Circulating Extracellular microRNA in Systemic Autoimmunity

  • Niels H. H. HeegaardEmail author
  • Anting Liu Carlsen
  • Kerstin Skovgaard
  • Peter M. H. Heegaard
Part of the Experientia Supplementum book series (EXS, volume 106)


MicroRNAs (miRNAs) are differentially regulated in healthy, activated, inflamed, neoplastic, or otherwise pathological cells and tissues. While their main functions are executed intracellularly, many miRNAs can reproducibly be detected extracellularly in plasma and serum. This circulating, extracellular miRNA is protected against degradation by complexation with carrier proteins and/or by being enclosed in subcellular membrane vesicles. This, together with their tissue- and disease-specific expression, has fuelled the interest in using circulating microRNA profiles as harbingers of disease, i.e., as diagnostic analytes and as clues to dysregulated pathways in disease. Many studies show that inflammation and immune dysregulation, e.g., in autoimmune diseases, are associated with distinct miRNA expression changes in targeted tissues and in innate and adaptive immunity cells such as lymphocytes, natural killer cells, neutrophil granulocytes, and monocyte–macrophages. Exploratory studies (only validated in a few cases) also show that specific profiles of circulating miRNAs are associated with different systemic autoimmune diseases including systemic lupus erythematosus (SLE), systemic sclerosis, and rheumatoid arthritis. Even though the link between cellular alterations and extracellular profiles is still unpredictable, the data suggest that circulating miRNAs in autoimmunity may become diagnostically useful. Here, we review important circulating miRNAs in animal models of inflammation and in systemic autoimmunity and summarize some proposed functions of miRNAs in immune regulation and dysregulation. We conclude that the studies suggest new hypotheses and additional experiments, and that further diagnostic development is highly dependent on analytical method development and on obtaining sufficient numbers of uniformly processed samples from clinically well-characterized patients and controls.


Circulating microRNA Autoimmune disease Immune system Animal models Immunomodulation 


  1. Ai J, Zhang R, Li Y et al (2010) Circulating microRNA-1 as a potential novel biomarker for acute myocardial infarction. Biochem Biophys Res Commun 391:73–77PubMedCrossRefGoogle Scholar
  2. Alevizos I, Alexander S, Turner RJ et al (2011) MicroRNA expression profiles as biomarkers of minor salivary gland inflammation and dysfunction in Sjogren’s syndrome. Arthritis Rheum 63:535–544PubMedPubMedCentralCrossRefGoogle Scholar
  3. Baltimore D, Boldin MP, O’Connell RM et al (2008) MicroRNAs: new regulators of immune cell development and function. Nat Immunol 9:839–845PubMedCrossRefGoogle Scholar
  4. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297PubMedCrossRefGoogle Scholar
  5. Berschneider B, Ellwanger DC, Baarsma HA et al (2014) miR-92a regulates TGF-beta1-induced WISP1 expression in pulmonary fibrosis. Int J Biochem Cell Biol 53:432–441PubMedCrossRefGoogle Scholar
  6. Bertram A, Lovric S, Engel A et al (2015) Circulating ADAM17 level reflects disease activity in proteinase-3 ANCA-associated vasculitis. J Am Soc Nephrol [Epub ahead of print]Google Scholar
  7. Calin GA, Dumitru CD, Shimizu M et al (2002) Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 99:15524–15529PubMedPubMedCentralCrossRefGoogle Scholar
  8. Cappelli S, Bellando RS, Martinovic D et al (2012) “To be or not to be,” ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum 41:589–598PubMedCrossRefGoogle Scholar
  9. Carlsen AL, Schetter AJ, Nielsen CT et al (2013) Circulating microRNA expression profiles associated with systemic lupus erythematosus. Arthritis Rheum 65:1324–1334PubMedCrossRefGoogle Scholar
  10. Castro-Villegas C, Perez-Sanchez C, Escudero A et al (2015) Circulating miRNAs as potential biomarkers of therapy effectiveness in rheumatoid arthritis patients treated with anti-TNFalpha. Arthritis Res Ther 17:49PubMedPubMedCentralCrossRefGoogle Scholar
  11. Chafin CB, Regna NL, Caudell DL et al (2014) MicroRNA-let-7a promotes E2F-mediated cell proliferation and NFkappaB activation in vitro. Cell Mol Immunol 11:79–83PubMedCrossRefGoogle Scholar
  12. Chen CZ, Li L, Lodish HF et al (2004) MicroRNAs modulate hematopoietic lineage differentiation. Science 303:83–86PubMedCrossRefGoogle Scholar
  13. Cheng HH, Yi HS, Kim Y et al (2013) Plasma processing conditions substantially influence circulating microRNA biomarker levels. PLoS ONE 8, e64795PubMedPubMedCentralCrossRefGoogle Scholar
  14. Coskun M, Bjerrum JT, Seidelin JB et al (2012) MicroRNAs in inflammatory bowel disease-pathogenesis, diagnostics and therapeutics. World J Gastroenterol 18:4629–4634PubMedPubMedCentralCrossRefGoogle Scholar
  15. Costinean S, Zanesi N, Pekarsky Y et al (2006) Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc Natl Acad Sci USA 103:7024–7029PubMedPubMedCentralCrossRefGoogle Scholar
  16. Cray C, Zaias J, Altman NH (2009) Acute phase response in animals: a review. Comp Med 59:517–526PubMedPubMedCentralGoogle Scholar
  17. Dai Y, Huang YS, Tang M et al (2007) Microarray analysis of microRNA expression in peripheral blood cells of systemic lupus erythematosus patients. Lupus 16:939–946PubMedCrossRefGoogle Scholar
  18. De FB, Mondola P, Sasso A et al (2014) Small non-coding RNA signature in multiple sclerosis patients after treatment with interferon-beta. BMC Med Genomics 7:26. doi: 10.1186/1755-8794-7-26 CrossRefGoogle Scholar
  19. Deng X, Su Y, Wu H et al (2015) The role of microRNAs in autoimmune diseases with skin involvement. Scand J Immunol 81:153–165PubMedCrossRefGoogle Scholar
  20. Duroux-Richard I, Presumey J, Courties G et al (2011) MicroRNAs as new player in rheumatoid arthritis. Joint Bone Spine 78:17–22PubMedCrossRefGoogle Scholar
  21. Duroux-Richard I, Pers YM, Fabre S et al (2014) Circulating miRNA-125b is a potential biomarker predicting response to rituximab in rheumatoid arthritis. Mediators Inflamm 2014:342524PubMedPubMedCentralCrossRefGoogle Scholar
  22. Eis PS, Tam W, Sun L et al (2005) Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci USA 102:3627–3632PubMedPubMedCentralCrossRefGoogle Scholar
  23. Filkova M, Aradi B, Senolt L et al (2014) Association of circulating miR-223 and miR-16 with disease activity in patients with early rheumatoid arthritis. Ann Rheum Dis 73:1898–1904PubMedCrossRefGoogle Scholar
  24. Fontana L, Pelosi E, Greco P et al (2007) MicroRNAs 17-5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation. Nat Cell Biol 9:775–787PubMedCrossRefGoogle Scholar
  25. Fordham JB, Naqvi AR, Nares S (2015) Regulation of miR-24, miR-30b, and miR-142-3p during macrophage and dendritic cell differentiation potentiates innate immunity. J Leukoc Biol 98(2):195–207. doi: 10.1189/jlb.1A1014-519RR [Epub ahead of print]PubMedPubMedCentralCrossRefGoogle Scholar
  26. Furer V, Greenberg JD, Attur M et al (2010) The role of microRNA in rheumatoid arthritis and other autoimmune diseases. Clin Immunol 136:1–15PubMedCrossRefGoogle Scholar
  27. Geng L, Chaudhuri A, Talmon G et al (2014) MicroRNA-192 suppresses liver metastasis of colon cancer. Oncogene 33:5332–5340PubMedCrossRefGoogle Scholar
  28. Georgantas RW, Streicher K, Greenberg SA et al (2014) Inhibition of myogenic microRNAs 1, 133, and 206 by inflammatory cytokines links inflammation and muscle degeneration in adult inflammatory myopathies. Arthritis Rheum 66:1022–1033CrossRefGoogle Scholar
  29. Gidlof O, Andersson P, van der Pals J et al (2011) Cardiospecific microRNA plasma levels correlate with troponin and cardiac function in patients with ST elevation myocardial infarction, are selectively dependent on renal elimination, and can be detected in urine samples. Cardiology 118:217–226PubMedCrossRefGoogle Scholar
  30. Gidlof O, Smith JG, Miyazu K et al (2013) Circulating cardio-enriched microRNAs are associated with long-term prognosis following myocardial infarction. BMC Cardiovasc Disord 13:12PubMedPubMedCentralCrossRefGoogle Scholar
  31. Hajas A, Barath S, Szodoray P et al (2013) Derailed B cell homeostasis in patients with mixed connective tissue disease. Hum Immunol 74:833–841PubMedCrossRefGoogle Scholar
  32. Hashimi ST, Fulcher JA, Chang MH et al (2009) MicroRNA profiling identifies miR-34a and miR-21 and their target genes JAG1 and WNT1 in the coordinate regulation of dendritic cell differentiation. Blood 114:404–414PubMedPubMedCentralCrossRefGoogle Scholar
  33. Hecker M, Thamilarasan M, Koczan D et al (2013) MicroRNA expression changes during interferon-beta treatment in the peripheral blood of multiple sclerosis patients. Int J Mol Sci 14:16087–16110PubMedPubMedCentralCrossRefGoogle Scholar
  34. Heegaard NH, Schetter AJ, Welsh JA et al (2011) Circulating microRNA expression profiles in early stage non-small cell lung cancer. Int J Cancer 130:1378–1386PubMedPubMedCentralCrossRefGoogle Scholar
  35. Honda N, Jinnin M, Kira-Etoh T et al (2013) miR-150 down-regulation contributes to the constitutive type I collagen overexpression in scleroderma dermal fibroblasts via the induction of integrin beta3. Am J Pathol 182:206–216PubMedCrossRefGoogle Scholar
  36. Hong Y, Wu J, Zhao J et al (2013) miR-29b and miR-29c are involved in Toll-like receptor control of glucocorticoid-induced apoptosis in human plasmacytoid dendritic cells. PLoS ONE 8:e69926PubMedPubMedCentralCrossRefGoogle Scholar
  37. Hori SS, Gambhir SS (2011) Mathematical model identifies blood biomarker-based early cancer detection strategies and limitations. Sci Transl Med 3:109ra116PubMedPubMedCentralCrossRefGoogle Scholar
  38. Hu R, O’Connell RM (2013) MicroRNA control in the development of systemic autoimmunity. Arthritis Res Ther 15:202PubMedPubMedCentralCrossRefGoogle Scholar
  39. Huang X, Yuan T, Tschannen M et al (2013) Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genomics 14:319PubMedPubMedCentralCrossRefGoogle Scholar
  40. Inoue K, Jinnin M, Yamane K et al (2013) Down-regulation of miR-223 contributes to the formation of Gottron’s papules in dermatomyositis via the induction of PKCvarepsilon. Eur J Dermatol 23:160–167PubMedGoogle Scholar
  41. Iwamoto N, Vettori S, Maurer B et al (2014) Downregulation of miR-193b in systemic sclerosis regulates the proliferative vasculopathy by urokinase-type plasminogen activator expression. Ann Rheum Dis. doi: 10.1136/annrheumdis-2014-205326 [Epub ahead of print]Google Scholar
  42. Ji X, Takahashi R, Hiura Y et al (2009) Plasma miR-208 as a biomarker of myocardial injury. Clin Chem 55:1944–1949PubMedCrossRefGoogle Scholar
  43. Johnnidis JB, Harris MH, Wheeler RT et al (2008) Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature 451:1125–1129PubMedCrossRefGoogle Scholar
  44. Kawashita Y, Jinnin M, Makino T et al (2011) Circulating miR-29a levels in patients with scleroderma spectrum disorder. J Dermatol Sci 61:67–69PubMedCrossRefGoogle Scholar
  45. Kim TD, Lee SU, Yun S et al (2011) Human microRNA-27a* targets Prf1 and GzmB expression to regulate NK-cell cytotoxicity. Blood 118:5476–5486PubMedPubMedCentralCrossRefGoogle Scholar
  46. Kim SJ, Gregersen PK, Diamond B (2013) Regulation of dendritic cell activation by microRNA let-7c and BLIMP1. J Clin Invest 123:823–833PubMedPubMedCentralCrossRefGoogle Scholar
  47. Kluiver J, Poppema S, Blokzijl T et al (2005) BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J Pathol 207:243–249PubMedCrossRefGoogle Scholar
  48. Konsta OD, Thabet Y, Le DC et al (2014) The contribution of epigenetics in Sjogren’s Syndrome. Front Genet 5:71PubMedPubMedCentralCrossRefGoogle Scholar
  49. Krintel SB, Dehlendorff C, Hetland ML et al (2015) Prediction of treatment response to adalimumab: a double-blind placebo-controlled study of circulating microRNA in patients with early rheumatoid arthritis. Pharmacogenomics J. doi: 10.1038/tpj.2015.30 [Epub ahead of print]PubMedGoogle Scholar
  50. Lehmann SM, Kruger C, Park B et al (2012) An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat Neurosci 15:827–835PubMedCrossRefGoogle Scholar
  51. Li QJ, Chau J, Ebert PJ et al (2007) miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129:147–161PubMedCrossRefGoogle Scholar
  52. Li J, WanY GQ et al (2010a) Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis. Arthritis Res Ther 12:R81PubMedPubMedCentralCrossRefGoogle Scholar
  53. Li Y, Chan EY, Li J et al (2010b) MicroRNA expression and virulence in pandemic influenza virus-infected mice. J Virol 84:3023–3032PubMedPubMedCentralCrossRefGoogle Scholar
  54. Li Y, Li J, Belisle S et al (2011) Differential microRNA expression and virulence of avian, 1918 reassortant, and reconstructed 1918 influenza A viruses. Virology 421:105–113PubMedPubMedCentralCrossRefGoogle Scholar
  55. Loveday EK, Svinti V, Diederich S, Pasick J, Jean F (2012) Temporal- and strain-specific host microRNA molecular signatures associated with swine-origin H1N1 and avian-origin H7N7 influenza A virus infection. J Virol 86:6109–6122PubMedPubMedCentralCrossRefGoogle Scholar
  56. Lu MC, Lai NS, Chen HC et al (2013) Decreased microRNA(miR)-145 and increased miR-224 expression in T cells from patients with systemic lupus erythematosus involved in lupus immunopathogenesis. Clin Exp Immunol 171:91–99PubMedCrossRefGoogle Scholar
  57. Maciotta S, Meregalli M, Cassinelli L et al (2012) Hmgb3 is regulated by microRNA-206 during muscle regeneration. PLoS ONE 7, e43464PubMedPubMedCentralCrossRefGoogle Scholar
  58. MacLellan SA, MacAulay C, Lam S et al (2014) Pre-profiling factors influencing serum microRNA levels. BMC Clin Pathol 14:27PubMedPubMedCentralCrossRefGoogle Scholar
  59. Makino K, Jinnin M, Kajihara I et al (2012) Circulating miR-142-3p levels in patients with systemic sclerosis. Clin Exp Dermatol 37:34–39PubMedCrossRefGoogle Scholar
  60. Maurer B, Stanczyk J, Jungel A et al (2010) MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum 62:1733–1743PubMedCrossRefGoogle Scholar
  61. McCall MN, Kent OA, Yu J et al (2011) MicroRNA profiling of diverse endothelial cell types. BMC Med Genomics 4:78PubMedPubMedCentralCrossRefGoogle Scholar
  62. McDonald JS, Milosevic D, Reddi HV et al (2011) Analysis of circulating microRNA: preanalytical and analytical challenges. Clin Chem 57:833–840PubMedCrossRefGoogle Scholar
  63. Mi S, Zhang J, Zhang W et al (2013) Circulating microRNAs as biomarkers for inflammatory diseases. Microrna 2:63–71PubMedCrossRefGoogle Scholar
  64. Michael A, Bajracharya SD, Yuen PS et al (2010) Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis 16:34–38PubMedCrossRefGoogle Scholar
  65. Moldovan L, Batte KE, Trgovcich J et al (2014) Methodological challenges in utilizing miRNAs as circulating biomarkers. J Cell Mol Med 18:371–390PubMedPubMedCentralCrossRefGoogle Scholar
  66. Murata K, Yoshitomi H, Tanida S et al (2010) Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 12:R86PubMedPubMedCentralCrossRefGoogle Scholar
  67. Naghavian R, Ghaedi K, Kiani-Esfahani A et al (2015) miR-141 and miR-200a, revelation of new possible players in modulation of Th17/Treg differentiation and pathogenesis of multiple sclerosis. PLoS ONE 10:e0124555PubMedPubMedCentralCrossRefGoogle Scholar
  68. Nair VS, Pritchard CC, Tewari M et al (2014) Design and analysis for studying microRNAs in human disease: a primer on -omic technologies. Am J Epidemiol 180:140–152PubMedPubMedCentralCrossRefGoogle Scholar
  69. Nakashima T, Jinnin M, Yamane K et al (2012) Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts. J Immunol 188:3573–3583PubMedCrossRefGoogle Scholar
  70. Niederer F, Trenkmann M, Ospelt C et al (2012) Down-regulation of microRNA-34a* in rheumatoid arthritis synovial fibroblasts promotes apoptosis resistance. Arthritis Rheum 64:1771–1779PubMedCrossRefGoogle Scholar
  71. O’Connell RM, Rao DS, Chaudhuri AA et al (2010) Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 10:111–122PubMedCrossRefGoogle Scholar
  72. O’Connell RM, Rao DS, Baltimore D (2012) microRNA regulation of inflammatory responses. Annu Rev Immunol 30:295–312PubMedCrossRefGoogle Scholar
  73. O’Neill LA, Sheedy FJ, McCoy CE (2011) MicroRNAs: the fine-tuners of Toll-like receptor signaling. Nat Rev Immunol 11:163–175PubMedCrossRefGoogle Scholar
  74. Okada Y, Jinnin M, Makino T et al (2014) MIRSNP rs2910164 of miR-146a is associated with the muscle involvement in polymyositis/dermatomyositis. Int J Dermatol 53:300–304PubMedCrossRefGoogle Scholar
  75. Olivieri F, Rippo MR, Procopio AD et al (2013) Circulating inflamma-miRs in aging and age-related diseases. Front Genet 4:121PubMedPubMedCentralCrossRefGoogle Scholar
  76. Olsen HG, Skovgaard K, Nielsen OL et al (2013) Organization and biology of the porcine serum amyloid A (SAA) gene cluster: isoform specific responses to bacterial infection. PLoS ONE 8, e76695PubMedPubMedCentralCrossRefGoogle Scholar
  77. Oshikawa Y, Jinnin M, Makino T et al (2013) Decreased miR-7 expression in the skin and sera of patients with dermatomyositis. Acta Derm Venereol 93:273–276PubMedCrossRefGoogle Scholar
  78. Pan W, Zhu S, Yuan M et al (2010) MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1. J Immunol 184:6773–6781PubMedCrossRefGoogle Scholar
  79. Papadopoulou AS, Dooley J, Linterman MA et al (2011) The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-alpha receptor. Nat Immunol 13:181–187PubMedPubMedCentralCrossRefGoogle Scholar
  80. Parlato M, Cavaillon JM (2015) Host response biomarkers in the diagnosis of sepsis: a general overview. Methods Mol Biol 1237:149–211PubMedCrossRefGoogle Scholar
  81. Pauley KM, Satoh M, Chan AL et al (2008) Up-regulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther 10:R101PubMedPubMedCentralCrossRefGoogle Scholar
  82. Pauley KM, Cha S, Chan EK (2009) MicroRNA in autoimmunity and autoimmune diseases. J Autoimmun 32:189–194PubMedPubMedCentralCrossRefGoogle Scholar
  83. Pedersen IM, Cheng G, Wieland S et al (2007) Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449:919–922PubMedPubMedCentralCrossRefGoogle Scholar
  84. Podolska A, Anthon C, Bak M et al (2012) Profiling microRNAs in lung tissue from pigs infected with Actinobacillus pleuropneumoniae. BMC Genomics 13:459PubMedPubMedCentralCrossRefGoogle Scholar
  85. Pritchard CC, Cheng HH, Tewari M (2012a) MicroRNA profiling: approaches and considerations. Nat Rev Genet 13:358–369PubMedPubMedCentralCrossRefGoogle Scholar
  86. Pritchard CC, Kroh E, Wood B et al (2012b) Blood cell origin of circulating microRNAs: a cautionary note for cancer biomarker studies. Cancer Prev Res 5:492–497CrossRefGoogle Scholar
  87. Rane S, He M, Sayed D et al (2009) Downregulation of miR-199a derepresses hypoxia-inducible factor-1alpha and Sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes. Circ Res 104:879–886PubMedPubMedCentralCrossRefGoogle Scholar
  88. Reid G, Kirschner MB, van Zandwijk N (2011) Circulating microRNAs: association with disease and potential use as biomarkers. Crit Rev Oncol Hematol 80:193–208PubMedCrossRefGoogle Scholar
  89. Rivero SJ, Diaz-Jouanen E, Alarcon-Segovia D (1978) Lymphopenia in systemic lupus erythematosus. Clinical, diagnostic, and prognostic significance. Arthritis Rheum 21:295–305PubMedCrossRefGoogle Scholar
  90. Rodriguez A, Vigorito E, Clare S et al (2007) Requirement of bic/microRNA-155 for normal immune function. Science 316:608–611PubMedPubMedCentralCrossRefGoogle Scholar
  91. Salama A, Fichou N, Allard M et al (2014) MicroRNA-29b modulates innate and antigen-specific immune responses in mouse models of autoimmunity. PLoS ONE 9, e106153PubMedPubMedCentralCrossRefGoogle Scholar
  92. Sayed AS, Xia K, Salma U et al (2014) Diagnosis, prognosis and therapeutic role of circulating miRNAs in cardiovascular diseases. Heart Lung Circ 23:503–510PubMedCrossRefGoogle Scholar
  93. Schetter AJ, Heegaard NH, Harris CC (2010) Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis 31:37–49PubMedCrossRefGoogle Scholar
  94. Semaan N, Frenzel L, Alsaleh G et al (2011) miR-346 controls release of TNF-alpha protein and stability of its mRNA in rheumatoid arthritis via tristetraprolin stabilization. PLoS ONE 6:e19827PubMedPubMedCentralCrossRefGoogle Scholar
  95. Shan H, Zhang Y, Lu Y et al (2009) Downregulation of miR-133 and miR-590 contributes to nicotine-induced atrial remodelling in canines. Cardiovasc Res 83:465–472PubMedCrossRefGoogle Scholar
  96. Sheedy FJ, Palsson-McDermott E, Hennessy EJ et al (2010) Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol 11:141–147PubMedCrossRefGoogle Scholar
  97. Shimada S, Jinnin M, Ogata A et al (2013) Serum miR-21 levels in patients with dermatomyositis. Clin Exp Rheumatol 31:161–162PubMedGoogle Scholar
  98. Sing T, Jinnin M, Yamane K et al (2012) microRNA-92a expression in the sera and dermal fibroblasts increases in patients with scleroderma. Rheumatology 51:1550–1556PubMedCrossRefGoogle Scholar
  99. Singh RP, Massachi I, Manickavel S et al (2013) The role of miRNA in inflammation and autoimmunity. Autoimmun Rev 12:1160–1165PubMedCrossRefGoogle Scholar
  100. Skoglund C, Carlsen AL, Weiner M et al (2015) Circulating microRNA expression pattern separates patients with anti-neutrophil cytoplasmic antibody associated vasculitis from healthy controls. Clin Exp Rheumatol 33:64–71Google Scholar
  101. Skovgaard K, Mortensen S, Boye M et al (2009) Rapid and widely disseminated acute phase protein response after experimental bacterial infection of pigs. Vet Res 40:23PubMedPubMedCentralCrossRefGoogle Scholar
  102. Skovgaard K, Cirera S, Vasby D et al (2013) Expression of innate immune genes, proteins and microRNAs in lung tissue of pigs infected experimentally with influenza virus (H1N2). Innate Immun 19:531–544PubMedCrossRefGoogle Scholar
  103. Stagakis E, Bertsias G, Verginis P et al (2011) Identification of novel microRNA signatures linked to human lupus disease activity and pathogenesis: miR-21 regulates aberrant T cell responses through regulation of PDCD4 expression. Ann Rheum Dis 70:1496–1506PubMedCrossRefGoogle Scholar
  104. Stanczyk J, Pedrioli DM, Brentano F et al (2008) Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum 58:1001–1009PubMedCrossRefGoogle Scholar
  105. Stanczyk J, Ospelt C, Karouzakis E et al (2011) Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum 63:373–381PubMedPubMedCentralCrossRefGoogle Scholar
  106. Steen SO, Iversen LV, Carlsen AL et al (2015) The circulating cell-free microRNA profile in systemic sclerosis is distinct from both healthy controls and systemic lupus erythematosus. J Rheumatol 42:214–221PubMedCrossRefGoogle Scholar
  107. Stittrich AB, Haftmann C, Sgouroudis E et al (2010) The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat Immunol 11:1057–1062PubMedCrossRefGoogle Scholar
  108. Susan Due Kay SD, Carlsen AL, Voss A, Poulsen MK, Diederichsen AC, Heegaard NHH (2015) Associations of circulating cell-free micro-RNA with vasculopathy and vascular events in SLE patients. Accepted Abstract, American College of Rheumatology Annual Meeting, San FranciscoGoogle Scholar
  109. Takemoto R, Jinnin M, Wang Z et al (2013) Hair miR-29a levels are decreased in patients with scleroderma. Exp Dermatol 22:832–833PubMedCrossRefGoogle Scholar
  110. Tanaka S, Suto A, Ikeda K et al (2013) Alteration of circulating miRNAs in SSc: miR-30b regulates the expression of PDGF receptor beta. Rheumatology 52:1963–1972PubMedCrossRefGoogle Scholar
  111. Tanaka T, Arai M, Jiang X et al (2014) Downregulation of microRNA-431 by human interferon-beta inhibits viability of medulloblastoma and glioblastoma cells via upregulation of SOCS6. Int J Oncol 44:1685–1690PubMedGoogle Scholar
  112. Tandon M, Gallo A, Jang SI et al (2012) Deep sequencing of short RNAs reveals novel microRNAs in minor salivary glands of patients with Sjogren’s syndrome. Oral Dis 18:127–131PubMedCrossRefGoogle Scholar
  113. Tang Y, Luo X, Cui H et al (2009) MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum 60:1065–1075PubMedCrossRefGoogle Scholar
  114. Tang X, Tian X, Zhang Y et al (2013) Correlation between the frequency of Th17 cell and the expression of microRNA-206 in patients with dermatomyositis. Clin Dev Immunol 2013:345347PubMedPubMedCentralGoogle Scholar
  115. Te JL, Dozmorov IM, Guthridge JM et al (2010) Identification of unique microRNA signature associated with lupus nephritis. PLoS ONE 5, e10344PubMedPubMedCentralCrossRefGoogle Scholar
  116. Thai TH, Calado DP, Casola S et al (2007) Regulation of the germinal center response by microRNA-155. Science 316:604–608PubMedCrossRefGoogle Scholar
  117. Tili E, Michaille JJ, Cimino A (2007) Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 179:5082–5089PubMedCrossRefGoogle Scholar
  118. Tili E, Michaille JJ, Costinean S et al (2008) MicroRNAs, the immune system and rheumatic disease. Nat Clin Pract Rheumatol 4:534–541PubMedCrossRefGoogle Scholar
  119. Tili E, Croce CM, Michaille JJ (2009) miR-155: on the crosstalk between inflammation and cancer. Int Rev Immunol 28:264–284PubMedCrossRefGoogle Scholar
  120. Turchinovich A, Weiz L, Langheinz A et al (2011) Characterization of extracellular circulating microRNA. Nucleic Acids Res 39:7223–7233PubMedPubMedCentralCrossRefGoogle Scholar
  121. Vettori S, Gay S, Distler O (2012) Role of MicroRNAs in fibrosis. Open Rheumatol J 6:130–139PubMedPubMedCentralCrossRefGoogle Scholar
  122. Vickers KC, Roteta LA, Hucheson-Dilks H et al (2015) Mining diverse small RNA species in the deep transcriptome. Trends Biochem Sci 40:4–7PubMedCrossRefGoogle Scholar
  123. Vigorito E, Perks KL, Abreu-Goodger C et al (2007) microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 27:847–859PubMedPubMedCentralCrossRefGoogle Scholar
  124. Volinia S, Calin GA, Liu CG et al (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103:2257–2261PubMedPubMedCentralCrossRefGoogle Scholar
  125. Wang G, Tam LS, Li EK et al (2011) Serum and urinary free microRNA level in patients with systemic lupus erythematosus. Lupus 20:493–500PubMedCrossRefGoogle Scholar
  126. Wang H, Peng W, Ouyang X et al (2012a) Circulating microRNAs as candidate biomarkers in patients with systemic lupus erythematosus. Transl Res 160(3):198–206PubMedCrossRefGoogle Scholar
  127. Wang K, Yuan Y, Cho JH et al (2012b) Comparing the MicroRNA spectrum between serum and plasma. PLoS ONE 7, e41561PubMedPubMedCentralCrossRefGoogle Scholar
  128. Wang Y, Brahmakshatriya V, Lupiani B et al (2012c) Integrated analysis of microRNA expression and mRNA transcriptome in lungs of avian influenza virus infected broilers. BMC Genomics 13:278PubMedPubMedCentralCrossRefGoogle Scholar
  129. Wang Y, Zhang Y, Huang J et al (2014) Increase of circulating miR-223 and insulin-like growth factor-1 is associated with the pathogenesis of acute ischemic stroke in patients. BMC Neurol 14:77PubMedPubMedCentralCrossRefGoogle Scholar
  130. Weber JA, Baxter DH, Zhang S et al (2010) The microRNA spectrum in 12 body fluids. Clin Chem 56:1733–1741PubMedPubMedCentralCrossRefGoogle Scholar
  131. Wen Z, Xu L, Chen X et al (2013) Autoantibody induction by DNA-containing immune complexes requires HMGB1 with the TLR2/microRNA-155 pathway. J Immunol 190:5411–5422PubMedCrossRefGoogle Scholar
  132. Wendlandt EB, Graff JW, Gioannini TL et al (2012) The role of microRNAs miR-200b and miR-200c in TLR4 signaling and NF-kappaB activation. Innate Immun 18:846–855PubMedPubMedCentralCrossRefGoogle Scholar
  133. Williams Z, Ben-Dov IZ, Elias R et al (2013) Comprehensive profiling of circulating microRNA via small RNA sequencing of cDNA libraries reveals biomarker potential and limitations. Proc Natl Acad Sci USA 110:4255–4260PubMedPubMedCentralCrossRefGoogle Scholar
  134. Witwer KW (2015) Circulating microRNA biomarker studies: pitfalls and potential solutions. Clin Chem 61:56–63PubMedCrossRefGoogle Scholar
  135. Wuttge DM, Carlsen AL, Teku G et al (2015) Specific autoantibody profiles and disease subgroups correlate with circulating micro-RNA in systemic sclerosis. Rheumatology. doi: 10.1093/rheumatology/kev234 [ePub ahead of print]PubMedGoogle Scholar
  136. Xiao C, Calado DP, Galler G et al (2007) MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 131:146–159PubMedCrossRefGoogle Scholar
  137. Yu D, Tan AH, Hu X et al (2007) Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450:299–303PubMedCrossRefGoogle Scholar
  138. Yu H, Lu J, Zuo L et al (2012) Epstein-Barr virus down-regulates microRNA 203 through the oncoprotein latent membrane protein 1: a contribution to increased tumor incidence in epithelial cells. J Virol 86:3088–3099PubMedPubMedCentralCrossRefGoogle Scholar
  139. Zhao X, Tang Y, Qu B et al (2010) MicroRNA-125a contributes to elevated inflammatory chemokine RANTES levels via targeting KLF13 in systemic lupus erythematosus. Arthritis Rheum 62:3425–3435PubMedCrossRefGoogle Scholar
  140. Zhao S, Wang Y, Liang Y et al (2011) MicroRNA-126 regulates DNA methylation in CD4+ T cells and contributes to systemic lupus erythematosus by targeting DNA methyltransferase 1. Arthritis Rheum 63:1376–1386PubMedCrossRefGoogle Scholar
  141. Zhou B, Wang S, Mayr C et al (2007) miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely. Proc Natl Acad Sci USA 104:7080–7085PubMedPubMedCentralCrossRefGoogle Scholar
  142. Zhou X, Jeker LT, Fife BT et al (2008) Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med 205:1983–1991PubMedPubMedCentralCrossRefGoogle Scholar
  143. Zhu S, Pan W, Song X et al (2012) The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-alpha. Nat Med 18:1077–1086PubMedCrossRefGoogle Scholar
  144. Zilahi E, Tarr T, Papp G et al (2012) Increased microRNA-146a/b, TRAF6 gene and decreased IRAK1 gene expressions in the peripheral mononuclear cells of patients with Sjogren’s syndrome. Immunol Lett 141:165–168PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Niels H. H. Heegaard
    • 1
    • 2
    Email author
  • Anting Liu Carlsen
    • 3
    • 4
  • Kerstin Skovgaard
    • 5
  • Peter M. H. Heegaard
    • 5
  1. 1.Department of Autoimmunology and BiomarkersStatens Serum InstitutCopenhagen SDenmark
  2. 2.Department of Clinical Biochemistry and PharmacologyOdense University HospitalOdense CDenmark
  3. 3.Department of Congenital DisordersStatens Serum InstitutCopenhagen SDenmark
  4. 4.Department of Autoimmunology and BiomarkersStatens Serum InstitutCopenhagen SDenmark
  5. 5.National Veterinary InstituteTechnical University of DenmarkLyngbyDenmark

Personalised recommendations