Decreased expression of hsa-miR-142-3p and hsa-miR-155-5p in common variable immunodeficiency and involvement of their target genes and biological pathways
Main Article Content
Keywords
common variable immunodeficiency, inborn errors of immunity, epigenetic, microRNA, systems biology
Abstract
Common variable immunodeficiency (CVID) is the most common symptomatic and heterogeneous type of inborn errors of immunity (IEI). However, the pathogenesis process of this disease is often unknown. Epigenetic modifications may be involved in unresolved patients. MiR-142 and miR-155 were identified as immune system modulators and dysregulated in autoimmune and inflammatory diseases. We assessed hsa-miR-142-3p and hsa-miR-155-5p expression in a selected cohort of unresolved CVID cases and identified experimentally validated targets of these miRNAs. We constructed a protein–protein interaction (PPI) network from the common targets of two miRNAs and determined the hub genes. The hub genes’ expression was investigated in GEO datasets. Gene ontology (GO) and pathway enrichment analysis were done for target genes. Hsa-miR-142-3p and hsa-miR-155-5p expression were significantly reduced in CVID patients. Evaluation of the PPI network demonstrated some hub genes in which pathogenic mutations have been reported in IEI, and other hub genes directly contribute to immune responses and the pathophysiology of IEI. Expression analysis of hub genes showed that they were significantly dysregulated in validating the CVID cohort. The pathway enrichment analysis indicated the involvement of the FOXO-mediated signaling pathway, TGFβ receptor complex, and VEGFR2-mediated vascular permeability. Considering the dysregulation of hsa-miR-142-3p and hsa-miR-155-5p in CVID and the known role of their target genes in the immune system, their involvement in the pathogenesis of CVID can be suggested.
References
1 Szczawinska-Poplonyk A, Schwartzmann E, Bukowska-Olech E, Biernat M, Gattner S, Korobacz T, et al. The pediatric common variable immunodeficiency-from genetics to therapy: A review. Eur J Pediatr. 2022:1–13. 10.1007/s00431-021-04287-6
2 Ramirez NJ, Posadas-Cantera S, Caballero-Oteyza A, Camacho-Ordonez N, Grimbacher B. There is no gene for CVID-novel monogenetic causes for primary antibody deficiency. Curr Opin Immunol. 2021;72:176–85. 10.1016/j.coi.2021.05.010
3 Tallmadge RL, Shen L, Tseng CT, Miller SC, Barry J, Felippe MJB. Bone marrow transcriptome and epigenome profiles of equine common variable immunodeficiency patients unveil block of B lymphocyte differentiation. Clin Immunol. 2015;160(2):261–76. 10.1016/j.clim.2015.05.005
4 de Valles-Ibáñez G, Esteve-Sole A, Piquer M, González-Navarro EA, Hernandez-Rodriguez J, Laayouni H, et al. Evaluating the genetics of common variable immunodeficiency: Monogenetic model and beyond. Front immunol. 2018;9:636. 10.3389/fimmu.2018.00636
5 Maffucci P, Filion CA, Boisson B, Itan Y, Shang L, Casanova J-L, et al. Genetic diagnosis using whole exome sequencing in common variable immunodeficiency. Front immunol. 2016;7:220. 10.3389/fimmu.2016.00220
6 Rodríguez-Ubreva J, Arutyunyan A, Bonder MJ, Del Pino-Molina L, Clark SJ, de la Calle-Fabregat C, et al. Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses. Nat Commun. 2022;13(1):1779. 10.1038/s41467-022-29450-x
7 Gareev I, Ramirez ME, Goncharov E, Ivliev D, Shumadalova A, Ilyasova T, et al. MiRNAs and lncRNAs in the regulation of innate immune signaling. Non-coding RNA Research. 2023. 10.1016/j.ncrna.2023.07.002
8 Rae W. Indications to epigenetic dysfunction in the pathogenesis of common variable immunodeficiency. Arch Immunol Ther Exp. 2017;65(2):101–10. 10.1007/s00005-016-0414-x
9 Babaha F, Yazdani R, Shahkarami S, Esfahani ZH, Abolhahassani H, Sadr M, et al. Evaluation of miR-210 expression in common variable immunodeficiency: patients with unsolved genetic defect. Allergol Immunopathol. 2021;49(2):84–93. 10.15586/aei.v49i2.39
10 De Felice B, Nigro E, Polito R, Rossi FW, Pecoraro A, Spadaro G, et al. Differently expressed microRNA in response to the first Ig replacement therapy in common variable immunodeficiency patients. Sci Rep. 2020;10(1):21482. 10.1038/s41598-020-77100-3
11 Esfahani ZH, Yazdani R, Shahkarami S, Babaha F, Abolhassani H, Sadr M, et al. Evaluation of microRNA-125b-5p and transcription factors BLIMP1 and IRF4 expression in unsolved common variable immunodeficiency patients. Iran J Allergy Asthma Immunol. 2021;20(6):700–10. 10.18502/ijaai.v20i6.8021
12 Amato G, Vita F, Quattrocchi P, Minciullo PL, Pioggia G, Gangemi S. Involvement of miR-142 and miR-155 in non-infectious complications of CVID. Mol. 2020;25(20):4760. 10.3390/molecules25204760
13 Gottmann P, Ouni M, Zellner L, Jähnert M, Rittig K, Walther D, et al. Polymorphisms in miRNA binding sites involved in metabolic diseases in mice and humans. Sci Rep. 2020;10(1):7202. 10.1038/s41598-020-64326-4
14 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):1763–70. 10.1016/j.jaip.2019.02.004
15 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. 10.1038/s41436-018-0012-x
16 Bolger AM, Lohse M, Usadel B. Trimmomatic: A flexible trimmer for illumina sequence data. Bioinformatics. 2014;30(15):2114–20. 10.1093/bioinformatics/btu170
17 Li H, Durbin R. Fast and accurate short read alignment with Burrows–Wheeler transform. bioinformatics. 2009;25(14):1754–60. 10.1093/bioinformatics/btp324
18 Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. bioinformatics. 2009;25(16):2078–9. 10.1093/bioinformatics/btp352
19 Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–23. 10.1038/gim.2015.30
20 Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human inborn errors of immunity: 2022 update on the classification from the international union of immunological societies expert committee. J Clin Immunol. 2022;42(7):1473–507. 10.1007/s10875-022-01289-3
21 Hojjati F, Roointan A, Gholaminejad A, Eshraghi Y, Gheisari Y. Identification of key genes and biological regulatory mechanisms in diabetic nephropathy: Meta-analysis of gene expression datasets. Nefrologia. 2023;43(5):575–86. 10.1016/j.nefro.2022.06.003
22 Wong L, Tsang YS, Kenny R, Lyburn M, McMahon LP. MiR-423-5p as optimal endogenous control for quantification of circulating microRNAs in patients With CKD. Kidney Int Rep. 2023;8(10):2150–2. 10.1016/j.ekir.2023.07.018
23 Wang S, Tao R, Ming T, Wang M, Liu J, He G, et al. Expression profile analysis and stability evaluation of 18 small RNAs in the Chinese Han population. Electrophoresis. 2020;41(23):2021–8. 10.1002/elps.202000058
24 Liu X, Zhang L, Cheng K, Wang X, Ren G, Xie P. Identification of suitable plasma-based reference genes for miRNAome analysis of major depressive disorder. J Affect Disord. 2014;163:133–9. 10.1016/j.jad.2013.12.035
25 Guo Y, Zhou X, Gao F, Wang M, Yang Q, Li X, et al. MiR-423-5p is a novel endogenous control for the quantification of circulating miRNAs in human esophageal squamous cell carcinoma. Heliyon. 2023;9(4). 10.1016/j.heliyon.2023.e14515
26 Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, et al. The STRING database in 2011: Functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res. 2010;39(suppl_1):D561–D8. 10.1093/nar/gkq973
27 Chin C-H, Chen S-H, Wu H-H, Ho C-W, Ko M-T, Lin C-Y. CytoHubba: Identifying hub objects and sub-networks from complex interactome. BMC Syst Biol. 2014;8 Suppl 4(Suppl 4): 10.1186/1752-0509-8-S4-S11
28 Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504. 10.1101/gr.1239303
29 Driessen GJ, IJspeert H, Wentink M, Yntema HG, van Hagen PM, van Strien A, et al. Increased PI3K/Akt activity and deregulated humoral immune response in human PTEN deficiency. J Allergy Clin Immunol. 2016;138(6):1744–7. e5. 10.1016/j.jaci.2016.07.010
30 Redmond MT, Scherzer R, Prince BT. Novel genetic discoveries in primary immunodeficiency disorders. Clin Rev Allergy Immunol. 2022;63(1):55–74. 10.1007/s12016-021-08881-2
31 Kantaputra P, Daroontum T, Chuamanochan M, Chaowattanapanit S, Intachai W, Olsen B, et al. Loss of function TGFBR2 variant as a contributing factor in generalized pustular psoriasis and adult-onset immunodeficiency. Genes. 2022;14(1):103. 10.3390/genes14010103
32 Offer SM, Pan-Hammarström Q, Hammarström L, Harris RS. Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID. PLoS One. 2010;5(8):e12260. 10.1371/journal.pone.0012260
33 Körholz J, Gabrielyan A, Sowerby JM, Boschann F, Chen L-S, Paul D, et al. One gene, many facets: Multiple immune pathway dysregulation in SOCS1 haploinsufficiency. Front immunol. 2021;12:680334. 10.3389/fimmu.2021.680334
34 Hashim IF, Mokhtar AMA. Small Rho GTPases and their associated RhoGEFs mutations promote immunological defects in primary immunodeficiencies. Int J Biochem Cell Biol. 2021;137:106034. 10.1016/j.biocel.2021.106034
35 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;34:524–43. 10.1007/s10875-014-0053-0
36 Peng S. Foxo in the immune system. Oncogene. 2008;27(16):2337–44. 10.1038/onc.2008.26
37 McGettrick AF, O’Neill LA. The role of HIF in immunity and inflammation. Cell Metab. 2020;32(4):524–36. 10.1016/j.cmet.2020.08.002
38 Kong S, McBurney MW, Fang D. Sirtuin 1 in immune regulation and autoimmunity. Immunol Cell Biol. 2012;90(1):6–13. 10.1038/icb.2011.102
39 Chen C-Z, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303(5654):83–6. 10.1126/science.1091903
40 Shrestha A, Mukhametshina RT, Taghizadeh S, Vásquez-Pacheco E, Cabrera-Fuentes H, Rizvanov A, et al. MicroRNA-142 is a multifaceted regulator in organogenesis, homeostasis, and disease. Dev Dyn. 2017;246(4):285–90. 10.1002/dvdy.24477
41 Fordham JB, Naqvi AR, Nares S. Regulation of miR-24, miR-30b, and miR-142-3p during macrophage and dendritic cell differentiation potentiates innate immunity. J Leukoc Biol. 2015;98(2):195–207. 10.1189/jlb.1A1014-519RR
42 Mandolesi G, De Vito F, Musella A, Gentile A, Bullitta S, Fresegna D, et al. miR-142-3p is a key regulator of IL-1β-dependent synaptopathy in neuroinflammation. J Neurosci. 2017;37(3):546–61. 10.1523/JNEUROSCI.0851-16.2016
43 Chapnik E, Rivkin N, Mildner A, Beck G, Pasvolsky R, Metzl-Raz E, et al. miR-142 orchestrates a network of actin cytoskeleton regulators during megakaryopoiesis. Elife. 2014;3:e01964. 10.7554/eLife.01964
44 Mildner A, Chapnik E, Manor O, Yona S, Kim K-W, Aychek T, et al. Mononuclear phagocyte miRNome analysis identifies miR-142 as critical regulator of murine dendritic cell homeostasis. Blood. 2013;121(6):1016–27. 10.1182/blood-2012-07-445999
45 Yamada Y, Kosaka K, Miyazawa T, Kurata-Miura K, Yoshida T. miR-142-3p enhances FcεRI-mediated degranulation in mast cells. Biochem Biophys Res Commun. 2014;443(3):980–6. 10.1016/j.bbrc.2013.12.078
46 Talebi F, Ghorbani S, Chan WF, Boghozian R, Masoumi F, Ghasemi S, et al. MicroRNA-142 regulates inflammation and T cell differentiation in an animal model of multiple sclerosis. J Neuroinflammation. 2017;14:1–14. 10.1186/s12974-017-0832-7
47 Kramer NJ, Wang W-L, Reyes EY, Kumar B, Chen C-C, Ramakrishna C, et al. Altered lymphopoiesis and immunodeficiency in miR-142 null mice. Blood, Blood, Am J Hematol Jun 11;125(24):3720-30. doi: 10.1182/blood-2014-10-603951. Epub 2015 Apr 30
48 Graham NM, Wang W-L, Reyes E, Boldin MP. The role of microRNA-142 in B cell activation and effector functions. J Immunol. 2022;208(1_Supplement):168.02-.02. 10.4049/jimmunol.208.Supp.168.02
49 Alivernini S, Gremese E, McSharry C, Tolusso B, Ferraccioli G, McInnes IB, et al. MicroRNA-155-at the critical interface of innate and adaptive immunity in arthritis. Front immunol. 2018;8:1932. 10.3389/fimmu.2017.01932
50 Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, et al. Requirement of bic/microRNA-155 for normal immune function. Science. 2007;316(5824):608–11. 10.1126/science.1139253
51 Seddiki N, Brezar V, Ruffin N, Lévy Y, Swaminathan S. Role of mi R-155 in the regulation of lymphocyte immune function and disease. Immunol. 2014;142(1):32–8. 10.1111/imm.12227
52 Testa U, Pelosi E, Castelli G, Labbaye C. miR-146 and miR-155: Two key modulators of immune response and tumor development. Non-Coding RNA. 2017;3(3):22. 10.3390/ncrna3030022
53 Due H, Svendsen P, Bødker JS, Schmitz A, Bøgsted M, Johnsen HE, et al. miR-155 as a biomarker in B-cell malignancies. Biomed Res Int. 2016;2016. 10.1155/2016/9513037
54 Hu J, Huang S, Liu X, Zhang Y, Wei S, Hu X. miR-155: An important role in inflammation response. J Immunol Res. 2022;2022. 10.1155/2022/7437281
55 Trotta R, Chen L, Ciarlariello D, Josyula S, Mao C, Costinean S, et al. miR-155 regulates IFN-γ production in natural killer cells. Blood. 2012;119(15):3478–85. 10.1182/blood-2011-12-398099
56 Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, Merck E, et al. MicroRNA-155 is required for effector CD8+ T cell responses to virus infection and cancer. Immunity. 2013;38(4):742–53. 10.1016/j.immuni.2012.12.006
57 Calame K. MicroRNA-155 function in B cells. Immunity. 2007;27(6):825–7. 10.1016/j.immuni.2007.11.010
58 Zhang J, Cheng Y, Cui W, Li M, Li B, Guo L. MicroRNA-155 modulates Th1 and Th17 cell differentiation and is associated with multiple sclerosis and experimental autoimmune encephalomyelitis. J Neuroimmunol. 2014;266(1–2):56–63. 10.1016/j.jneuroim.2013.09.019
59 Kim HJ, Park SO, Byeon HW, Eo JC, Choi JY, Tanveer M, et al. T cell-intrinsic miR-155 is required for Th2 and Th17-biased responses in acute and chronic airway inflammation by targeting several different transcription factors. Immunol. 2022;166(3):357–79. 10.1111/imm.13477
60 Sharma S. Immunomodulation: A definitive role of microRNA-142. Dev Comp Immunol. 2017;77:150–6. 10.1016/j.dci.2017.08.001
61 Suzuki A, Kaisho T, Ohishi M, Tsukio-Yamaguchi M, Tsubata T, Koni PA, et al. Critical roles of Pten in B cell homeostasis and immunoglobulin class switch recombination. J Exp Med. 2003;197(5):657–67. 10.1084/jem.20021101
62 He F, Ru X, Wen T. NRF2, a transcription factor for stress response and beyond. Int J Mol Sci. 2020;21(13):4777. 10.3390/ijms21134777
63 Olagnier D, Brandtoft A, Gunderstofte C, Villadsen N, Krapp C, Thielke A, et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 9, 3506. 2018. 10.1038/s41467-018-05861-7
64 Johnston CJ, Smyth DJ, Dresser DW, Maizels RM. TGF-β in tolerance, development and regulation of immunity. Cell Immunol. 2016;299:14–22. 10.1016/j.cellimm.2015.10.006
65 Tamayo E, Alvarez P, Merino R. TGFβ superfamily members as regulators of B cell development and function-implications for autoimmunity. Int J Mol Sci. 2018;19(12):3928. 10.3390/ijms19123928
66 Gardès P, Forveille M, Alyanakian M-A, Aucouturier P, Ilencikova D, Leroux D, et al. Human MSH6 deficiency is associated with impaired antibody maturation. J Immunol. 2012;188(4):2023–9. 10.4049/jimmunol.1102984
67 Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol. 2007;7(6):454–65. 10.1038/nri2093
68 Thaventhiran JE, Lango Allen H, Burren OS, Rae W, Greene D, Staples E, et al. Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature. 2020;583(7814):90–5. 10.1038/s41586-020-2265-1
69 Gerasimčik N, He M, Dahlberg CI, Kuznetsov NV, Severinson E, Westerberg LS. The small Rho GTPases Rac1 and Rac2 are important for T-cell independent antigen responses and for suppressing switching to IgG2b in mice. Front immunol. 2017;8:1264. 10.3389/fimmu.2017.01264
70 Accetta D, Syverson G, Bonacci B, Reddy S, Bengtson C, Surfus J, et al. Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-cell lymphopenia. J Allergy Clin Immunol. 2011;127(2):535–8. e2. 10.1016/j.jaci.2010.10.013
71 Aliyu M, Zohora FT, Anka AU, Ali K, Maleknia S, Saffarioun M, et al. Interleukin-6 cytokine: An overview of the immune regulation, immune dysregulation, and therapeutic approach. Int Immunopharmacol. 2022;111:109130. 10.1016/j.intimp.2022.109130
72 Shen P, Deng X, Chen Z, Ba X, Qin K, Huang Y, et al. SIRT1: A potential therapeutic target in autoimmune diseases. Front immunol. 2021;12:779177. 10.3389/fimmu.2021.779177
73 Ghirotto B, Terra FF, Câmara NOS, Basso PJ. Sirtuins in B lymphocytes metabolism and function. World J Exp Med. 2019;9(1):1. 10.5493/wjem.v9.i1.1
74 Vasudevan S. Posttranscriptional upregulation by microRNAs. Wiley Interdiscip Rev RNA. 2012;3(3):311–30. 10.1002/wrna.121
75 Valinezhad Orang A, Safaralizadeh R, Kazemzadeh-Bavili M. Mechanisms of miRNA-mediated gene regulation from common downregulation to mRNA-specific upregulation. Int J Genomics. 2014;2014. 10.1155/2014/970607
76 Kim ME, Kim DH, Lee JS. Foxo transcription factors: Applicability as a novel immune cell regulators and therapeutic targets in oxidative stress-related diseases. Int J Mol Sci. 2022;23(19):11877. 10.3390/ijms231911877
77 Mertowska P, Mertowski S, Podgajna M, Grywalska E. The Importance of the Transcription Factor Foxp3 in the Development of Primary Immunodeficiencies. J Clin Med. 2022;11(4):947. 10.3390/jcm11040947
78 Yang J, Yan J, Liu B. Targeting VEGF/VEGFR to modulate antitumor immunity. Front immunol. 2018;9:978. 10.3389/fimmu.2018.00978
79 Geindreau M, Ghiringhelli F, Bruchard M. Vascular endothelial growth factor, a key modulator of the anti-tumor immune response. Int J Mol Sci. 2021;22(9):4871. 10.3390/ijms22094871
80 Li Y-L, Zhao H, Ren X-B. Relationship of VEGF/VEGFR with immune and cancer cells: Staggering or forward? Cancer Biol Med. 2016;13(2):206. 10.20892/j.issn.2095-3941.2015.0070
81 Turkowski K, Brandenburg S, Mueller A, Kremenetskaia I, Bungert AD, Blank A, et al. VEGF as a modulator of the innate immune response in glioblastoma. Glia. 2018;66(1):161–74. 10.1002/glia.23234
82 Mimura K, Kono K, Takahashi A, Kawaguchi Y, Fujii H. Vascular endothelial growth factor inhibits the function of human mature dendritic cells mediated by VEGF receptor-2. Cancer Immunol Immunother. 2007;56:761–70. 10.1007/s00262-006-0234-7
83 Li J, Li X-L, Li C-Q. Immunoregulation mechanism of VEGF signaling pathway inhibitors and its efficacy on the kidney. Am J Med Sci. 2023. 10.1016/j.amjms.2023.09.005
84 Tofighi Zavareh F, Mirshafiey A, Yazdani R, Keshtkar AA, Abolhassani H, Bagheri Y, et al. Lymphocytes subsets in correlation with clinical profile in CVID patients without monogenic defects. Expert Rev Clin Immunol. 2021;17(9):1041–51. 10.1080/1744666X.2021.1954908
85 Hücker SM, Fehlmann T, Werno C, Weidele K, Lüke F, Schlenska-Lange A, et al. Single-cell microRNA sequencing method comparison and application to cell lines and circulating lung tumor cells. Nat Commun. 2021;12(1):4316. 10.1038/s41467-021-24611-w
86 Ho V, Baker JR, Willison KR, Barnes PJ, Donnelly LE, Klug DR. Single cell quantification of microRNA from small numbers of non-invasively sampled primary human cells. Communications Biology. 2023;6(1):458. 10.1038/s42003-023-04845-8
87 Friman V, Quinti I, Davydov AN, Shugay M, Farroni C, Engström E, et al. Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations. Cell Rep. 2023;42(5). 10.1016/j.celrep.2023.112446
88 Strohmeier V, Andrieux G, Unger S, Pascual-Reguant A, Klocperk A, Seidl M, et al. Interferon-driven immune dysregulation in common variable immunodeficiency-associated villous atrophy and norovirus infection. J Clin Immunol. 2023;43(2):371–90. 10.1007/s10875-022-01379-2
89 Keller B, Strohmeier V, Harder I, Unger S, Payne KJ, Andrieux G, et al. The expansion of human T-bethighCD21low B cells is T cell dependent. Sci immunol. 2021;6(64):eabh0891.
2 Ramirez NJ, Posadas-Cantera S, Caballero-Oteyza A, Camacho-Ordonez N, Grimbacher B. There is no gene for CVID-novel monogenetic causes for primary antibody deficiency. Curr Opin Immunol. 2021;72:176–85. 10.1016/j.coi.2021.05.010
3 Tallmadge RL, Shen L, Tseng CT, Miller SC, Barry J, Felippe MJB. Bone marrow transcriptome and epigenome profiles of equine common variable immunodeficiency patients unveil block of B lymphocyte differentiation. Clin Immunol. 2015;160(2):261–76. 10.1016/j.clim.2015.05.005
4 de Valles-Ibáñez G, Esteve-Sole A, Piquer M, González-Navarro EA, Hernandez-Rodriguez J, Laayouni H, et al. Evaluating the genetics of common variable immunodeficiency: Monogenetic model and beyond. Front immunol. 2018;9:636. 10.3389/fimmu.2018.00636
5 Maffucci P, Filion CA, Boisson B, Itan Y, Shang L, Casanova J-L, et al. Genetic diagnosis using whole exome sequencing in common variable immunodeficiency. Front immunol. 2016;7:220. 10.3389/fimmu.2016.00220
6 Rodríguez-Ubreva J, Arutyunyan A, Bonder MJ, Del Pino-Molina L, Clark SJ, de la Calle-Fabregat C, et al. Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses. Nat Commun. 2022;13(1):1779. 10.1038/s41467-022-29450-x
7 Gareev I, Ramirez ME, Goncharov E, Ivliev D, Shumadalova A, Ilyasova T, et al. MiRNAs and lncRNAs in the regulation of innate immune signaling. Non-coding RNA Research. 2023. 10.1016/j.ncrna.2023.07.002
8 Rae W. Indications to epigenetic dysfunction in the pathogenesis of common variable immunodeficiency. Arch Immunol Ther Exp. 2017;65(2):101–10. 10.1007/s00005-016-0414-x
9 Babaha F, Yazdani R, Shahkarami S, Esfahani ZH, Abolhahassani H, Sadr M, et al. Evaluation of miR-210 expression in common variable immunodeficiency: patients with unsolved genetic defect. Allergol Immunopathol. 2021;49(2):84–93. 10.15586/aei.v49i2.39
10 De Felice B, Nigro E, Polito R, Rossi FW, Pecoraro A, Spadaro G, et al. Differently expressed microRNA in response to the first Ig replacement therapy in common variable immunodeficiency patients. Sci Rep. 2020;10(1):21482. 10.1038/s41598-020-77100-3
11 Esfahani ZH, Yazdani R, Shahkarami S, Babaha F, Abolhassani H, Sadr M, et al. Evaluation of microRNA-125b-5p and transcription factors BLIMP1 and IRF4 expression in unsolved common variable immunodeficiency patients. Iran J Allergy Asthma Immunol. 2021;20(6):700–10. 10.18502/ijaai.v20i6.8021
12 Amato G, Vita F, Quattrocchi P, Minciullo PL, Pioggia G, Gangemi S. Involvement of miR-142 and miR-155 in non-infectious complications of CVID. Mol. 2020;25(20):4760. 10.3390/molecules25204760
13 Gottmann P, Ouni M, Zellner L, Jähnert M, Rittig K, Walther D, et al. Polymorphisms in miRNA binding sites involved in metabolic diseases in mice and humans. Sci Rep. 2020;10(1):7202. 10.1038/s41598-020-64326-4
14 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):1763–70. 10.1016/j.jaip.2019.02.004
15 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. 10.1038/s41436-018-0012-x
16 Bolger AM, Lohse M, Usadel B. Trimmomatic: A flexible trimmer for illumina sequence data. Bioinformatics. 2014;30(15):2114–20. 10.1093/bioinformatics/btu170
17 Li H, Durbin R. Fast and accurate short read alignment with Burrows–Wheeler transform. bioinformatics. 2009;25(14):1754–60. 10.1093/bioinformatics/btp324
18 Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. bioinformatics. 2009;25(16):2078–9. 10.1093/bioinformatics/btp352
19 Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–23. 10.1038/gim.2015.30
20 Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human inborn errors of immunity: 2022 update on the classification from the international union of immunological societies expert committee. J Clin Immunol. 2022;42(7):1473–507. 10.1007/s10875-022-01289-3
21 Hojjati F, Roointan A, Gholaminejad A, Eshraghi Y, Gheisari Y. Identification of key genes and biological regulatory mechanisms in diabetic nephropathy: Meta-analysis of gene expression datasets. Nefrologia. 2023;43(5):575–86. 10.1016/j.nefro.2022.06.003
22 Wong L, Tsang YS, Kenny R, Lyburn M, McMahon LP. MiR-423-5p as optimal endogenous control for quantification of circulating microRNAs in patients With CKD. Kidney Int Rep. 2023;8(10):2150–2. 10.1016/j.ekir.2023.07.018
23 Wang S, Tao R, Ming T, Wang M, Liu J, He G, et al. Expression profile analysis and stability evaluation of 18 small RNAs in the Chinese Han population. Electrophoresis. 2020;41(23):2021–8. 10.1002/elps.202000058
24 Liu X, Zhang L, Cheng K, Wang X, Ren G, Xie P. Identification of suitable plasma-based reference genes for miRNAome analysis of major depressive disorder. J Affect Disord. 2014;163:133–9. 10.1016/j.jad.2013.12.035
25 Guo Y, Zhou X, Gao F, Wang M, Yang Q, Li X, et al. MiR-423-5p is a novel endogenous control for the quantification of circulating miRNAs in human esophageal squamous cell carcinoma. Heliyon. 2023;9(4). 10.1016/j.heliyon.2023.e14515
26 Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, et al. The STRING database in 2011: Functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res. 2010;39(suppl_1):D561–D8. 10.1093/nar/gkq973
27 Chin C-H, Chen S-H, Wu H-H, Ho C-W, Ko M-T, Lin C-Y. CytoHubba: Identifying hub objects and sub-networks from complex interactome. BMC Syst Biol. 2014;8 Suppl 4(Suppl 4): 10.1186/1752-0509-8-S4-S11
28 Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504. 10.1101/gr.1239303
29 Driessen GJ, IJspeert H, Wentink M, Yntema HG, van Hagen PM, van Strien A, et al. Increased PI3K/Akt activity and deregulated humoral immune response in human PTEN deficiency. J Allergy Clin Immunol. 2016;138(6):1744–7. e5. 10.1016/j.jaci.2016.07.010
30 Redmond MT, Scherzer R, Prince BT. Novel genetic discoveries in primary immunodeficiency disorders. Clin Rev Allergy Immunol. 2022;63(1):55–74. 10.1007/s12016-021-08881-2
31 Kantaputra P, Daroontum T, Chuamanochan M, Chaowattanapanit S, Intachai W, Olsen B, et al. Loss of function TGFBR2 variant as a contributing factor in generalized pustular psoriasis and adult-onset immunodeficiency. Genes. 2022;14(1):103. 10.3390/genes14010103
32 Offer SM, Pan-Hammarström Q, Hammarström L, Harris RS. Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID. PLoS One. 2010;5(8):e12260. 10.1371/journal.pone.0012260
33 Körholz J, Gabrielyan A, Sowerby JM, Boschann F, Chen L-S, Paul D, et al. One gene, many facets: Multiple immune pathway dysregulation in SOCS1 haploinsufficiency. Front immunol. 2021;12:680334. 10.3389/fimmu.2021.680334
34 Hashim IF, Mokhtar AMA. Small Rho GTPases and their associated RhoGEFs mutations promote immunological defects in primary immunodeficiencies. Int J Biochem Cell Biol. 2021;137:106034. 10.1016/j.biocel.2021.106034
35 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;34:524–43. 10.1007/s10875-014-0053-0
36 Peng S. Foxo in the immune system. Oncogene. 2008;27(16):2337–44. 10.1038/onc.2008.26
37 McGettrick AF, O’Neill LA. The role of HIF in immunity and inflammation. Cell Metab. 2020;32(4):524–36. 10.1016/j.cmet.2020.08.002
38 Kong S, McBurney MW, Fang D. Sirtuin 1 in immune regulation and autoimmunity. Immunol Cell Biol. 2012;90(1):6–13. 10.1038/icb.2011.102
39 Chen C-Z, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303(5654):83–6. 10.1126/science.1091903
40 Shrestha A, Mukhametshina RT, Taghizadeh S, Vásquez-Pacheco E, Cabrera-Fuentes H, Rizvanov A, et al. MicroRNA-142 is a multifaceted regulator in organogenesis, homeostasis, and disease. Dev Dyn. 2017;246(4):285–90. 10.1002/dvdy.24477
41 Fordham JB, Naqvi AR, Nares S. Regulation of miR-24, miR-30b, and miR-142-3p during macrophage and dendritic cell differentiation potentiates innate immunity. J Leukoc Biol. 2015;98(2):195–207. 10.1189/jlb.1A1014-519RR
42 Mandolesi G, De Vito F, Musella A, Gentile A, Bullitta S, Fresegna D, et al. miR-142-3p is a key regulator of IL-1β-dependent synaptopathy in neuroinflammation. J Neurosci. 2017;37(3):546–61. 10.1523/JNEUROSCI.0851-16.2016
43 Chapnik E, Rivkin N, Mildner A, Beck G, Pasvolsky R, Metzl-Raz E, et al. miR-142 orchestrates a network of actin cytoskeleton regulators during megakaryopoiesis. Elife. 2014;3:e01964. 10.7554/eLife.01964
44 Mildner A, Chapnik E, Manor O, Yona S, Kim K-W, Aychek T, et al. Mononuclear phagocyte miRNome analysis identifies miR-142 as critical regulator of murine dendritic cell homeostasis. Blood. 2013;121(6):1016–27. 10.1182/blood-2012-07-445999
45 Yamada Y, Kosaka K, Miyazawa T, Kurata-Miura K, Yoshida T. miR-142-3p enhances FcεRI-mediated degranulation in mast cells. Biochem Biophys Res Commun. 2014;443(3):980–6. 10.1016/j.bbrc.2013.12.078
46 Talebi F, Ghorbani S, Chan WF, Boghozian R, Masoumi F, Ghasemi S, et al. MicroRNA-142 regulates inflammation and T cell differentiation in an animal model of multiple sclerosis. J Neuroinflammation. 2017;14:1–14. 10.1186/s12974-017-0832-7
47 Kramer NJ, Wang W-L, Reyes EY, Kumar B, Chen C-C, Ramakrishna C, et al. Altered lymphopoiesis and immunodeficiency in miR-142 null mice. Blood, Blood, Am J Hematol Jun 11;125(24):3720-30. doi: 10.1182/blood-2014-10-603951. Epub 2015 Apr 30
48 Graham NM, Wang W-L, Reyes E, Boldin MP. The role of microRNA-142 in B cell activation and effector functions. J Immunol. 2022;208(1_Supplement):168.02-.02. 10.4049/jimmunol.208.Supp.168.02
49 Alivernini S, Gremese E, McSharry C, Tolusso B, Ferraccioli G, McInnes IB, et al. MicroRNA-155-at the critical interface of innate and adaptive immunity in arthritis. Front immunol. 2018;8:1932. 10.3389/fimmu.2017.01932
50 Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, et al. Requirement of bic/microRNA-155 for normal immune function. Science. 2007;316(5824):608–11. 10.1126/science.1139253
51 Seddiki N, Brezar V, Ruffin N, Lévy Y, Swaminathan S. Role of mi R-155 in the regulation of lymphocyte immune function and disease. Immunol. 2014;142(1):32–8. 10.1111/imm.12227
52 Testa U, Pelosi E, Castelli G, Labbaye C. miR-146 and miR-155: Two key modulators of immune response and tumor development. Non-Coding RNA. 2017;3(3):22. 10.3390/ncrna3030022
53 Due H, Svendsen P, Bødker JS, Schmitz A, Bøgsted M, Johnsen HE, et al. miR-155 as a biomarker in B-cell malignancies. Biomed Res Int. 2016;2016. 10.1155/2016/9513037
54 Hu J, Huang S, Liu X, Zhang Y, Wei S, Hu X. miR-155: An important role in inflammation response. J Immunol Res. 2022;2022. 10.1155/2022/7437281
55 Trotta R, Chen L, Ciarlariello D, Josyula S, Mao C, Costinean S, et al. miR-155 regulates IFN-γ production in natural killer cells. Blood. 2012;119(15):3478–85. 10.1182/blood-2011-12-398099
56 Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, Merck E, et al. MicroRNA-155 is required for effector CD8+ T cell responses to virus infection and cancer. Immunity. 2013;38(4):742–53. 10.1016/j.immuni.2012.12.006
57 Calame K. MicroRNA-155 function in B cells. Immunity. 2007;27(6):825–7. 10.1016/j.immuni.2007.11.010
58 Zhang J, Cheng Y, Cui W, Li M, Li B, Guo L. MicroRNA-155 modulates Th1 and Th17 cell differentiation and is associated with multiple sclerosis and experimental autoimmune encephalomyelitis. J Neuroimmunol. 2014;266(1–2):56–63. 10.1016/j.jneuroim.2013.09.019
59 Kim HJ, Park SO, Byeon HW, Eo JC, Choi JY, Tanveer M, et al. T cell-intrinsic miR-155 is required for Th2 and Th17-biased responses in acute and chronic airway inflammation by targeting several different transcription factors. Immunol. 2022;166(3):357–79. 10.1111/imm.13477
60 Sharma S. Immunomodulation: A definitive role of microRNA-142. Dev Comp Immunol. 2017;77:150–6. 10.1016/j.dci.2017.08.001
61 Suzuki A, Kaisho T, Ohishi M, Tsukio-Yamaguchi M, Tsubata T, Koni PA, et al. Critical roles of Pten in B cell homeostasis and immunoglobulin class switch recombination. J Exp Med. 2003;197(5):657–67. 10.1084/jem.20021101
62 He F, Ru X, Wen T. NRF2, a transcription factor for stress response and beyond. Int J Mol Sci. 2020;21(13):4777. 10.3390/ijms21134777
63 Olagnier D, Brandtoft A, Gunderstofte C, Villadsen N, Krapp C, Thielke A, et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 9, 3506. 2018. 10.1038/s41467-018-05861-7
64 Johnston CJ, Smyth DJ, Dresser DW, Maizels RM. TGF-β in tolerance, development and regulation of immunity. Cell Immunol. 2016;299:14–22. 10.1016/j.cellimm.2015.10.006
65 Tamayo E, Alvarez P, Merino R. TGFβ superfamily members as regulators of B cell development and function-implications for autoimmunity. Int J Mol Sci. 2018;19(12):3928. 10.3390/ijms19123928
66 Gardès P, Forveille M, Alyanakian M-A, Aucouturier P, Ilencikova D, Leroux D, et al. Human MSH6 deficiency is associated with impaired antibody maturation. J Immunol. 2012;188(4):2023–9. 10.4049/jimmunol.1102984
67 Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol. 2007;7(6):454–65. 10.1038/nri2093
68 Thaventhiran JE, Lango Allen H, Burren OS, Rae W, Greene D, Staples E, et al. Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature. 2020;583(7814):90–5. 10.1038/s41586-020-2265-1
69 Gerasimčik N, He M, Dahlberg CI, Kuznetsov NV, Severinson E, Westerberg LS. The small Rho GTPases Rac1 and Rac2 are important for T-cell independent antigen responses and for suppressing switching to IgG2b in mice. Front immunol. 2017;8:1264. 10.3389/fimmu.2017.01264
70 Accetta D, Syverson G, Bonacci B, Reddy S, Bengtson C, Surfus J, et al. Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-cell lymphopenia. J Allergy Clin Immunol. 2011;127(2):535–8. e2. 10.1016/j.jaci.2010.10.013
71 Aliyu M, Zohora FT, Anka AU, Ali K, Maleknia S, Saffarioun M, et al. Interleukin-6 cytokine: An overview of the immune regulation, immune dysregulation, and therapeutic approach. Int Immunopharmacol. 2022;111:109130. 10.1016/j.intimp.2022.109130
72 Shen P, Deng X, Chen Z, Ba X, Qin K, Huang Y, et al. SIRT1: A potential therapeutic target in autoimmune diseases. Front immunol. 2021;12:779177. 10.3389/fimmu.2021.779177
73 Ghirotto B, Terra FF, Câmara NOS, Basso PJ. Sirtuins in B lymphocytes metabolism and function. World J Exp Med. 2019;9(1):1. 10.5493/wjem.v9.i1.1
74 Vasudevan S. Posttranscriptional upregulation by microRNAs. Wiley Interdiscip Rev RNA. 2012;3(3):311–30. 10.1002/wrna.121
75 Valinezhad Orang A, Safaralizadeh R, Kazemzadeh-Bavili M. Mechanisms of miRNA-mediated gene regulation from common downregulation to mRNA-specific upregulation. Int J Genomics. 2014;2014. 10.1155/2014/970607
76 Kim ME, Kim DH, Lee JS. Foxo transcription factors: Applicability as a novel immune cell regulators and therapeutic targets in oxidative stress-related diseases. Int J Mol Sci. 2022;23(19):11877. 10.3390/ijms231911877
77 Mertowska P, Mertowski S, Podgajna M, Grywalska E. The Importance of the Transcription Factor Foxp3 in the Development of Primary Immunodeficiencies. J Clin Med. 2022;11(4):947. 10.3390/jcm11040947
78 Yang J, Yan J, Liu B. Targeting VEGF/VEGFR to modulate antitumor immunity. Front immunol. 2018;9:978. 10.3389/fimmu.2018.00978
79 Geindreau M, Ghiringhelli F, Bruchard M. Vascular endothelial growth factor, a key modulator of the anti-tumor immune response. Int J Mol Sci. 2021;22(9):4871. 10.3390/ijms22094871
80 Li Y-L, Zhao H, Ren X-B. Relationship of VEGF/VEGFR with immune and cancer cells: Staggering or forward? Cancer Biol Med. 2016;13(2):206. 10.20892/j.issn.2095-3941.2015.0070
81 Turkowski K, Brandenburg S, Mueller A, Kremenetskaia I, Bungert AD, Blank A, et al. VEGF as a modulator of the innate immune response in glioblastoma. Glia. 2018;66(1):161–74. 10.1002/glia.23234
82 Mimura K, Kono K, Takahashi A, Kawaguchi Y, Fujii H. Vascular endothelial growth factor inhibits the function of human mature dendritic cells mediated by VEGF receptor-2. Cancer Immunol Immunother. 2007;56:761–70. 10.1007/s00262-006-0234-7
83 Li J, Li X-L, Li C-Q. Immunoregulation mechanism of VEGF signaling pathway inhibitors and its efficacy on the kidney. Am J Med Sci. 2023. 10.1016/j.amjms.2023.09.005
84 Tofighi Zavareh F, Mirshafiey A, Yazdani R, Keshtkar AA, Abolhassani H, Bagheri Y, et al. Lymphocytes subsets in correlation with clinical profile in CVID patients without monogenic defects. Expert Rev Clin Immunol. 2021;17(9):1041–51. 10.1080/1744666X.2021.1954908
85 Hücker SM, Fehlmann T, Werno C, Weidele K, Lüke F, Schlenska-Lange A, et al. Single-cell microRNA sequencing method comparison and application to cell lines and circulating lung tumor cells. Nat Commun. 2021;12(1):4316. 10.1038/s41467-021-24611-w
86 Ho V, Baker JR, Willison KR, Barnes PJ, Donnelly LE, Klug DR. Single cell quantification of microRNA from small numbers of non-invasively sampled primary human cells. Communications Biology. 2023;6(1):458. 10.1038/s42003-023-04845-8
87 Friman V, Quinti I, Davydov AN, Shugay M, Farroni C, Engström E, et al. Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations. Cell Rep. 2023;42(5). 10.1016/j.celrep.2023.112446
88 Strohmeier V, Andrieux G, Unger S, Pascual-Reguant A, Klocperk A, Seidl M, et al. Interferon-driven immune dysregulation in common variable immunodeficiency-associated villous atrophy and norovirus infection. J Clin Immunol. 2023;43(2):371–90. 10.1007/s10875-022-01379-2
89 Keller B, Strohmeier V, Harder I, Unger S, Payne KJ, Andrieux G, et al. The expansion of human T-bethighCD21low B cells is T cell dependent. Sci immunol. 2021;6(64):eabh0891.
Article Sidebar
Published
Jan 1, 2025
Article Details
How to Cite
Ranjbarnejad, T., Gholaminejad, A., Abolhassani, H., Sherkat, R., Salehi, M., & Sharifi, M. (2025). Decreased expression of hsa-miR-142-3p and hsa-miR-155-5p in common variable immunodeficiency and involvement of their target genes and biological pathways. Allergologia Et Immunopathologia, 53(1), 153-169. https://doi.org/10.15586/aei.v53i1.1234
Section
Original Articles
How to Cite
Ranjbarnejad, T., Gholaminejad, A., Abolhassani, H., Sherkat, R., Salehi, M., & Sharifi, M. (2025). Decreased expression of hsa-miR-142-3p and hsa-miR-155-5p in common variable immunodeficiency and involvement of their target genes and biological pathways. Allergologia Et Immunopathologia, 53(1), 153-169. https://doi.org/10.15586/aei.v53i1.1234