Evaluation of MicroRNA-125b-5p and Transcription Factors BLIMP1 and IRF4 Expression in Unsolved Common Variable Immunodeficiency Patients
Common variable immunodeficiency (CVID) is the most prevalent form of symptomatic primary humoral immunodeficiencies characterized by failure in the final differentiation of B lymphocytes. The majority of CVID cases have no identified genetic defect, and epigenetic alteration could be involved in the pathogenesis of CVID. Hence, we aimed to evaluate the expression of hsa-miR-125b-5p -and, B lymphocyte-induced maturation protein-1(BLIMP-1) and interferon regulatory protein-4 (IRF-4) in a group of CVID patients with no definitive genetic diagnosis in comparison with healthy individuals.
Ten CVID patients (all known genes excluded) and 10 age and sex-matched healthy controls participated in the study. B lymphocytes were isolated and expression of miR-125b-5p, IRF4, and BLIMP1 were evaluated by real-time polymerase chain reaction (RT-PCR). Moreover, B cell subsets were analyzed by flow cytometry.
The results showed that the relative expression of miR-125b-5p in CVID patients was increased while it was decreased for the BLIMP1 and IRF4 transcription factors compared with the healthy controls. Although a reduction was observed in switched and non-switched memory B cells among all high-miR patients, these subsets were decreased in patients with normal miR expression (71.0% and 85.0%, respectively).
Our results suggest that overexpression of miR-125b-5p affects the terminal differentiation of B cells in a selected group of CVID patients by downregulating the BLIMP-1 gene and more intensively for the IRF-4 gene expressions.
2. Ganjalikhani-Hakemi M, Yazdani R, Esmaeili M, Abolhassani H, Rae W, Azizi G, et al. Role of Apoptosis in the Pathogenesis of Common Variable Immunodeficiency (CVID). Endocr Metab Immune Disord Drug Targets. 2017;17(4):332-40.
3. Abolhassani H, Sagvand BT, Shokuhfar T, Mirminachi B, Rezaei N, Aghamohammadi A. A review on guidelines for management and treatment of common variable immunodeficiency. Expert Rev Clin Immunol. 2013;9(6):561-74; quiz 75.
4. 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 Investig Allergol Clin Immunol. 2018;28(3):172-81.
5. Rae W. Indications to Epigenetic Dysfunction in the Pathogenesis of Common Variable Immunodeficiency. Arch Immunol Ther Exp (Warsz). 2017;65(2):101-10.
6. 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):243-51.
7. Abolhassani H, Hammarström L, Cunningham-Rundles C. Current genetic landscape in common variable immune deficiency. Blood. 2020;135(9):656-67.
8. Li G, Zan H, Xu Z, Casali P. Epigenetics of the antibody response. Trends Immunol. 2013;34(9):460-70.
9. Coffre M, Koralov SB. miRNAs in B Cell Development and Lymphomagenesis. Trends Mol Med. 2017;23(8):721-36.
10. Zhang J, Jima DD, Jacobs C, Fischer R, Gottwein E, Huang G, et al. Patterns of microRNA expression characterize stages of human B-cell differentiation. Blood. 2009;113(19):4586-94.
11. Yazdani R, Seify R, Ganjalikhani-Hakemi M, Abolhassani H, Eskandari N, Golsaz-Shirazi F, et al. Comparison of various classifications for patients with common variable immunodeficiency (CVID) using measurement of B-cell subsets. Allergol Immunopathol (Madr). 2017;45(2):183-92.
12. Bao Y, Cao X. Epigenetic Control of B Cell Development and B-Cell-Related Immune Disorders. Clin Rev Allergy Immunol. 2016;50(3):301-11.
13. Gururajan M, Haga CL, Das S, Leu CM, Hodson D, Josson S, et al. MicroRNA 125b inhibition of B cell differentiation in germinal centers. Int Immunol. 2010;22(7):583-92.
14. Malumbres R, Sarosiek KA, Cubedo E, Ruiz JW, Jiang X, Gascoyne RD, et al. Differentiation stage-specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas. Blood. 2009;113(16):3754-64.
15. Tsai DY, Hung KH, Lin IY, Su ST, Wu SY, Chung CH, et al. Uncovering MicroRNA Regulatory Hubs that Modulate Plasma Cell Differentiation. Sci Rep. 2015;5(1):17957.
16. Rodríguez-Cortez VC, Del Pino-Molina L, Rodríguez-Ubreva J, Ciudad L, Gómez-Cabrero D, Company C, et al. Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition. Nat Commun. 2015;6:7335.
17. Del Pino-Molina L, Rodríguez-Ubreva J, Torres Canizales J, Coronel-Díaz M, Kulis M, Martín-Subero JI, et al. Impaired CpG Demethylation in Common Variable Immunodeficiency Associates With B Cell Phenotype and Proliferation Rate. Front Immunol. 2019;10:878.
18. 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.
19. Itan Y, Casanova JL. Novel primary immunodeficiency candidate genes predicted by the human gene connectome. Front Immunol. 2015;6:142.
20. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120(1):15-20.
21. Wang X. miRDB: a microRNA target prediction and functional annotation database with a wiki interface. Rna. 2008;14(6):1012-7.
22. Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 2006;34(Database issue):D140-4.
23. Azizi G, Abolhassani H, Kiaee F, Tavakolinia N, Rafiemanesh H, Yazdani R, et al. Autoimmunity and its association with regulatory T cells and B cell subsets in patients with common variable immunodeficiency. Allergol Immunopathol (Madr). 2018;46(2):127-35.
24. 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):816-32.
25. Yazdani R, Abolhassani H, Kiaee F, Habibi S, Azizi G, Tavakol M, et al. Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort. J Allergy Clin Immunol Pract. 2019;7(3):864-78.e9.
26. Azizi G, Pouyani MR, Abolhassani H, Sharifi L, Dizaji MZ, Mohammadi J, et al. Cellular and molecular mechanisms of immune dysregulation and autoimmunity. Cell Immunol. 2016;310:14-26.
27. Habibi S, Zaki-Dizaji M, Rafiemanesh H, Lo B, Jamee M, Gámez-Díaz L, et al. Clinical, Immunologic, and Molecular Spectrum of Patients with LPS-Responsive Beige-Like Anchor Protein Deficiency: A Systematic Review. J Allergy Clin Immunol Pract. 2019;7(7):2379-86.e5.
28. Ahn S, Cunningham-Rundles C. Role of B cells in common variable immune deficiency. Expert Rev Clin Immunol. 2009;5(5):557-64.
29. Blanco E, Pérez-Andrés M, Arriba-Méndez S, Serrano C, Criado I, Del Pino-Molina L, et al. Defects in memory B-cell and plasma cell subsets expressing different immunoglobulin-subclasses in patients with CVID and immunoglobulin subclass deficiencies. J Allergy Clin Immunol. 2019;144(3):809-24.
30. Yazdani R, Fatholahi M, Ganjalikhani-Hakemi M, Abolhassani H, Azizi G, Hamid KM, et al. Role of apoptosis in common variable immunodeficiency and selective immunoglobulin A deficiency. Mol Immunol. 2016;71(8):1-9.
31. Yazdani R, Ganjalikhani-Hakemi M, Esmaeili M, Abolhassani H, Vaeli S, Rezaei A, et al. Impaired Akt phosphorylation in B-cells of patients with common variable immunodeficiency. Clin Immunol. 2017;175(5):124-32.
32. Indrevær RL, Moskaug J, Paur I, Bøhn SK, Jørgensen SF, Blomhoff R, et al. IRF4 Is a Critical Gene in Retinoic Acid-Mediated Plasma Cell Formation and Is Deregulated in Common Variable Immunodeficiency-Derived B Cells. J Immunol. 2015;195(6):2601-11.
33. Sciammas R, Shaffer AL, Schatz JH, Zhao H, Staudt LM, Singh H. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity. 2006;25(2):225-36.
34. Taubenheim N, von Hornung M, Durandy A, Warnatz K, Corcoran L, Peter HH, et al. Defined blocks in terminal plasma cell differentiation of common variable immunodeficiency patients. J Immunol. 2005;175(8):5498-503.
35. Afshar-Ghasemlou S, Esmaeil N, Sherkat R, Yazdani R, Abbasi-Rad F, Ganjalikhani-Hakemi M, et al. Increased IRF4 expression in isolated B cells from common variable immunodeficiency (CVID) patients. Allergol Immunopathol (Madr). 2019;47(1):52-9.
36. Farrokhi S, Abbasi-Rad F, Esmaeil N, Sherkat R, Yazdani R, Afshar-Ghasemlou S, et al. Increased Expression of B Lymphocyte Induced Maturation Protein 1 (BLIMP1) in Patients with Common Variable Immunodeficiency (CVID). Iran J Allergy Asthma Immunol. 2020;19(4):437-46.
37. Kramer NJ, Wang WL, Reyes EY, Kumar B, Chen CC, Ramakrishna C, et al. Altered lymphopoiesis and immunodeficiency in miR-142 null mice. Blood. 2015;125(24):3720-30.
|Issue||Vol 20 No 6 (2021)|
|Common Variable Immunodeficiency Epigenesis MicroRNAs Primary immunodeficiency diseases;|
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