Epigenetics and autoimmunity, with special emphasis on methylation

Laboratory of Immunology, Brest University Medical School Hospital, Brest, France.
The Keio Journal of Medicine 03/2011; 60(1):10-6. DOI: 10.2302/kjm.60.10
Source: PubMed

ABSTRACT Epigenetics signifies stable and heritable changes in gene expression without changes in the genetic code. There is a wealth of emerging evidence for such processes in promoting autoimmunity. The first clue is that inhibition of DNA methyl transferases (DNMTs) induces systemic lupus erythematosus (SLE) in animals. Similar immune-mediated disorders have been generated by injecting normal T cells incubated with DNMT inhibitors into healthy mice. Further, monozygotic twins display differences in DNA methylation that parallel discordances in SLE. Moreover, defects in DNA methylation characterize lymphocytes from SLE, synoviocytes from rheumatoid arthritis, and neural cells from multiple sclerosis patients. It has also been shown that DNA hypomethylation of T and B cells correlates with reduced DNMT efficacy and histone acetylation in SLE. Once a gene promoter has been demethylated, the gene recovers its capacity to be transcribed, e.g., genes for cytokines, activation receptors on cells, and endogenous retroviruses. This outcome has been associated with a blockage of the Erk pathway and/or a growth arrest at the G0/G1 interface of the cell cycle. Of importance is the fact that these changes can be reversed. For example, blockade of the interleukin-6 autocrine loop in SLE B cells restores DNA methylation status, thus opening new perspectives for therapy.

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Available from: Yves Renaudineau, Aug 27, 2015
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    • "Important immune response mediators controlled by methylation include INFg, IL-2, IL-4, CD11a, CD70, and protein phosphatase 2A (PP2A), among others [1] [2]. The protein arginine methyltransferase (PRMT) family of enzymes has emerged as a key regulator in T cell activation including modulating the DNA binding ability of phosphorylated STAT1 and the promoter activity of NFAT [3] [4]. "
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    ABSTRACT: Modifications of both DNA and protein by methylation are key factors in normal T and B cell immune responses as well as in the development of autoimmune disease. For example, the failure to maintain the methylation status of CpG dinucleotides in DNA triggers T cell autoreactivity. Methylated proteins are known targets of autoimmunity, including the symmetrical dimethylarginine residues of SmD1 and SmD3 in SLE. Herein, we demonstrate that altering the metabolism of S-adenosylmethionine (SAM), the major methyl donor for transmethylation reactions, can suppress T cell immunity. A by-product of SAM metabolism, 5'-Deoxy-5'-methylthioadenosine (MTA), a byproduct of SAM metabolism and an indirect inhibitor of methyltransferases, inhibits T cell responses including T cell activation markers, Th1/Th2 cytokines and TCR-related signaling events. Moreover, treatment of the lupus-prone MRL/lpr mouse with MTA markedly ameliorates splenomegaly, lymphadenopathy, autoantibody titers as well as IgG deposition and cellular infiltration in the kidney. Incubation of cells with SAM, which increases intracellular MTA levels, inhibits both TCR-mediated T cell proliferation and BCR (anti-IgM)-triggered B cell proliferation in a dose-dependent manner. These studies define the central role of MTA and SAM in immune responses and provide a simple approach to altering lymphocyte transmethylation and T cell mediated autoimmune syndromes.
    Autoimmunity 10/2012; 46(1). DOI:10.3109/08916934.2012.732133 · 2.75 Impact Factor
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    • "Interestingly, these modifications are notably increased by known environmental factors associated with SLE pathology, such as exposure to UV light, infection and drugs or by endogenous factors such as sex, pregnancy and stress. These observations may partly explain why SLE is predominantly observed in women and that SLE prevalence increases with age [3]. Among epigenetic modifications that contribute to altered epigenome regulation in SLE, particular attention has been focused on DNA methylation. "
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    ABSTRACT: The prominent feature of immunological defects in systemic lupus erythematosus (SLE) is the production of autoantibodies (auto-Abs) to nuclear antigens including DNA, histones and RNP. In addition, there is growing evidence that epigenetic changes play a key role in the pathogenesis of SLE. Autoreactive CD4(+) T cells and B cells in patients with SLE have evidence of altered patterns of DNA methylation as well as post-translational modifications of histones and ribonucleoproteins (RNP). A key question that has emerged from these two characteristic features of SLE is whether the two processes are linked. New data provide support for such a link. For example, there is evidence that hypomethylated DNA is immunogenic, that anti-histone auto-Abs in patients with SLE bind epigenetic-sensitive hot spots and that epigenetically-modified RNP-derived peptides can modulate lupus disease. All in all, the available evidence indicates that a better understanding of dysregulation in epigenetics in SLE may offer opportunities to develop new biomarkers and novel therapeutic strategies.
    Journal of Autoimmunity 06/2012; 39(3):154-60. DOI:10.1016/j.jaut.2012.05.015 · 7.02 Impact Factor
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    • "Active SLE -Global DNA hypomethylation -Reduced DNMT-1 mRNA levels [67] [94] [98] "
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    ABSTRACT: The activation of immune cells is mediated by a network of signaling proteins that can undergo post-translational modifications critical for their activity. Methylation of nucleic acids or proteins can have major effects on gene expression as well as protein repertoire diversity and function. Emerging data indicate that indeed many immunologic functions, particularly those of T cells, including thymic education, differentiation and effector function are highly dependent on methylation events. The critical role of methylation in immunocyte biology is further documented by evidence that autoimmune phenomena may be curtailed by methylation inhibitors. Additionally, epigenetic alterations imprinted by methylation can also exert effects on normal and abnormal immune responses. Further work in defining methylation effects in the immune system is likely to lead to a more detailed understanding of the immune system and may point to the development of novel therapeutic approaches.
    Clinical Immunology 12/2011; 143(1):8-21. DOI:10.1016/j.clim.2011.10.007 · 3.99 Impact Factor
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