Main Article Content
Primary immunodeficiency diseases, Common Variable immunodeficiency, epigenetic, microRNA, T cell deficiency
Background: Common variable immunodeficiency (CVID) is one of the most prevalent forms of primary immunodeficiency diseases (PID). CVID is characterized by failure in the final differentiation of B lymphocytes and impaired antibody production but the pathogenesis is not known in the majority of patients. We postulated that the expression pattern of miRNAs in unsolved CVID patients might be the underlying epigenetic cause of the disease. Therefore, we aimed to assess the expression of hsa-miR-210-5p and FOXP3 transcription factor in CVID cases in comparison with healthy individuals.
Methods: Eleven CVID cases with no genetic defects (all PID known genes excluded) and 10 sex and age-matched healthy individuals were enrolled in the study. T lymphocytes were purified from PBMC, and expression levels of miR-210-5p and FOXP3 mRNA were evaluated by real-time PCR.
Results: We demonstrated that miR-210 expression in patients was significantly higher than the control group (P = 0.03). FOXP3 expression was slightly lower in patients compared with healthy controls (P = 0.86). There was a negative correlation between miR and gene expression (r: −0.11, P = 0.73). Among various clinical complications, autoimmunity showed a considerable rate in high-miR patients (P = 0.12, 42.8%), while autoimmunity was not observed in normal miR-210 patients.
Conclusions: Our results suggest a role for miR-210 in the pathogenesis of autoimmunity in CVID patients. Further studies would better elucidate epigenetic roles in CVID patients with no genetic defects.
2. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry working definitions for the clinical diagnosis of inborn errors of immunity. J Allergy Clin Immunol Pract. 2019;7(6):1763–1770. https://doi.org/10.1016/j. jaip.2019.02.004
3. Azizi G, Abolhassani H, Asgardoon MH, Rahnavard J, Dizaji MZ, Yazdani R, et al. The use of immunoglobulin therapy in primary immunodeficiency diseases. Endocr Metab Immune Disord Drug Targets. 2016;16(2):80–88. https://doi.org/10.2174 /1871530316666160724214418
4. Abolhassani H, Aghamohammadi A, Fang M, Rezaei N, Jiang C, Liu X, et al. Clinical implications of systematic phenotyping and exome sequencing in patients with primary antibody deficiency. Genet Med. 2019;21(1):243–251. https://doi.org/ 10.1038/s41436-018-0012-x
5. Bonilla FA, Barian I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, et al. International Consensus Document (ICON): common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4(1):38–59. https:// doi.org/10.1016/j.jaip.2015.07.025
6. Rae W. Indications to epigenetic dysfunction in the pathogenesis of common variable immunodeficiency. Arch Immunol Ther.Exp (Warsz.) 2017;65(2):101–110. https://doi.org/10.1007/s00005-016-0414-x
7. Pagani M, Rossetti G, Panzeri I, de Candia P, Bonnal RJ, Rossi RL, et al. Role of microRNAs and long-noncoding RNAs in CD4(+) T-cell differentiation. Immunol Rev. 2013;253(1):82– 96. https://doi.org/10.1111/imr.12055
8. Belver L, Papavasiliou FN, Ramiro AR. MicroRNA control of lymphocyte differentiation and function. Curr Opin Immunol. 2011;23(3):368–373. https://doi.org/10.1016/j.coi.2011.02. 001
9. Dooley J, Linterman MA, Liston A. MicroRNA regulation of T-cell development. Immunol Rev. 2013;253(1):53–64. https:// doi.org/10.1111/imr.12049
10. O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol. 2010;10(2):111–122. https:// doi.org/10.1038/nri2708
11. Rodriguez-Cortez VC, Del Pino-Molina L, Rodriguez-Ubreva J, Ciudad L, Gomez-Cabrero D, Company C, et al. Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naive-to-memory B-cell transition. Nat Commun. 2015;6:7335. https://doi. org/10.1038/ncomms8335
12. Del Pino-Molina L, Rodriguez-Ubreva J, Torres Canizales J, Coronel-Diaz M, Kulis M, Martin- Subero JI, et al. Impaired CpG demethylation in common variable immunodeficiency associates with B cell phenotype and proliferation rate. Front Immunol. 2019;10:878. https://doi.org/10.3389/fimmu.2019. 00878
13. Martinez-Cano J, Campos-Sanchez E, Cobaleda C. Epigenetic priming in immunodeficiencies. Front Cell Dev Biol. 2019;7:125. https://doi.org/10.3389/fcell.2019.00125
14. Abolhassani H, Kiaee F, Tavakol M, Chavoshzadeh Z, Mahdaviani SA, Momen T, et al. Fourth update on the Iranian National Registry of primary immunodeficiencies: integration of molecular diagnosis. J Clin Immunol. 2018;38(7):816–832. https://doi.org/10.1007/s10875-018-0556-1
15. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human inborn errors of immunity: 2019 Update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40(1):24–64. https://doi.org/10.1007/s10875-019-00737-x https://doi.org/10.1007/s10875-020-00763-0
16. Itan Y, Casanova JL. Novel primary immunodeficiency candidate genes predicted by the human gene connectome. Front Immunol. 2015;6:142. https://doi.org/10.3389/fimmu. 2015.00142
17. Azizi G, Mirshafiey A, Abolhassani H, Yazdani R, Jafarnezhad-Ansariha F, Shaghaghi M, et al. Circulating helper T-Cell subsets and regulatory T cells in patients with common variable immunodeficiency without known monogenic disease. J Invest Allerg Clin Immunol. 2018;28(3):172–181. https://doi.org/10.18176/ jiaci.0231
18. Aghamohammadi A, Abolhassani H, Moazzami K, Parvaneh N, Rezaei N. Correlation between common variable immunodeficiency clinical phenotypes and parental consanguinity in children and adults. J Invest Allerg Clin Immunol. 2010;20(5): 372–379.
19. Patuzzo G, Barbieri A, Tinazzi E, Veneri D, Argentino G, Moretta F, et al. Autoimmunity and infection in common vari-able immunodeficiency (CVID). Autoimmun Rev. 2016;15(9):877– 882. https://doi.org/10.1016/j.autrev.2016.07.011
20. Oksenhendler E, Gerard L, Fieschi C, Malphettes M, Mouillot G, Jaussaud R, et al. Infections in 252 patients with common variable immunodeficiency. Clin Infect Dis. 2008; 46(10):1547– 1554.
21. Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112(2):277–286. https://doi.org/10.1182/blood-2007-11-124545
22. Salavoura K, Kolialexi A, Tsangaris G, Mavrou A. Development of cancer in patients with primary immunodeficiencies. Anticancer Res. 2008;28(2B):1263–1269. Retrieved from http:// http://ar.iiarjournals.org/
23. Hippen KL, Loschi M, Nicholls J, MacDonald KPA, Blazar BR. Effects of microRNA on regulatory T cells and implications for adoptive cellular therapy to ameliorate graft-versus-host disease. Front Immunol. 2018;9:57. https://doi.org/10.3389/ fimmu.2018.00057
24. Bavelloni A, Ramazzotti G, Poli A, Piazzi M, Focaccia E, Blalock W, et al. MiRNA-210: a current overview. Anticancer Res. 2017;37(12):6511–6521. https://doi.org/10.21873/anticanres.12107
25. Camps C, Buffa FM, Colella S, Moore J, Sotiriou C, Sheldon H, et al. hsa-miR-210 Is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin Cancer Res. 2008;14(5):1340–1348. https://doi.org/10.1158/1078-0432. CCR-07-1755
26. Wang J, Zhao J, Shi M, Ding Y, Sun H, Yuan F, et al. Elevated expression of miR-210 predicts poor survival of cancer patients: a systematic review and meta-analysis. PLoS one. 2014;9(2):e89223. https://doi.org/10.1371/journal.pone.0089223
27. Greither T, Grochola LF, Udelnow A, Lautenschlager C, Wurl P, Taubert H. Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival. Int J Cancer. 2010;126(1):73–80. https://doi.org/10.1002/ijc.24687
28. Zhao A, Li G, Peoc’h M, Genin C, Gigante M. Serum miR-210 as a novel biomarker for molecular diagnosis of clear cell renal cell carcinoma. Exp Mol Pathol. 2013;94(1):115–120. https:// doi.org/10.1016/j.yexmp.2012.10.005
29. Wu R, Zeng J, Yuan J, Deng X, Huang Y, Chen L, et al. MicroRNA-210 overexpression promotes psoriasis-like inflammation by inducing Th1 and Th17 cell differentiation. J Clin Invest. 2018;128(6):2551–2568. https://doi.org/10.1172/JCI97426
30. Long CM, Lukomska E, Marshall NB, Nayak A, Anderson SE. Potential inhibitory influence of miRNA 210 on regulatory T cells during epicutaneous chemical sensitization. Genes. 2017;8(1):9. https://doi.org/10.3390/genes8010009
31. Huang X, Zuo J. Emerging roles of miR-210 and other non-coding RNAs in the hypoxic response. Acta Biochim Biophys Sin. 2014;46(3):220–232. https://doi.org/10.1093/abbs/gmt141
32. Yang Y, Zhang J, Xia T, Li G, Tian T, Wang M, et al. MicroRNA-210 promotes cancer angiogenesis by targeting fibroblast growth factor receptor-like 1 in hepatocellular car-cinoma. Oncol Reports. 2016;36(5):2553–2562. https://doi.org/10.3892/or.2016.5129
33. Varzaneh FN, Keller B, Unger S, Aghamohammadi A, Warnatz K, Rezaei N. Cytokines in common variable immunodeficiency as signs of immune dysregulation and potential therapeutic targets – a review of the current knowledge. J Clin Immunol. 2014;34(5):524–543. https://doi.org/10.1007/s10875-014-0053-0
34. Fayyad-Kazan H, Rouas R, Fayyad-Kazan M, Badran R, El Zein N, Lewalle P, et al. MicroRNA profile of circulating CD4-positive regulatory T cells in human adults and impact of dif-ferentially expressed microRNAs on expression of two genes essential to their function. J Biol Chem. 2012;287(13):9910– 9922. https://doi.org/10.1074/jbc.M111.337154
35. Genre J, Errante PR, Kokron CM, Toledo-Barros M, Camara NO, Rizzo LV. Reduced frequency of CD4(+)CD25(HIGH) FOXP3(+) cells and diminished FOXP3 expression in patients with Common Variable Immunodeficiency: a link to autoimmunity? Clin Immunol (Orlando, FL). 2009;132(2):215–221. https://doi.org/10.1016/j.clim.2009.03.519
36. Zhao M, Wang LT, Liang GP, Zhang P, Deng XJ, Tang Q, et al. Up-regulation of microRNA-210 induces immune dysfunction via targeting FOXP3 in CD4(+) T cells of psoriasis vulgaris. Clin Immunol (Orlando, FL). 2014;150(1):22–30. https://doi. org/10.1016/j.clim.2013.10.009
37. Xie Z, Chang C, Zhou Z. Molecular mechanisms in autoimmune type 1 diabetes: a critical review. Clin Rev Allergy Immunol. 2014;47(2):174–192. https://doi.org/10.1007/s12016-014-8428-9 https://doi.org/10.1007/s12016-014-8422-2
38. Huang Q, Chen SS, Li J, Tao SS, Wang M, Leng RX, et al. miR-210 expression in PBMCs from patients with systemic lupus erythematosus and rheumatoid arthritis. Ir J Med Sci. 2018;187(1):243–249. https://doi.org/10.1007/s11845-017-1634-8
39. Zheng L, Zhuang C, Wang X, Ming L. Serum miR-146a, miR-155, and miR-210 as potential markers of Graves’ disease. J Clin Lab Anal. 2018;32(2):e22266. https://doi.org/10.1002/jcla.22266
40. Azizi G, Rezaei N, Kiaee F, Tavakolinia N, Yazdani R, Mirshafiey A, et al. T-Cell abnormalities in common variable immunodeficiency. J Invest Allerg Clin Immunol. 2016;26(4):233– 243. https://doi.org/10.18176/jiaci.0069