Systemic Lupus Erythematosus: Genetic and Epigenetic View

Abstract

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex aetiology, in which susceptibility is determined by the combination of genetic, environmental, epigenetic and stochastic factors. SLE is very heterogeneous in its clinical manifestations and the presence of different autoantibodies may predict different set of clinical outcome. However, despite considerable accumulated knowledge, the detailed pathogenesis of SLE still remains unknown. Several studies have indicated the importance of deoxyribonucleic acid (DNA) hypomethylation in the aetiology of SLE. Recent advances in high‐throughput genotyping technologies and high‐density genetic association studies have identified and replicated many SLE susceptibility genes in different populations. In this article, we outline our current understanding of some genetic and epigenetic aspects of SLE.

Keywords: SLE; Candidate gene; Linkage; Association; Epigenetic; DNA methylation

Figure 1.

Malar rash in a lupus patient. The erythematous eruptions involve the dorsum of the nose and the malar areas, and spare the nasolabial folds. Reproduced with permission from Sawalha AH, Diaz L and Harley JB (2006) Systemic lupus erythematosus. In: Diaz L (Ed.) Principles of Molecular Medicine, 2nd edn, pp. 970–978. Totowa: Humana Press Inc.

Figure 2.

Inhibiting DNA methylation induces T‐cell autoreactivity in vitro and autoimmunity in vivo. T cells treated with the DNA methylation inhibitor 5‐azacytidine overexpress methylation sensitive genes such as CD11a and CD70. These T cells become autoreactive and capable of stimulating autologous B cells in vitro, an effect that can be inhibited by anti‐CD70 antibodies. Upon adoptive transfer into mice, 5‐azacytidine treated T cells induce a lupus‐like autoimmune phenotype characterized by the production of autoantibodies and the development of glomerulonephritis, alveolitis and central nervous system (CNS) lupus lesions.

Figure 3.

Abnormal T‐cell DNA methylation in the pathogenesis of lupus. ERK pathway signalling is defective in lupus T cells. DNA methyltransferase 1 enzyme (DNMT1) is regulated in part by signalling through the ERK pathway, and therefore the expression of DNMT1 is reduced in lupus T cells. This results in T‐cell DNA hypomethylation and overexpression of methylation senstive genes such as CD11a, CD70 and Perforin, making T cells autoreactive and capable of inducing autoimmunity.

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References

Aitman TJ, Dong R, Vyse TJ et al. (2006) Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 439(7078): 851–855.

Alarcón‐Riquelme ME (2003) A RUNX trio with a taste for autoimmunity. Nature Genetics 35(4): 299–300.

Atagunduz P, Appel H, Kuon W et al. (2005) HLA‐B27‐restricted CD8+ T cell response to cartilage‐derived self peptides in ankylosing spondylitis. Arthritis and Rheumatism 52: 892–901.

Ballestar E, Esteller M and Richardson BC (2006) The epigenetic face of systemic lupus erythematosus. Journal of Immunology 176(12): 7143–7147.

Busslinger M and Flavell RA (1983) DNA methylation and the regulation of globin gene expression. Progress in Clinical and Biological Research 134: 193–203.

Cornacchia E, Golbus J, Maybaum J et al. (1988) Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity. Journal of Immunology 140(7): 2197–2200.

Deng C, Kaplan MJ, Yang J et al. (2001) Decreased Ras‐mitogen‐activated protein kinase signaling may cause DNA hypomethylation in T lymphocytes from lupus patients. Arthritis and Rheumatism 44(2): 397–407.

Deng C, Lu Q, Zhang Z et al. (2003) Hydralazine may induce autoimmunity by inhibiting extracellular signal‐regulated kinase pathway signaling. Arthritis and Rheumatism 48(3): 746–756.

Fanciulli M, Norsworthy PJ, Petretto E et al. (2007) FCGR3B copy number variation is associated with susceptibility to systemic, but not organ‐specific, autoimmunity. Nature Genetics 39(6): 721–723.

Graham DS, Manku H, Wagner S et al. (2007) Association of IRF5 in UK SLE families identifies a variant involved in polyadenylation. Human Molecular Genetics 16: 579–591.

Graham RR, Ortmann WA, Langefeld CD et al. (2002) Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus. American Journal of Human Genetics 71(3): 543–553.

Gregersen PK, Lee HS, Batliwalla F and Begovich AB (2006) PTPN22: setting thresholds for autoimmunity. Seminars in Immunology 18: 214–223.

Hauptmann G, Tappeiner G and Schifferli JA (1988) Inherited deficiency of the fourth component of human complement. Immunodeficiency Reviews 1: 3–22.

Helms C, Cao L, Krueger JG et al. (2003) A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nature Genetics 35(4): 349–356.

Hiromine Y, Ikegami H, Fujisawa T et al. (2007) Metabolism. Trinucleotide repeats of programmed cell death‐1 gene are associated with susceptibility to type 1 diabetes mellitus. Metabolism 56(7): 905–909.

Lee JY, Goldman D, Piliero LM, Petri M and Sullivan KE (2001) Interferon‐gamma polymorphisms in systemic lupus erythematosus. Genes and Immunity 2: 254–257.

Lee YH and Nath SK (2005) Systemic lupus erythematosus susceptibility loci defined by genome scan meta‐analysis. Human Genetics 118: 434–443.

Nakashima H, Inoue H, Akahoshi M et al. (1999) The combination of polymorphisms within interferon‐gamma receptor 1 and receptor 2 associated with the risk of systemic lupus erythematosus. FEBS Letters 453: 187–190.

Nath SK, Kilpatrick J and Harley JB (2004) Genetics of human systemic lupus erythematosus: the emerging picture. Current Opinion in Immunology 16(6): 794–800.

Nielsen C, Hansen D, Husby S, Jacobsen BB and Lillevang ST (2003) Association of a putative regulatory polymorphism in the PD‐1 gene with susceptibility to type 1 diabetes. Tissue Antigens 62: 492–497.

Oelke K, Lu Q, Richardson D 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(6): 1850–1860.

Pascual V, Farkas L and Banchereau J (2006) Systemic lupus erythematosus: all roads lead to type I interferons. Current Opinion in Immunology 18: 676–682.

Prokunina L, Castillejo‐López C, Oberg F et al. (2002) A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nature Genetics 32(4): 666–669.

Prokunina L, Padyukov L, Bennet A et al. (2004) Association of the PD‐1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope. Arthritis and Rheumatism 50: 1770–1773.

Remmers EF, Plenge RM, Lee AT et al. (2007) STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. New England Journal of Medicine 357: 977–986.

Richardson BC, Strahler JR, Pivirotto TS et al. (1992) Phenotypic and functional similarities between 5‐azacytidine‐treated T cells and a T cell subset in patients with active systemic lupus erythematosus. Arthritis and Rheumatism 35(6): 647–662.

Sawalha AH and Harley JB (2004) Antinuclear autoantibodies in systemic lupus erythematosus. Current Opinion in Rheumatology 16(5): 534–540.

Sawalha AH and Jeffries M (2007) Defective DNA methylation and CD70 overexpression in CD4+ T cells in MRL/lpr lupus‐prone mice. European Journal of Immunology 37(5): 1407–1413.

Sawalha AH and Richardson BC (2005) DNA methylation in the pathogenesis of systemic lupus erythematosus. Current Pharmacogenomics 3: 73–78.

Sestak AL, Nath SK, Sawalha AH et al. (2007) Current status of lupus genetics. Arthritis Research & Therapy 9(3): 210.

Sigurdsson S, Nordmark G, Goring HH et al. (2005) Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. American Journal of Human Genetics 76: 528–537.

Sullivan KE, Petri MA, Schmeckpeper BJ, McLean RH and Winkelstein JA (1994) Prevalence of a mutation causing C2 deficiency in systemic lupus erythematosus. Journal of rheumatology 21: 1128–1133.

Tokuhiro S, Yamada R, Chang X et al. (2003) An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nature Genetics 35(4): 341–348.

Wilson AG, Gordon C, di Giovine FS et al. (1994) A genetic association between systemic lupus erythematosus and tumor necrosis factor alpha. European Journal of Immunology 24: 191–195.

Yang Y, Chung EK, Wu YL et al. (2007) Gene copy‐number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. American Journal of Human Genetics 80(6): 1037–1054.

Yang Y, Chung EK, Zhou B et al. (2004) The intricate role of complement componenet C4 in human systemic lupus erythematosus. Current Directions in Autoimmunity 7: 98–132.

Yao X, Li YM, Hu ZJ, Li WZ and Chen ZQ (2005) Polymorphisms within the interferon‐gamma receptor associated with systemic lupus erythematosus [in Chinese]. Zhonghua Yi Xue Yi Chuan Xue Az Zhi 22: 320–323.

Yung RL, Quddus J, Chrisp CE et al. (1995) Mechanism of drug‐induced lupus. I. Cloned Th2 cells modified with DNA methylation inhibitors in vitro cause autoimmunity in vivo. Journal of Immunology 154(6): 3025–3035.

Further Reading

DeWan A, Klein RJ and Hoh J (2007) Linkage disequilibrium mapping for complex disease genes. Methods in Molecular Biology 376: 85–107.

Huber LC, Stanczyk J, Jüngel A and Gay S (2007) Epigenetics in inflammatory rheumatic diseases. Arthritis and Rheumatism. 56: 3523–3531.

Jacob CO, Reiff A, Armstrong DL et al. (2007) Identification of novel susceptibility genes in childhood‐onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform. Arthritis and Rheumatism 56(12): 4164–4173.

Kozyrev SV and Alarcon‐Riquelme ME (2007) The genetics and biology of Irf5‐mediated signaling in lupus. Autoimmunity 40(8): 591–601.

Moonesinghe R, Khoury MJ, Liu T and Ioannidis JP (2008) Required sample size and nonreplicability thresholds for heterogeneous genetic associations. Proceedings of the National Academy of Sciences of the USA 105(2): 617–622.

Rhodes B and Vyse TJ (2007) General aspects of the genetics of SLE. Autoimmunity 40(8): 550–559.

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Nath, Swapan K, and Sawalha, Amr H(Jul 2008) Systemic Lupus Erythematosus: Genetic and Epigenetic View. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006092]