Systemic Lupus Erythematosus: Genetic and Epigenetic View


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