Abstract
The etiology of systemic lupus erythematosus (SLE) involves a complex interaction of genetic and environmental factors. Investigations have shown that environmentally driven epigenetic changes contribute to the etiology of SLE. Here, we hypothesize that aberrant DNA methylation may contribute to the activation of the immune machinery and trigger lupus disease activity. A whole genome methylation array was applied to investigate the DNA methylation changes between 12 pairs of active SLE patients and healthy controls. The results were further confirmed in 66 SLE patients, 102 healthy controls. The methylation statuses of the IL10 and IL1R2 genes were significantly reduced in the SLE patient samples relative to the healthy controls (age-adjusted odds ratios, 64.2 and 16.9, respectively, P<0.0001). There was a trend toward SLE patients having hypomethylated IL10 and IL1R2 genes accompanied by greater disease activity. We observed that the methylation degree of IL10 and IL1R2 genes were reduced in the rheumatoid arthritis (RA) patients as well but the hypomethylation change was more significant in IL1R2 genes than in the IL10 genes in RA patients. This study demonstrated that DNA hypomethylation might be associated with SLE. Hypomethylated IL10 and IL1R2 genes may provide potential epigenetic markers as clinical predictors for autoimmune diseases.
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References
Kassi E, Moutsatsou P . Estrogen receptor signaling and its relationship to cytokines in systemic lupus erythematosus. J Biomed Biotechnol 2010; 2010: 317452.
Deng C, Lu Q, Zhang Z, Rao T, Attwood J, Yung R et al. Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling. Arthritis Rheum 2003; 48: 746–756.
Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 2009; 41: 1228–1233.
Gorelik G, Fang JY, Wu A, Sawalha AH, Richardson B . Impaired T cell protein kinase C delta activation decreases ERK pathway signaling in idiopathic and hydralazine-induced lupus. J Immunol 2007; 179: 5553–5563.
Sawalha AH, Webb R, Han S, Kelly JA, Kaufman KM, Kimberly RP et al. Common variants within MECP2 confer risk of systemic lupus erythematosus. PLoS ONE 2008; 3: e1727.
Deapen D, Escalante A, Weinrib L, Horwitz D, Bachman B, Roy-Burman P et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 1992; 35: 311–318.
Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S, Johnson M . Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 1990; 33: 1665–1673.
Oelke K, Lu Q, Richardson D, Wu A, Deng C, Hanash S et al. Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors. Arthritis Rheum 2004; 50: 1850–1860.
Scheinbart LS, Johnson MA, Gross LA, Edelstein SR, Richardson BC . Procainamide inhibits DNA methyltransferase in a human T cell line. J Rheumatol 1991; 18: 530–534.
Sawalha AH, Jeffries M, Webb R, Lu Q, Gorelik G, Ray D et al. Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation-sensitive genes similar to lupus patients. Genes Immun 2008; 9: 368–378.
Cornacchia E, Golbus J, Maybaum J, Strahler J, Hanash S, Richardson B . Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity. J Immunol 1988; 140: 2197–2200.
Ballestar E, Esteller M, Richardson BC . The epigenetic face of systemic lupus erythematosus. J Immunol 2006; 176: 7143–7147.
Llorente L, Richaud-Patin Y, Fior R, Alcocer-Varela J, Wijdenes J, Fourrier BM et al. In vivo production of interleukin-10 by non-T cells in rheumatoid arthritis, Sjogren′s syndrome, and systemic lupus erythematosus. A potential mechanism of B lymphocyte hyperactivity and autoimmunity. Arthritis Rheum 1994; 37: 1647–1655.
Hagiwara E, Gourley MF, Lee S, Klinman DK . Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10:interferon-gamma-secreting cells in the peripheral blood. Arthritis Rheum 1996; 39: 379–385.
Houssiau FA, Lefebvre C, Vanden Berghe M, Lambert M, Devogelaer JP, Renauld JC . Serum interleukin 10 titers in systemic lupus erythematosus reflect disease activity. Lupus 1995; 4: 393–395.
Llorente L, Richaud-Patin Y, Wijdenes J, Alcocer-Varela J, Maillot MC, Durand-Gasselin I et al. Spontaneous production of interleukin-10 by B lymphocytes and monocytes in systemic lupus erythematosus. Eur Cytokine Netw 1993; 4: 421–427.
Park YB, Lee SK, Kim DS, Lee J, Lee CH, Song CH . Elevated interleukin-10 levels correlated with disease activity in systemic lupus erythematosus. Clin Exp Rheumatol 1998; 16: 283–288.
Brown MA . Genetics of ankylosing spondylitis. Curr Opin Rheumatol 2010; 22: 126–132.
Kulkarni O, Anders HJ . Chemokines in lupus nephritis. Front Biosci 2008; 13: 3312–3320.
Lourenco EV, Cava A . Cytokines in systemic lupus erythematosus. Curr Mol Med 2009; 9: 242–254.
Linker-Israeli M, Deans RJ, Wallace DJ, Prehn J, Ozeri-Chen T, Klinenberg JR . Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis. J Immunol 1991; 147: 117–123.
Viallard JF, Pellegrin JL, Ranchin V, Schaeverbeke T, Dehais J, Longy-Boursier M et al. Th1 (IL-2, interferon-gamma (IFN-gamma)) and Th2 (IL-10, IL-4) cytokine production by peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE). Clin Exp Immunol 1999; 115: 189–195.
Johanneson B, Lima G, von Salome J, Alarcon-Segovia D, Alarcón-Riquelme ME . A major susceptibility locus for systemic lupus erythemathosus maps to chromosome 1q31. Am J Hum Genet 2002; 71: 1060–1071.
Lopez P, Gutierrez C, Suárez A . IL-10 and TNFalpha genotypes in SLE. J Biomed Biotechnol 2010; 2010: 838390.
Nath SK, Harley JB, Lee YH . Polymorphisms of complement receptor 1 and interleukin-10 genes and systemic lupus erythematosus: a meta-analysis. Hum Genet 2005; 118: 225–234.
Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J et al. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res 2010; 20: 170–179.
Mellor-Pita S, Citores MJ, Castejon R, Yebra-Bango M, Tutor-Ureta P, Rosado S et al. Monocytes and T lymphocytes contribute to a predominance of interleukin 6 and interleukin 10 in systemic lupus erythematosus. Cytometry B Clin Cytom 2009; 76B: 261–270.
al-Janadi M, al-Dalaan A, al-Balla S, al-Humaidi M, Raziuddin S . Interleukin-10 (IL-10) secretion in systemic lupus erythematosus and rheumatoid arthritis: IL-10-dependent CD4+CD45RO+ T cell-B cell antibody synthesis. J Clin Immunol 1996; 16: 198–207.
Murakawa Y, Takada S, Ueda Y, Suzuki N, Hoshino T, Sakane T . Characterization of T lymphocyte subpopulations responsible for deficient interleukin 2 activity in patients with systemic lupus erythematosus. J Immunol 1985; 134: 187–195.
Chun HY, Chung JW, Kim HA, Yun JM, Jeon JY, Ye YM et al. Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus. J Clin Immunol 2007; 27: 461–466.
Zhao M, Tang J, Gao F, Wu X, Liang Y, Yin H et al. Hypomethylation of IL10 and IL13 promoters in CD4+ T cells of patients with systemic lupus erythematosus. J Biomed Biotechnol 2010; 2010: 931018.
Merrill JT, Erkan D, Buyon JP . Challenges in bringing the bench to bedside in drug development for SLE. Nat Rev Drug Discov 2004; 3: 1036–1046.
Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH . Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992; 35: 630–640.
Bell CG, Teschendorff AE, Rakyan VK, Maxwell AP, Beck S, Savage DA . Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus. BMC Med Genomics 2010; 3: 33.
Bibikova M LJ, Barnes B, Saedinia-Melnyk S, Zhou L, Shen R, Gunderson K . Genome-wide DNA methylation profiling using Infinium assay. Epigenomics 2009; 1: 177–200.
Alvarez S, Suela J, Valencia A, Fernandez A, Wunderlich M, Agirre X et al. DNA methylation profiles and their relationship with cytogenetic status in adult acute myeloid leukemia. PLoS One 2010; 5: e12197.
Acknowledgements
We would like to thank all of the SLE patients and healthy controls who participated in this study, as well as I-Ting Chung (GeneTech Biotech, Taipei, Taiwan) for helping with the array analysis. This work was supported by grants from the National Scientific Council (NSC 99-2314-B-002 -072 -MY3 and NSC 98-2314-B-002-142), from the National Taiwan University Hospital-Taipei Veterans General Hospital joint research program (NTUH-TVGH100-07) and from National Taiwan University Hospital (NTUH.100-M1747).
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Lin, SY., Hsieh, SC., Lin, YC. et al. A whole genome methylation analysis of systemic lupus erythematosus: hypomethylation of the IL10 and IL1R2 promoters is associated with disease activity. Genes Immun 13, 214–220 (2012). https://doi.org/10.1038/gene.2011.74
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DOI: https://doi.org/10.1038/gene.2011.74
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