NeuroMolecular Medicine

, Volume 17, Issue 2, pp 83–96 | Cite as

Epigenetics of Multiple Sclerosis: An Updated Review

  • Cem İsmail Küçükali
  • Murat Kürtüncü
  • Arzu Çoban
  • Merve Çebi
  • Erdem TüzünEmail author
Review Paper


Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized with autoimmune response against myelin proteins and progressive axonal loss. The heterogeneity of the clinical course and low concordance rates in monozygotic twins have indicated the involvement of complex heritable and environmental factors in MS pathogenesis. MS is more often transmitted to the next generation by mothers than fathers suggesting an epigenetic influence. One of the possible reasons of this parent-of-origin effect might be the human leukocyte antigen-DRB1*15 allele, which is the major risk factor for MS and regulated by epigenetic mechanisms such as DNA methylation and histone deacetylation. Moreover, major environmental risk factors for MS, vitamin D deficiency, smoking and Ebstein–Barr virus are all known to exert epigenetic changes. In the last few decades, compelling evidence implicating the role of epigenetics in MS has accumulated. Increased or decreased acetylation, methylation and citrullination of genes regulating the expression of inflammation and myelination factors appear to be particularly involved in the epigenetics of MS. Although much less is known about epigenetic factors causing neurodegeneration, epigenetic mechanisms regulating axonal loss, apoptosis and mitochondrial dysfunction in MS are in the process of identification. Additionally, expression levels of several microRNAs (miRNAs) (e.g., miR-155 and miR-326) are increased in MS brains and potential mechanisms by which these factors might influence MS pathogenesis have been described. Certain miRNAs may also be potentially used as diagnostic biomarkers in MS. Several reagents, especially histone deacetylase inhibitors have been shown to ameliorate the symptoms of experimental allergic encephalomyelitis. Ongoing efforts in this field are expected to result in characterization of epigenetic factors that can be used in prediction of treatment responsive MS patients, diagnostic screening panels and treatment methods with specific mechanism of action.


Multiple sclerosis Epigenetics Genetics miRNA Autoimmunity 


Conflict of interest

Authors declare no conflict of interest.


  1. Agarwal, S., & Rao, A. (1998). Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity, 9, 765–775.PubMedGoogle Scholar
  2. Alevizos, I., & Illei, G. G. (2010). MicroRNAs in Sjogren’s syndrome as a prototypic autoimmune disease. Autoimmunity Reviews, 9, 618–621.PubMedCentralPubMedGoogle Scholar
  3. Ascherio, A., & Munger, K. L. (2007). Environmental risk factors for multiple sclerosis. Part I: The role of infection. Annals of Neurology, 61, 288–299.PubMedGoogle Scholar
  4. Balada, E., Ordi-Ros, J., & Vilardell-Tarres, M. (2007). DNA methylation and systemic lupus erythematosus. Annals of the New York Academy of Sciences, 1108, 27–136.Google Scholar
  5. Balada, E., Ordi-Ros, J., & Vilardell-Tarrés, M. (2009). Molecular mechanisms mediated by human endogenous retroviruses (HERVs) in autoimmunity. Reviews in Medical Virology, 19, 273–286.PubMedGoogle Scholar
  6. Ballestar, E. (2010). Epigenetics lessons from twins: Prospects for autoimmune disease. Clinical Reviews in Allergy and Immunology, 39, 30–41.PubMedGoogle Scholar
  7. Baranzini, S. E., Mudge, J., van Velkinburgh, J. C., et al. (2010). Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature, 464, 1351–1356.PubMedCentralPubMedGoogle Scholar
  8. Baranzini, S. E., & Nickles, D. (2012). Genetics of multiple sclerosis: Swimming in an ocean of data. Current Opinion in Neurology, 25, 239–245.PubMedGoogle Scholar
  9. Bartel, D. P. (2004). MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 116, 281–297.PubMedGoogle Scholar
  10. Bestor, T. H. (2000). The DNA methyltransferases of mammals. Human Molecular Genetics, 9, 2395–2402.PubMedGoogle Scholar
  11. Bulosan, M., Pauley, K. M., Yo, K., Chan, E. K., Katz, J., Peck, A. B., et al. (2009). Inflammatory caspases are critical for enhanced cell death in the target tissue of Sjogren’s syndrome before disease onset. Immunology and Cell Biology, 87, 81–90.PubMedGoogle Scholar
  12. Calabrese, R., Zampieri, M., Mechelli, R., Annibali, V., Guastafierro, T., Ciccarone, F., et al. (2012). Methylation-dependent PAD2 upregulation in multiple sclerosis peripheral blood. Multiple Sclerosis Journal, 18, 299–304.PubMedGoogle Scholar
  13. Camelo, S., Iglesias, A. H., Hwang, D., Due, B., Ryu, H., Smith, K., et al. (2005). Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. Journal of Neuroimmunology, 164, 10–21.PubMedGoogle Scholar
  14. Carrillo-Vico, A., Leech, M. D., & Anderton, S. M. (2010). Contribution of myelin autoantigen citrullination to T cell autoaggression in the central nervous system. The Journal of Immunology, 184, 2839–2846.PubMedGoogle Scholar
  15. Chang, T. C., & Mendell, J. T. (2007). microRNAs in vertebrate physiology and human disease. Annual Review of Genomics and Human Genetics, 8, 215–239.PubMedGoogle Scholar
  16. Chiang, E. P., Wang, Y. C., Chen, W. W., & Tang, F. Y. (2009). Effects of insulin and glucose on cellularmetabolic fluxes in homocysteine transsulfuration, remethylation, S-adenosylmethionine synthesis, and global deoxyribonucleic acid methylation. Journal of Clinical Endocrinology and Metabolism, 94, 1017–1025.PubMedGoogle Scholar
  17. Christophi, G. P., Hudson, C. A., Gruber, R. C., Christophi, C. P., Mihai, C., Mejico, L. J., et al. (2008). SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients. Laboratory Investigation, 88, 243–255.PubMedCentralPubMedGoogle Scholar
  18. Christophi, G. P., Panos, M., Hudson, C. A., Tsikkou, C., Mihai, C., Mejico, L. J., et al. (2009). Interferon-β treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1. Clinical Immunology, 133, 27–44.PubMedCentralPubMedGoogle Scholar
  19. Coquet, J. M., Middendorp, S., van der Horst, G., Kind, J., Veraar, E. A., Xiao, Y., et al. (2013). The CD27 and CD70 costimulatory pathway inhibits effector function of T helper 17 cells and attenuates associated autoimmunity. Immunity, 38, 53–65.PubMedGoogle Scholar
  20. Cox, M. B., Cairns, M. J., Gandhi, K. S., Carroll, A. P., Moscovis, S., Stewart, G. J., et al. (2010). MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood. PLoS One, 5, e12132.PubMedCentralPubMedGoogle Scholar
  21. D’Souza, C. A., Wood, D. D., She, Y. M., & Moscarello, M. A. (2005). Autocatalytic cleavage of myelin basic protein: An alternative to molecular mimicry. Biochemistry, 44, 12905–12913.PubMedGoogle Scholar
  22. Deng, C., Lu, Q., Zhang, Z., Rao, T., Attwood, J., Yung, R., et al. (2003). Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling. Arthritis and Rheumatism, 48, 746–756.PubMedGoogle Scholar
  23. Du, C., Liu, C., Kang, J., Zhao, G., Ye, Z., Huang, S., et al. (2009). MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nature Immunology, 10, 1252–1259.PubMedGoogle Scholar
  24. Dupont, C., Armant, D. R., & Brenner, C. A. (2009). Epigenetics: Definition, mechanisms and clinical perspective. Seminars in Reproductive Medicine, 27, 351–357.PubMedCentralPubMedGoogle Scholar
  25. Ebers, G. C., et al. (2004). Parent-of-origin effect in multiple sclerosis: Observations in half-siblings. Lancet, 363, 1773–1774.PubMedGoogle Scholar
  26. Egger, G., Liang, G., Aparicio, A., & Jones, P. A. (2004). Epigenetics in human disease and prospects for epigenetic therapy. Nature, 429, 457–463.PubMedGoogle Scholar
  27. Escobar, T., Yu, C. R., Muljo, S. A., & Egwuagu, C. E. (2013). STAT3 activates miR-155 in Th17 cells and acts in concert to promote experimental autoimmune uveitis. Investigative Ophthalmology & Visual Science, 54, 4017–4025.Google Scholar
  28. Ezhkova, E., Pasolli, H. A., Parker, J. S., Stokes, N., Su, I. H., Hannon, G., et al. (2009). Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell, 136, 1122–1135.PubMedCentralPubMedGoogle Scholar
  29. Fali, T., Le Dantec, C., Thabet, Y., Jousse, S., Hanrotel, C., Youinou, P., et al. (2013). DNA methylation modulates HRES1/p28 expression in B cells from patients with Lupus. Autoimmunity,. doi: 10.3109/08916934.2013.826207.PubMedCentralPubMedGoogle Scholar
  30. Faraco, G., et al. (2011). The therapeutic potential of HDAC inhibitors in the treatment of multiple sclerosis. Molecular Medicine, 17, 442–447.PubMedCentralPubMedGoogle Scholar
  31. Fatemi, M., Pao, M. M., Jeong, S., Gal-Yam, E. N., Egger, G., Weisenberger, D. J., et al. (2005). Footprinting of mammalian promoters: Use of a CpG DNA methyltransferase revealing nucleosome positions at a single molecule level. Nucleic Acids Research, 33, e176.PubMedCentralPubMedGoogle Scholar
  32. Fraga, M. F., Ballestar, E., Paz, M. F., et al. (2005). Epigenetic differences arise during the lifetime of monozygotic twins. Proceedings of the National Academy of Sciences of the United States of America, 102, 10604–10609.PubMedCentralPubMedGoogle Scholar
  33. Gao, B., Kong, Q., Kemp, K., Zhao, Y. S., & Fang, D. (2012). Analysis of sirtuin 1 expression reveals a molecular explanation of IL-2-mediated reversal of T-cell tolerance. Proceedings of the National Academy of Sciences of the United States of America, 109, 899–904.PubMedCentralPubMedGoogle Scholar
  34. Goodell, M. A., & Godley, L. A. (2013). Perspectives and future directions for epigenetics in hematology. Blood, 121, 5131–5137.PubMedCentralPubMedGoogle Scholar
  35. Gourraud, P. A., Harbo, H. F., Hauser, S. L., & Baranzini, S. E. (2012). The genetics of multiple sclerosis: An up-to-date review. Immunological Reviews, 248, 87–103.PubMedGoogle Scholar
  36. Grabiec, A. M., Tak, P. P., & Reedquist, K. A. (2008). Targeting histone deacetylase activity in rheumatoid arthritis and asthma as prototypes of inflammatory disease: Should we keep our HATs on? Arthritis Research and Therapy, 10, 226.PubMedCentralPubMedGoogle Scholar
  37. Graves, M., Benton, M., Lea, R., Boyle, M., Tajouri, L., Macartney-Coxson, D., et al. (2013). Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis. Mult: Scler. doi: 10.1177/1352458513516529.Google Scholar
  38. Gray, S. G., & Dangond, F. (2006). Rationale for the use of histone deacetylase inhibitors as a dual therapeutic modality in multiple sclerosis. Epigenetics, 1, 67–75.PubMedGoogle Scholar
  39. Grogan, J. L., Mohrs, M., Harmon, B., et al. (2001). Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity, 14, 205–215.PubMedGoogle Scholar
  40. Guan, H., Nagarkatti, P. S., & Nagarkatti, M. (2011). CD44 Reciprocally regulates the differentiation of encephalitogenic Th1/Th17 and Th2/regulatory T cells through epigenetic modulation involving DNA methylation of cytokine gene promoters, thereby controlling the development of experimental autoimmune encephalomyelitis. The Journal of Immunology, 186, 6955–6964.PubMedCentralPubMedGoogle Scholar
  41. Haasch, D., Chen, Y. W., Reilly, R. M., Chiou, X. G., Koterski, S., Smith, M. L., et al. (2002). T cell activation induces a noncoding RNA transcript sensitive to inhibition by immunosuppressant drugs and encoded by the proto-oncogene, BIC. Cellular Immunology, 217, 78–86.PubMedGoogle Scholar
  42. Hauser, S. L., & Oksenberg, J. R. (2006). The neurobiology of multiple sclerosis: Genes, inflammation, and neurodegeneration. Neuron, 52, 61–76.PubMedGoogle Scholar
  43. Hecker, M., Thamilarasan, M., Koczan, D., Schröder, I., Flechtner, K., Freiesleben, S., et al. (2013). MicroRNA expression changes during interferon-beta treatment in the peripheral blood of multiple sclerosis patients. International Journal of Molecular Sciences, 14, 16087–16110.PubMedCentralPubMedGoogle Scholar
  44. Hernán, M. A., Olek, M. J., & Ascherio, A. (2001). Cigarette smoking and incidence of multiple sclerosis. American Journal of Epidemiology, 154, 69–74.PubMedGoogle Scholar
  45. Hu, N., Qiu, X., Luo, Y., et al. (2008). Abnormal histone modification patterns in lupus CD4+ T cells. Journal of Rheumatology, 35, 804–810.PubMedGoogle Scholar
  46. Huber, L. C., Brock, M., Hemmatazad, H., Giger, O. T., Moritz, F., Trenkmann, M., et al. (2007). Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. Arthritis and Rheumatism, 56, 1087–1093.PubMedGoogle Scholar
  47. Huynh, J. L., & Casaccia, P. (2013). Epigenetic mechanisms in multiple sclerosis: Implications for pathogenesis and treatment. Lancet Neurology, 12, 195–206.PubMedCentralGoogle Scholar
  48. Inkster, B., Strijbis, E. M., Vounou, M., Kappos, L., Radue, E. W., Matthews, P. M., et al. (2013). Histone deacetylase gene variants predict brain volume changes in multiple sclerosis. Neurobiology of Aging, 34, 238–247.PubMedGoogle Scholar
  49. Jacob, C., Christen, C. N., Pereira, J. A., Somandin, C., Baggiolini, A., Lötscher, P., et al. (2011). HDAC1 and HDAC2 control the transcriptional program of myelination and the survival of Schwann cells. Nature Neuroscience, 14, 429–436.PubMedGoogle Scholar
  50. Januchowski, R., Wudarski, M., Chwalińska-Sadowska, H., & Jagodzinski, P. P. (2008). Prevalence of ZAP-70, LAT, SLP-76, and DNMT1 expression in CD4+ T cells of patients with SLE. Clinical Rheumatology, 27, 21–27.PubMedGoogle Scholar
  51. Junker, A., Krumbholz, M., Eisele, S., et al. (2009). MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain, 132, 3342–3352.PubMedGoogle Scholar
  52. Kaplan, M. J., Lu, Q., Wu, A., Attwood, J., & Richardson, B. (2004). Demethylation of promoter regulatory elements contributes to perforin overexpression in CD41 lupus T cells. The Journal of Immunology, 172, 3652–3661.PubMedGoogle Scholar
  53. Karouzakis, E., Gay, R. E., Michel, B. A., Gay, S., & Neidhart, M. (2009). DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis and Rheumatism, 60, 3613–3622.PubMedGoogle Scholar
  54. Keller, A., Leidinger, P., Lange, J., Borries, A., Schroers, H., Scheffler, M., et al. (2009). Multiple sclerosis: microRNA expression profiles accurately differentiate patients with relapsing-remitting disease from healthy controls. PLoS One, 4, e7440.PubMedCentralPubMedGoogle Scholar
  55. Koch, M., Kingwell, E., Rieckmann, P., & Tremlett, H. (2009). The natural history of primary progressive multiple sclerosis. Neurology, 73, 1996–2002.PubMedGoogle Scholar
  56. Koch, M. W., Metz, L. M., & Kovalchuk, O. (2013a). Epigenetics and miRNAs in the diagnosis and treatment of multiple sclerosis. Trends in Molecular Medicine, 19, 23–30.PubMedGoogle Scholar
  57. Koch, M. W., Metz, L. M., & Kovalchuk, O. (2013b). Epigenetic changes in patients with multiple sclerosis. Nature Reviews Neurology, 9, 35–43.PubMedGoogle Scholar
  58. Korganow, A. S., Knapp, A. M., Nehme-Schuster, H., Soulas-Sprauel, P., Poindron, V., Pasquali, J. L., et al. (2010). Peripheral B cell abnormalities in patients with systemic lupus erythematosus in quiescent phase: Decreased memory B cells and membrane CD19 expression. Journal of Autoimmunity, 34, 426–434.PubMedGoogle Scholar
  59. Kouzarides, T. (2007). Chromatin modifications and their function. Cell, 128, 693–705.PubMedGoogle Scholar
  60. Kremer, D., Schichel, T., Förster, M., Tzekova, N., Bernard, C., van der Valk, P., et al. (2013). Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation. Ann: Neurol. doi: 10.1002/ana.23970.Google Scholar
  61. Kumagai, C., Kalman, B., Middleton, F. A., Vyshkina, T., & Massa, P. T. (2012). Increased promoter methylation of the immune regulatory gene SHP-1 in leukocytes of multiple sclerosis subjects. Journal of Neuroimmunology, 246, 51–57.PubMedCentralPubMedGoogle Scholar
  62. Lal, G., Zhang, N., van der Touw, W., et al. (2009). Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. The Journal of Immunology, 182, 259–273.PubMedCentralPubMedGoogle Scholar
  63. Lauer, K. (2010). Environmental risk factors in multiple sclerosis. Expert Review of Neurotherapeutics, 10, 421–440.PubMedGoogle Scholar
  64. Lee, B. H., Yegnasubramanian, S., Lin, X., & Nelson, W. G. (2005). Procainamide is a specific inhibitor of DNA methyltransferase 1. Journal of Biological Chemistry, 280, 40749–40756.PubMedCentralPubMedGoogle Scholar
  65. Lei, W., Luo, Y., Lei, W., et al. (2009). Abnormal DNA methylation in CD4+ T cells from patients with SLE, systemic sclerosis, and dermatomyositis. Scandinavian Journal of Rheumatology, 38, 369–374.PubMedGoogle Scholar
  66. Li, H., & Richardson, W. D. (2009). Genetics meets epigenetics: HDACs and Wnt signaling in myelin development and regeneration. Nature Neuroscience, 12, 815–817.PubMedGoogle Scholar
  67. Liggett, T., Melnikov, A., Tilwalli, S., Yi, Q., Chen, H., Replogle, C., et al. (2010). Methylation patterns of cell-free plasma DNA in relapsing-remitting multiple sclerosis. Journal of the Neurological Sciences, 290, 16–21.PubMedCentralPubMedGoogle Scholar
  68. Liu, Y., Chen, Y., & Richardson, B. (2009). Decreased DNA methyltransferase levels contribute to abnormal gene expression in “senescent” CD4(+) CD28(−) T cells. Clin. Immunol., 132, 257–265.PubMedCentralPubMedGoogle Scholar
  69. Liu, B., Tahk, S., Yee, K. M., Fan, G., & Shuai, K. (2010). The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression. Science, 330, 521–525.PubMedCentralPubMedGoogle Scholar
  70. Lu, Q., Wu, A., & Richardson, B. C. (2005). Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs. The Journal of Immunology, 174, 6212–6219.PubMedGoogle Scholar
  71. Lu, Q., Wu, A., Tesmer, L., Ray, D., Yousif, N., & Richardson, B. (2007). Demethylation of CD40LG on the inactive X in T cells from women with lupus. The Journal of Immunology, 179, 6352–6358.PubMedGoogle Scholar
  72. Ma, J., Wang, R., Fang, X., Ding, Y., & Sun, Z. (2011). Critical role of TCF-1 in repression of the IL-17 gene. PLoS One, 6, e24768.PubMedCentralPubMedGoogle Scholar
  73. Makar, K. W., & Wilson, C. B. (2004). DNA methylation is a nonredundant repressor of the Th2 effector program. The Journal of Immunology, 173, 4402–4406.PubMedGoogle Scholar
  74. Marin-Husstege, M., Muggironi, M., Liu, A., & Casaccia-Bonnefil, P. (2002). Histone deacetylase activity is necessary for oligodendrocyte lineage progression. Journal of Neuroscience, 22, 10333–10345.PubMedGoogle Scholar
  75. Mastronardi, F. G., Noor, A., Wood, D. D., Paton, T., & Moscarello, M. A. (2007). Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated. Journal of Neuroscience Research, 85, 2006–2016.PubMedGoogle Scholar
  76. Mastronardi, F. G., Wood, D. D., Mei, J., Raijmakers, R., Tseveleki, V., Dosch, H. M., et al. (2006). Increased citrullination of histone H3 in multiple sclerosis brain and animal models of demyelination: A role for tumor necrosis factor-induced peptidylarginine deiminase 4 translocation. Journal of Neuroscience, 26, 11387–11396.PubMedGoogle Scholar
  77. Mazari, L., Ouarzane, M., & Zouali, M. (2007). Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus. Proceedings of the National Academy of Sciences of the United States of America, 104, 6317–6322.PubMedCentralPubMedGoogle Scholar
  78. Mikovits, J. A., Young, H. A., Vertino, P., et al. (1998). Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-gamma) promoter and subsequent downregulation of IFN-γ production. Molecular and Cellular Biology, 18, 5166–5177.PubMedCentralPubMedGoogle Scholar
  79. Mishra, N., Reilly, C. M., Brown, D. R., Ruiz, P., & Gilkeson, G. S. (2003). Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. Journal of Clinical Investigation, 111, 539–552.PubMedCentralPubMedGoogle Scholar
  80. Moscarello, M. A., Brady, G. W., Fein, D. B., Wood, D. D., & Cruz, T. F. (1986). The role of charge microheterogeneity of basic protein in the formation and maintenance of the multilayered structure of myelin: A possible role in multiple sclerosis. Journal of Neuroscience Research, 15, 87–99.PubMedGoogle Scholar
  81. Moscarello, M. A., Wood, D. D., Ackerley, C., & Boulias, C. (1994). Myelin in multiple sclerosis is developmentally immature. Journal of Clinical Investigation, 94, 146–154.PubMedCentralPubMedGoogle Scholar
  82. Mullen, A. C., Hutchins, A. S., Villarino, A. V., et al. (2001). Cell cycle controlling the silencing and functioning of mammalian activators. Current Biology, 11, 1695–1699.PubMedGoogle Scholar
  83. Muñoz-Culla, M., Irizar, H., & Otaegui, D. (2013). The genetics of multiple sclerosis: Review of current and emerging candidates. Application of Clinical Genetics, 6, 63–73.PubMedCentralPubMedGoogle Scholar
  84. Murugaiyan, G., Beynon, V., Mittal, A., Joller, N., & Weiner, H. L. (2011). Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. The Journal of Immunology, 187, 2213–2221.PubMedCentralPubMedGoogle Scholar
  85. Musse, A. A., Boggs, J. M., & Harauz, G. (2006). Deimination of membrane-bound myelin basic protein in multiple sclerosis exposes an immunodominant epitope. Proceedings of the National Academy of Sciences of the United States of America, 103, 4422–4427.PubMedCentralPubMedGoogle Scholar
  86. Musse, A. A., Li, Z., Ackerley, C. A., Bienzle, D., Lei, H., Poma, R., et al. (2008). Peptidylarginine deiminase 2 (PAD2) overexpression in transgenic mice leads to myelin loss in the central nervous system. Disease Models and Mechanisms, 1, 229–240.PubMedCentralPubMedGoogle Scholar
  87. Nakkuntod, J., Avihingsanon, Y., Mutirangura, A., & Hirankarn, N. (2011). Hypomethylation of LINE-1 but not Alu in lymphocyte subsets of systemic lupus erythematosus patients. Clinica Chimica Acta, 412, 1457–1461.Google Scholar
  88. Neidhart, M., Rethage, J., Kuchen, S., Kunzler, P., Crowl, R. M., Billingham, M. E., et al. (2000). Retrotransposable L1 elements expressed in rheumatoid arthritis synovial tissue: Association with genomic DNA hypomethylation and influence on gene expression. Arthritis and Rheumatism, 43, 2634–2647.PubMedGoogle Scholar
  89. Nieves, J., Cosman, F., Herbert, J., Shen, V., & Lindsay, R. (1994). High prevalence of vitamin D deficiency and reduced bone mass in multiple sclerosis. Neurology, 44, 1687–1692.PubMedGoogle Scholar
  90. Noorbakhsh, F., Ellestad, K. K., Maingat, F., Warren, K. G., Han, M. H., Steinman, L., et al. (2011). Impaired neurosteroid synthesis in multiple sclerosis. Brain, 134, 2703–2721.PubMedCentralPubMedGoogle Scholar
  91. O’Connell, R. M., Kahn, D., Gibson, W. S., Round, J. L., Scholz, R. L., Chaudhuri, A. A., et al. (2010). MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity, 33, 607–619.PubMedCentralPubMedGoogle Scholar
  92. Oelke, K., Lu, Q., Richardson, D., Wu, A., Deng, C., Hanash, S., et al. (2004). Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors. Arthritis and Rheumatism, 50, 1850–1860.PubMedGoogle Scholar
  93. Oksenberg, J. R., & Baranzini, S. E. (2010). Multiple sclerosis genetics—Is the glass half full, or half empty? Nature Reviews Neurology, 6, 429–437.PubMedGoogle Scholar
  94. Otaegui, D., Baranzini, S. E., Armañanzas, R., Calvo, B., Muñoz-Culla, M., Khankhanian, P., et al. (2009). Differential micro RNA expression in PBMC from multiple sclerosis patients. PLoS One, 4, e6309.PubMedCentralPubMedGoogle Scholar
  95. Pandis, I., Ospelt, C., Karagianni, N., Denis, M. C., Reczko, M., Camps, C., et al. (2012). Identification of microRNA-221/222 and microRNA-323-3p association with rheumatoid arthritis via predictions using the human tumour necrosis factor transgenic mouse model. Annals of the Rheumatic Diseases, 71, 1716–1723.PubMedGoogle Scholar
  96. Pedre, X., Mastronardi, F., Bruck, W., Lopez-Rodas, G., Kuhlmann, T., & Casaccia, P. (2011). Changed histone acetylation patterns in normal-appearing white matter and early multiple sclerosis lesions. Journal of Neuroscience, 31, 3435–3445.PubMedCentralPubMedGoogle Scholar
  97. Perron, H., & Lang, A. (2010). The human endogenous retrovirus link between genes and environment in multiple sclerosis and in multifactorial diseases associating neuroinflammation. Clinical Reviews in Allergy and Immunology, 39, 51–61.PubMedGoogle Scholar
  98. Pritzker, L. B., Joshi, S., Gowan, J. J., Harauz, G., & Moscarello, M. A. (2000). Deimination of myelin basic protein. 1. Effect of deimination of arginyl residues of myelin basic protein on its structure and susceptibility to digestion by cathepsin D. Biochemistry, 39, 5374–5381.PubMedGoogle Scholar
  99. Quddus, J., Johnson, K. J., Gavalchin, J., Amento, E. P., Chrisp, C. E., Yung, R. L., et al. (1993). Treating activated CD4 þ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice. Journal of Clinical Investigation, 92, 38–53.PubMedCentralPubMedGoogle Scholar
  100. Ramagopalan, S. V., Dobson, R., Meier, U. C., & Giovannoni, G. (2010). Multiple sclerosis: Risk factors, prodromes, and potential causal pathways. Lancet Neurology, 9, 727–739.Google Scholar
  101. Ramagopalan, S. V., et al. (2008). Parental transmission of HLADRB1*15 in multiple sclerosis. Human Genetics, 122, 661–663.PubMedGoogle Scholar
  102. Razin, A. (1998). CpG methylation, chromatin structure and gene silencing-a three-way connection. EMBO Journal, 17, 4905–4908.PubMedCentralPubMedGoogle Scholar
  103. Reik, W., Dean, W., & Walter, J. (2001). Epigenetic reprogramming in mammalian development. Science, 293, 1089–1093.PubMedGoogle Scholar
  104. Reilly, C. M., Mishra, N., Miller, J. M., Joshi, D., Ruiz, P., Richon, V. M., et al. (2004). Modulation of renal disease in MRL/lpr mice by suberoylanilide hydroxamic acid. The Journal of Immunology, 173, 4171–4178.PubMedGoogle Scholar
  105. Richardson, B. (1986). Effect of an inhibitor of DNA methylation on T cells. II. 5-Azacytidine induces self-reactivity in antigen-specific T4+ cells. Human Immunology, 17, 456–470.PubMedGoogle Scholar
  106. Richardson, B., Scheinbart, L., Strahler, J., Gross, L., Hanash, S., & Johnson, M. (1990). Evidence for impaired T cell DNA methylation in SLE and rheumatoid arthritis. Arthritis and Rheumatism, 33, 1665–1673.PubMedGoogle Scholar
  107. Saemann, M. D., Bohmig, G. A., Osterreicher, C. H., Burtscher, H., Parolini, O., Diakos, C., et al. (2000). Anti-inflammatory effects of sodium butyrate on human monocytes: Potent inhibition of IL-12 and up-regulation of IL-10 production. The FASEB Journal, 14, 2380–2382.Google Scholar
  108. Scott, R. J., Booth, D. R., & Lechner-Scott, J. (2010). ANZgene multiple sclerosis genetics consortium. MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood. PLoS One, 5, e12132.PubMedCentralPubMedGoogle Scholar
  109. Shen, S., Sandoval, J., Swiss, V. A., et al. (2008). Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nature Neuroscience, 11, 1024–1034.PubMedCentralPubMedGoogle Scholar
  110. Shigaki, H., Baba, Y., Watanabe, M., Iwagami, S., Miyake, K., Ishimoto, T., et al. (2012). LINE-1 hypomethylation in noncancerous esophageal mucosae is associated with smoking history. Annals of Surgical Oncology, 19, 4238–4243.PubMedGoogle Scholar
  111. Sievers, C., Meira, M., Hoffmann, F., Fontoura, P., Kappos, L., & Lindberg, R. L. (2012). Altered microRNA expression in B lymphocytes in multiple sclerosis: Towards a better understanding of treatment effects. Clinical Immunology, 144, 70–79.PubMedGoogle Scholar
  112. Singer, N. G., Richardson, B. C., Powers, D., et al. (1996). Role of the CD6 glycoprotein in antigen-specific and autoreactive responses of cloned human T lymphocytes. Immunology, 88, 537–543.PubMedCentralPubMedGoogle Scholar
  113. Singleton, A. B., Hardy, J., Traynor, B. J., & Houlden, H. (2010). Towards a complete resolution of the genetic architecture of disease. Trends in Genetics, 26, S438–S442.Google Scholar
  114. Sobel, R. A. (2000). Genetic and epigenetic influence on EAE phenotypes induced with different encephalitogenic peptides. Journal of Neuroimmunology, 108, 45–52.PubMedGoogle Scholar
  115. Swank, R. L., & Dugan, B. B. (1990). Effect of low saturated fat diet in early and late cases of multiple sclerosis. Lancet, 336, 37–39.PubMedGoogle Scholar
  116. Teng, G., Hakimpour, P., Landgraf, P., Rice, A., Tuschl, T., Casellas, R., et al. (2008). MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity, 28, 621–629.PubMedCentralPubMedGoogle Scholar
  117. The International Multiple Sclerosis Genetics Consortium. (2007). Risk alleles for multiple sclerosis identified by a genomewide study. New England Journal of Medicine, 357, 851–862.Google Scholar
  118. Tranquill, L. R., Cao, L., Ling, N. C., Kalbacher, H., Martin, R. M., & Whitaker, J. N. (2000). Enhanced T cell responsiveness to citrulline-containing myelin basic protein in multiple sclerosis patients. Multiple Sclerosis, 6, 220–225.PubMedGoogle Scholar
  119. Urdinguio, R. G., Sanchez-Mut, J. V., & Esteller, M. (2009). Epigenetic mechanisms in neurological diseases: Genes, syndromes, and therapies. Lancet Neurology, 8, 1056–1072.Google Scholar
  120. Vossenaar, E. R., Zendman, A. J., van Venrooij, W. J., & Pruijn, G. J. (2003). PAD, a growing family of citrullinating enzymes: Genes, features and involvement in disease. BioEssays, 25, 1106–1118.PubMedGoogle Scholar
  121. Waschbisch, A., Atiya, M., Linker, R. A., Potapov, S., Schwab, S., & Derfuss, T. (2011). Glatiramer acetate treatment normalizes deregulated microRNA expression in relapsing remitting multiple sclerosis. PLoS One, 6, e24604.PubMedCentralPubMedGoogle Scholar
  122. Wilson, C. B., Makar, K. W., Shnyreva, B., et al. (2005). DNA methylation and the expanding epigenetics of T cell lineage commitment. Seminars in Immunology, 17, 105–119.PubMedGoogle Scholar
  123. Yang, H., Lee, S. M., Gao, B., Zhang, J., & Fang, D. (2013). The histone deacetylase Sirtuin 1 deacetylates IRF1 and programs dendritic cells to control Th17 differentiation during autoimmune inflammation. Journal of Biological Chemistry,. doi: 10.1074/jbc.M113.527531.Google Scholar
  124. Yoshida, M., Kijima, M., Akita, M., & Beppu, T. (1990). Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. Journal of Biological Chemistry, 265, 17174–17179.PubMedGoogle Scholar
  125. Young, H. A., Dray, J. F., & Farrar, W. L. (1986). Expression of transfected human interferon-gamma DNA: Evidence for cell-specific regulation. The Journal of Immunology, 136, 4700–4703.PubMedGoogle Scholar
  126. Young, H. A., Ghosh, P., Ye, J., et al. (1994). Differentiation of the T helper phenotypes by analysis of the methylation state of the IFN-gamma gene. The Journal of Immunology, 153, 3603–3610.PubMedGoogle Scholar
  127. Yung, R., Chang, S., Hemati, N., Johnson, K., & Richardson, B. (1997). Mechanisms of drug induced lupus. IV. Comparison of procainamide and hydralazine with analogs in vitro and in vivo. Arthritis and Rheumatism, 40, 1436–1443.PubMedGoogle Scholar
  128. Yung, R. L., Quddus, J., Chrisp, C. E., Johnson, K. J., & Richardson, B. C. (1995). Mechanism of drug-induced lupus. I. Cloned Th2 cells modified with DNA methylation inhibitors in vitro cause autoimmunity in vivo. The Journal of Immunology, 154, 3025–3035.PubMedGoogle Scholar
  129. Yung, R. L., & Richardson, B. C. (1994). Drug-induced lupus. Rheumatic Diseases Clinics of North America, 20, 61–86.PubMedGoogle Scholar
  130. Zhao, M., Tang, J., Gao, F., et al. (2010). Hypomethylation of IL-10 and IL-13 promoters in CD4+ T cells of patients with SLE. Journal of Biomedicine and Biotechnology, 2010, 9310–9318.Google Scholar
  131. Zhou, Y., & Lu, Q. (2008). DNA methylation in T cells from idiopathic lupus and drug-induced lupus patients. Autoimmunity Reviews, 7, 376–383.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Cem İsmail Küçükali
    • 1
  • Murat Kürtüncü
    • 2
  • Arzu Çoban
    • 2
  • Merve Çebi
    • 1
  • Erdem Tüzün
    • 1
    Email author
  1. 1.Department of Neuroscience, Institute for Experimental Medicine (DETAE)Istanbul UniversityIstanbulTurkey
  2. 2.Department of Neurology, Istanbul Faculty of MedicineIstanbul UniversityIstanbulTurkey

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