is a key regulator of pro inflammatory events in experimental autoimmune encephalomyelitis. Mult Scler. 2010;16(12):16.
21. Pender MP. Does Epstein-Barr virus infection in the brain drive the development of multiple sclerosis? Brain. 2009;132(12):3196-8.
22. Shimizu Y, Yokoyama K, Misu T, Takahashi T, Fujihara K, Kikuchi S, et al. Development of extensive brain lesions following interferon beta therapy in relapsing neuromyelitis optica and longitudinally extensive myelitis. J Neurol. 2008;255(2):305-7.
23. van der Pouw Kraan TC, Wijbrandts CA, van Baarsen LG, Voskuyl AE, Rustenburg F, Baggen JM, et al. Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann Rheum Dis. 2007;66(8):1008-14.
24. Wang AG, Lin YC, Wang SJ, Tsai CP, Yen MY. Early relapse in multiple sclerosis-associated optic neuritis following the use of interferon beta-1a in Chinese patients. Jpn J Ophthalmol. 2006;50(6):537-42.
25. Warabi Y, Matsumoto Y, Hayashi H. Interferon beta-1b exacerbates multiple sclerosis with severe optic nerve and spinal cord demyelination. J Neurol Sci. 2007;252(1):57-61.
26. 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-beta. Ann Neurol. 2009;65(5):499-509.
27. Ramgolam VS, Sha Y, Jin J, Zhang X, Markovic-Plese S. IFN-beta inhibits human Th17 cell differentiation. J Immunol. 2009;183(8):5418-27.
28. Hecker M, Thamilarasan M, Koczan D, Schroder I, Flechtner K, Freiesleben S, et al. MicroRNA expression changes during interferon-beta treatment in the peripheral blood of multiple sclerosis patients. Int J Mol Sci. 2013;14(8):16087-110.
29. Fattahi M, Rezaei N, Nematalahi FS, Shaygannejad V, Fouladi S, Karimi L, et al. MicroRNA-29b variants and MxA expression change during interferon beta therapy in patients with relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 2019;35:241-5.
30. Waschbisch A, Atiya M, Linker RA, Potapov S, Schwab S, Derfuss T. Glatiramer acetate treatment normalizes deregulated microRNA expression in relapsing remitting multiple sclerosis. PLoS One. 2011;6(9):e24604.
31. Taheri M1,Ghafouri-Fard, Solgi, Sayad, Mazdeh, Omrani. Determination of cytokine levels in multiple sclerosis patients and their relevance with patients' response to Cinnovex. Cytokine. 2017;96:138-143.
32. Alexander JS, Harris MK, Wells SR, Mills G, Chalamidas K, Ganta VC, et al. Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-beta1b. Mult Scler. 2010;16(7):801-9.
33. Kurtuncu M, Tuzun E, Turkoglu R, Petek-Balci B, Icoz S, Pehlivan M, et al. Effect of short-term interferon-beta treatment on cytokines in multiple sclerosis: significant modulation of IL-17 and IL-23. Cytokine. 2012;59(2):400-2.
34. Hartung HP, Steinman L, Goodin DS, Comi G, Cook S, Filippi M, et al. Interleukin 17F level and interferon beta response in patients with multiple sclerosis. JAMA Neurol. 2013;70(8):1017-21.
35. Bushnell SE ZZ, Stebbins CC, et al. Serum IL-17F does not predict poor response to IM IFNβ-1a in relapsing-remitting MS. Neurology. 2012;79(6):7.
36. Haak S, Croxford AL, Kreymborg K, Heppner FL, Pouly S, Becher B, et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J Clin Invest. 2009;119(1):61-9.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.