Multiple sclerosis etiology: Beyond genes and environment

Expert Review of Clinical Immunology

Volumn 6, Issue 3, 2010, Pages 481-490

  Mechelli, Rosella ^a   Annibali, Viviana ^a   Ristori, Giovanni ^a   Vittori, Danila ^a   Coarelli, Giulia ^a   Salvetti, Marco ^a  

^a SAPIENZA UNIVERSITY OF ROME   (Italy)

Author keywords

Alternative splicing; DNA methylation; Epigenetic changes; Histone acetylation; Microarray; Multiple sclerosis; Noncoding RNA; Virus

Indexed keywords

CD40 ANTIGEN; CD6 ANTIGEN; HISTONE DEACETYLASE INHIBITOR; HLA B ANTIGEN; HLA DR ANTIGEN; INTERFERON CONSENSUS SEQUENCE BINDING PROTEIN; INTERLEUKIN 12P35; INTERLEUKIN 2 RECEPTOR ALPHA; INTERLEUKIN 7 RECEPTOR ALPHA; LYMPHOCYTE FUNCTION ASSOCIATED ANTIGEN 3; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; MESSENGER RNA; MICRORNA; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE 1; PROTEIN ARGININE DEIMINASE; TRANSCRIPTOME; UNTRANSLATED RNA; VIRUS ENVELOPE PROTEIN;

ACETYLATION; ALTERNATIVE RNA SPLICING; CD4+ T LYMPHOCYTE; DIET; DNA METHYLATION; ENVIRONMENTAL FACTOR; EPIGENETICS; GENE EXPRESSION; GENETIC ASSOCIATION; GENETIC SUSCEPTIBILITY; HUMAN; MULTIPLE SCLEROSIS; NONHUMAN; PATHOGENESIS; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; SMOKE; SUN EXPOSURE;

ACETYLATION; ALTERNATIVE SPLICING; ANIMALS; DNA METHYLATION; EPIGENESIS, GENETIC; GENES, MHC CLASS II; GENETIC LOCI; GENETIC PREDISPOSITION TO DISEASE; HISTONES; HUMANS; MICE; MULTIPLE SCLEROSIS; RNA, UNTRANSLATED;

EID: 77952083398     PISSN: 1744666X     EISSN: None     Source Type: Journal    
DOI: 10.1586/ECI.10.11     Document Type: Review

References (102)

1. Compston A, Coles A. Multiple sclerosis. Lancet 372 (9648), 1502-1517 (2008).
2. Lincoln MR, Ramagopalan SV, Chao MJ et al. Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility. Proc. Natl Acad. Sci. USA 106 (18), 7542-7547 (2009).
3. Rioux JD, Goyette P, Vyse TJ et al. Mapping of multiple susceptibility variants within the MHC region for 7 immunemediated diseases. Proc. Natl Acad. Sci. USA 106 (44), 18680-18685 (2009).
4. Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene). Genome-wide association study identifes new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat. Genet. 41 (7), 824-828 (2009).
5. Hafer DA, Compston A, Sawcer S et al Risk alleles for multiple sclerosis identifed by a genomewide study. N. Engl. J. Med. 357 (9), 851-862 (2007).
6. Fugger L, Friese MA, Bell JI. From genes to function: the next challenge to understanding multiple sclerosis. Nat. Rev. Immunol. 9 (6), 408-417 (2009).
7. International Multiple Sclerosis Genetics Consortium (IMSGC). Comprehensive follow-up of the frst genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci. Hum. Mol. Genet. 19 (5), 953-962 (2010).
8. Brynedal B, Wojcik J, Esposito F et al MGAT5 alters the severity of multiple sclerosis. J. Neuroimmunol. 220 (1-2), 120-124 (2010).
9. De Jager PL, Jia X, Wang J et al. Metaanalysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat. Genet. 41 (7), 776-782 (2009).
10. De Jager PL, Chibnik LB, Cui J et al. Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score. Lancet Neurol. 8 (12), 1111-1119 (2009).
11. Baranzini SE, Galwey NW, Wang J et al. Pathway and network-based analysis of genome-wide association studies in multiple sclerosis. Hum. Mol. Genet. 18 (11), 2078-2090 (2009).
12. Goldstein DB. Common genetic variation and human traits. N. Engl. J. Med. 360 (17), 1696-1698 (2009).
13. Peltonen L. Old suspects found guilty - the first genome profile of multiple sclerosis. N. Engl. J. Med. 357 (9), 927-929 (2007).
14. Manolio TA, Collins FS, Cox NJ et al. Finding the missing heritability of complex diseases. Nature 461 (7265), 747-753 (2009).
15. Kong A, Steinthorsdottir V, Masson G et al. Parental origin of sequence variants associated with complex diseases. Nature 462 (7275), 868-874 (2009). • The effect of susceptibility variants may depend on the parent from who they are inherited; this variantion may be associated with DNA methylation changes.
16. *1501 and age of onset of multiple sclerosis. J. Hum. Genet. 54 (9), 547-549 (2009).
17. DeLorenze GN, Munger KL, Lennette ET, Orentreich N, Vogelman JH, Ascherio A. Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Arch. Neurol. 63 (6), 839-844 (2006).
18. + T-cell response in patients with early multiple sclerosis. Brain 131 (Pt 7), 1712-1721 (2008).
19. Lunemann JD, Jelcic I, Roberts S et al. EBNA1-specifc T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-γ and IL-2. J. Exp. Med. 205 (8), 1763-1773 (2008).
20. Pender MP, Csurhes PA, Lenarczyk A, Pfuger CM, Burrows SR. Decreased T cell reactivity to Epstein-Barr virus infected lymphoblastoid cell lines in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 80 (5), 498-505 (2009).
21. Cepok S, Zhou D, Srivastava R et al. Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J. Clin. Invest. 115 (5), 1352-1360 (2005).
22. Serafini B, Rosicarelli B, Franciotta D et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J. Exp. Med. 204 (12), 2899-2912 (2007). • This group obtained unprecedented evidence regarding the persistence of Epstein-Barr virus (EBV)-infected B cells in multiple sclerosis (MS) lesions and meningeal lymphoid structures.
23. Peferoen LA, Lamers F, Lodder LN et al. Epstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis. Brain (2009) (Epub ahead of print).
24. Willis SN, Stadelmann C, Rodig SJ et al. Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain 132 (Pt 12), 3318-3328 (2009).
25. Ebers GC. Environmental factors and multiple sclerosis. Lancet Neurol. 7 (3), 268-277 (2008).
26. *1501 is regulated by vitamin D. PLoS Genet. 5 (2), e1000369 (2009).
27. de Snoo F, Bender R, Glas A, Rutgers E. Gene expression profiling: decoding breast cancer. Surg. Oncol. 18 (4), 366-378 (2009).
28. Brazma A, Hingamp P, Quackenbush J et al. Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nat. Genet. 29 (4), 365-371 (2001).
29. Comabella M, Martin R. Genomics in multiple sclerosis - current state and future directions. J. Neuroimmunol. 187 (1-2), 1-8 (2007).
30. Kinter J, Zeis T, Schaeren-Wiemers N. RNA profiling of MS brain tissues. Int. MS J. 15 (2), 51-58 (2008).
31. Tajouri L, Fernandez F, Griffiths LR. Gene expression studies in multiple sclerosis. Curr. Genomics 8 (3), 181-189 (2007).
32. Dutta R, McDonough J, Yin X et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann. Neurol. 59 (3), 478-489 (2006).
33. Satoh J, Nakanishi M, Koike F et al. Microarray analysis identifies an aberrant expression of apoptosis and DNA damage-regulatory genes in multiple sclerosis. Neurobiol. Dis. 18 (3), 537-550 (2005).
34. Torkildsen O, Stansberg C, Angelskar SM et al. Upregulation of immunoglobulinrelated genes in cortical sections from multiple sclerosis patients. Brain Pathol (2009) (Epub ahead of print).
35. Brynedal B, Khademi M, Wallstrom E, Hillert J, Olsson T, Duvefelt K. Gene expression profiling in multiple sclerosis: a disease of the central nervous system, but with relapses triggered in the periphery? Neurobiol. Dis. 37 (3), 613-621 (2010).
36. Gurevich M, Tuller T, Rubinstein U, Or-Bach R, Achiron A. Prediction of acute multiple sclerosis relapses by transcription levels of peripheral blood cells. BMC Med. Genomics 2, 46 (2009).
37. Malmestrom C, Lycke J, Haghighi S et al. Relapses in multiple sclerosis are associated with increased CD8+ T-cell mediated cytotoxicity in CSF. J. Neuroimmunol. 196 (1-2), 159-165 (2008).
38. van Baarsen LG, van der Pouw Kraan TC, Kragt JJ et al. A subtype of multiple sclerosis defined by an activated immune defense program. Genes Immun. 7 (6), 522-531 (2006).
39. Satoh J, Misawa T, Tabunoki H, Yamamura T. Molecular network analysis of T-cell transcriptome suggests aberrant regulation of gene expression by NF-kB as a biomarker for relapse of multiple sclerosis. Dis. Markers 25 (1), 27-35 (2008).
40. Annibali V, Di Giovanni S, Cannoni S et al. Gene expression profiles reveal homeostatic dynamics during interferon-β therapy in multiple sclerosis. Autoimmunity 40 (1), 16-22 (2007).
41. Pigard N, Elovaara I, Kuusisto H et al. Therapeutic activities of intravenous immunoglobulins in multiple sclerosis involve modulation of chemokine expression. J. Neuroimmunol. 209 (1-2), 114-120 (2009).
42. Reder AT, Velichko S, Yamaguchi KD et al. IFN-β1b induces transient and variable gene expression in relapsingremitting multiple sclerosis patients independent of neutralizing antibodies or changes in IFN receptor RNA expression. J. Interferon Cytokine Res. 28 (5), 317-331 (2008).
43. Sellebjerg F, Krakauer M, Hesse D et al. Identification of new sensitive biomarkers for the in vivo response to interferon-β treatment in multiple sclerosis using DNA-array evaluation. Eur. J. Neurol 16 (12), 1291-1298 (2009).
44. Singh MK, Scott TF, LaFramboise WA, Hu FZ, Post JC, Ehrlich GD. Gene expression changes in peripheral blood mononuclear cells from multiple sclerosis patients undergoing β-interferon therapy. J. Neurol. Sci. 258 (1-2), 52-59 (2007).
45. Bomprezzi R, Ringner M, Kim S et al. Gene expression profile in multiple sclerosis patients and healthy controls: identifying pathways relevant to disease. Hum. Mol Genet. 12 (17), 2191-2199 (2003).
46. Ramanathan M, Weinstock-Guttman B, Nguyen LT et al. In vivo gene expression revealed by cDNA arrays: the pattern in relapsing-remitting multiple sclerosis patients compared with normal subjects. J. Neuroimmunol. 116 (2), 213-219 (2001).
47. Chabas D, Baranzini SE, Mitchell D et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294 (5547), 1731-1735 (2001).
48. Steinman L. A molecular trio in relapse and remission in multiple sclerosis. Nat. Rev. Immunol. 9 (6), 440-447 (2009).
49. Lock C, Hermans G, Pedotti R et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8 (5), 500-508 (2002).
50. Luco RF, Pan Q, Tominaga K, Blencowe BJ, Pereira-Smith OM, Misteli T. Regulation of alternative splicing by histone modifications. Science 327 (5968), 996-1000 (2010).
51. Schwartz S, Meshorer E, Ast G. Chromatin organization marks exon-intron structure. Nat. Struct. Mol. Biol. 16 (9), 990-995 (2009).
52. Tilgner H, Nikolaou C, Althammer S et al. Nucleosome positioning as a determinant of exon recognition. Nat. Struct. Mol. Biol 16 (9), 996-1001 (2009).
53. Rajan P, Elliott DJ, Robson CN, Leung HY. Alternative splicing and biological heterogeneity in prostate cancer. Nat. Rev. Urol. 6 (8), 454-460 (2009).
54. Gillett A, Maratou K, Fewings C et al. Alternative splicing and transcriptome profiling of experimental autoimmune encephalomyelitis using genome-wide exon arrays. PLoS One 4 (11), e7773 (2009).
55. Gregory SG, Schmidt S, Seth P et al. Interleukin 7 receptor a chain (IL-7R) shows allelic and functional association with multiple sclerosis. Nat. Genet. 39 (9), 1083-1091 (2007). • The work shows that the MS-associated IL-7R gene variant may be involved in MS development through the differential splicing of membrane-bound and soluble forms.
56. Kim VN. MicroRNA biogenesis: coordinated cropping and dicing. Nat. Rev. Mol. Cell Biol. 6 (5), 376-385 (2005).
57. Davalos V, Esteller M. MicroRNAs and cancer epigenetics: a macrorevolution. Curr. Opin. Oncol. 22 (1), 35-45 (2010).
58. Baltimore D, Boldin MP, O'Connell RM, Rao DS, Taganov KD. MicroRNAs: new regulators of immune cell development and function. Nat. Immunol. 9 (8), 839-845 (2008).
59. O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage infammatory response. Proc. Natl Acad. Sci. USA 104 (5), 1604-1609 (2007).
60. Nelson PT, Wang WX, Rajeev BW. MicroRNAs (miRNAs) in neurodegenerative diseases. Brain Pathol. 18 (1), 130-138 (2008).
61. Otaegui D, Baranzini SE, Armananzas R et al. Differential micro RNA expression in PBMC from multiple sclerosis patients. PLoS One 4 (7), e6309 (2009).
62. Keller A, Leidinger P, Lange J et al. Multiple sclerosis: microRNA expression profiles accurately differentiate patients with relapsing-remitting disease from healthy controls. PLoS One 4 (10), e7440 (2009). • The work proposes miRNA expression profiles in blood cells as a biomarker for MS and suggests that the deregulation of miRNA expression may play a role in the pathogenesis of the disease.
63. Lindberg RL, Hoffmann F, Mehling M, Kuhle J, Kappos L. Altered expression of miR-17-5p in CD4+ lymphocytes of relapsing-remitting multiple sclerosis patients. Eur. J. Immunol. 40 (3), 888-898 (2010).
64. Xiao C, Srinivasan L, Calado DP et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat. Immunol. 9 (4), 405-414 (2008).
65. Berger SL. An embarrassment of niches: the many covalent modifications of histones in transcriptional regulation. Oncogene 20 (24), 3007-3013 (2001).
66. Fischle W, Wang Y, Allis CD. Binary switches and modication cassettes in histone biology anfd beyond. Nature 425 (6957), 475-479 (2003).
67. Ruthenburg AJ, Li H, Patel DJ, Allis CD. Multivalent engagement of chromatin modifcations by linked binding modules. Nat. Rev. Mol. Cell Biol. 8 (12), 983-994 (2007).
68. Karberg S. Switching on epigenetic therapy. Cell 139 (6), 1029-1031 (2009). • This paper summarizes the therapeutic approaches that came from our growing understanding of epigenetic variations in human disease.
69. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 16 (1), 6-21 (2002).
70. Smallwood A, Esteve PO, Pradhan S, Carey M. Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev. 21 (10), 1169-1178 (2007).
71. Christensen BC, Houseman EA, Marsit CJ et al. Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet. 5 (8), e1000602 (2009).
72. Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nat. Rev. Genet. 8 (4), 253-262 (2007).
73. Brooks WH, Le Dantec C, Pers JO, Youinou P, Renaudineau Y. Epigenetics and autoimmunity. J. Autoimmun. 34 (3), J207-J219 (2010).
74. Campos EI, Reinberg D. Histones: annotating chromatin. Annu. Rev. Genet. 43559-43599 (2009).
75. Handel AE, Ebers GC, Ramagopalan SV. Epigenetics: molecular mechanisms and implications for disease. Trends Mol. Med. 16 (1), 7-16 (2010).
76. Robertson KD. DNA methylation and human disease. Nat. Rev. Genet. 6 (8), 597-610 (2005).
77. Sekigawa I, Okada M, Ogasawara H, Kaneko H, Hishikawa T, Hashimoto H. DNA methylation in systemic lupus erythematosus. Lupus 12 (2), 79-85 (2003).
78. Urdinguio RG, Sanchez-Mut JV, Esteller M. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol. 8 (11), 1056-1072 (2009).
79. Moscarello MA, Pritzker L, Mastronardi FG, Wood DD. Peptidylarginine deiminase: a candidate factor in demyelinating disease. J. Neurochem. 81 (2), 335-343 (2002).
80. Mastronardi FG, Noor A, Wood DD, Paton T, Moscarello MA. Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated. J. Neurosci. Res. 85 (9), 2006-2016 (2007). • The authors observe a dysregulation in peptidyl argininedeiminase 2 promoter DNA methylation, suggesting that this mechanism may control the integrity of myelin basic protein in MS brain tissue.
81. Mastronardi FG, Wood DD, Mei J et al. 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. J. Neurosci. 26 (44), 11387-11396 (2006).
82. Morris AC, Spangler WE, Boss JM. Methylation of class II trans-activator promoter IV: a novel mechanism of MHC class II gene control. J. Immunol. 164 (8), 4143-4149 (2000).
83. Ramagopalan SV, Dyment DA, Morrison KM et al. Methylation of class II transactivator gene promoter IV is not associated with susceptibility to multiple sclerosis. BMC Med. Genet. 9, 63 (2008).
84. Gialitakis M, Kretsovali A, Spilianakis C et al. Coordinated changes of histone modifcations and HDAC mobilization regulate the induction of MHC class II genes by Trichostatin A. Nucleic Acids Res. 34 (3), 765-772 (2006).
85. Camelo S, Iglesias AH, Hwang D et al. Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J. Neuroimmunol 164 (1-2), 10-21 (2005).
86. Guastafierro T, Cecchinelli B, Zampieri M et al. CCCTC-binding factor activates PARP-1 affecting DNA methylation machinery. J. Biol. Chem. 283 (32), 21873-21880 (2008).
87. Wacker DA, Ruhl DD, Balagamwala EH, Hope KM, Zhang T, Kraus WL. The DNA binding and catalytic domains of poly (ADP-ribose) polymerase 1 cooperate in the regulation of chromatin structure and transcription. Mol. Cell Biol. 27 (21), 7475-7485 (2007).
88. Selvaraj V, Soundarapandian MM, Chechneva O et al. PARP-1 deficiency increases the severity of disease in a mouse model of multiple sclerosis. J. Biol. Chem. 284 (38), 26070-26084 (2009).
89. Farez MF, Quintana FJ, Gandhi R, Izquierdo G, Lucas M, Weiner HL. Toll-like receptor 2 and poly (ADP-ribose) polymerase 1 promote central nervous system neuroinfammation in progressive EAE. Nat. Immunol. 10 (9), 958-964 (2009).
90. Ascherio A, Munger KL, Lennette ET et al. Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 286 (24), 3083-3088 (2001).
91. Lieberman PM. Chromatin regulation of virus infection. Trends Microbiol. 14 (3), 132-140 (2006).
92. Tempera I, Lieberman PM. Chromatin organization of gammaherpesvirus latent genomes. Biochim. Biophys. Acta 1799 (3-4), 236-245 (2009).
93. Babcock GJ, Hochberg D, Thorley-Lawson AD. The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity 13 (4), 497-506 (2000).
94. Schulz WA, Steinhoff C, Florl AR. Methylation of endogenous human retroelements in health and disease. Curr. Top. Microbiol. Immunol. 310, 211-250 (2006).
95. Antony JM, Ellestad KK, Hammond R et al. The human endogenous retrovirus envelope glycoprotein, syncytin-1, regulates neuroinfammation and its receptor expression in multiple sclerosis: a role for endoplasmic reticulum chaperones in astrocytes. J. Immunol. 179 (2), 1210-1224 (2007).
96. Perron H, Garson JA, Bedin F et al. Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Sclerosis. Proc. Natl Acad. Sci. USA 94 (14), 7583-7588 (1997).
97. Dolei A, Serra C, Mameli G et al. Multiple sclerosis-associated retrovirus (MSRV) in Sardinian MS patients. Neurology 58 (3), 471-473 (2002).
98. Sotgiu S, Arru G, Mameli G et al. Multiple sclerosis-associated retrovirus in early multiple sclerosis: a six-year follow-up of a Sardinian cohort. Mult. Scler. 12 (6), 698-703 (2006).
99. Sotgiu S, Serra C, Mameli G et al. Multiple sclerosis-associated retrovirus and MS prognosis: an observational study. Neurology 59 (7), 1071-1073 (2002).
100. Perron H, Suh M, Lalande B et al. Herpes simplex virus ICP0 and ICP4 immediate early proteins strongly enhance expression of a retrovirus harboured by a leptomeningeal cell line from a patient with multiple sclerosis. J. Gen. Virol. 74 (Pt 1), 65-72 (1993).
101. Aartsma-Rus A, van Ommen GJ. Less is more: therapeutic exon skipping for Duchenne muscular dystrophy. Lancet Neurol. 8 (10), 873-875 (2009).
102. Kinali M, Arechavala-Gomeza V, Feng L et al. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, pro of-of-concept study. Lancet Neurol. 8 (10), 918-928 (2009).