ReviewEpigenetics in autoimmune disorders: Highlights of the 10th Sjögren's Syndrome Symposium
Introduction
The mechanisms causing most human autoimmune diseases remain obscure. Although genes and genetic loci causing predispositions to autoimmunity are being identified, incomplete disease concordance in identical twins indicates that non-genetic factors and mechanisms also contribute to autoimmune etiologies. Eukaryotic gene expression requires not only the regulated activity of transcription factors, but also a transcriptionally permissive regional chromatin configuration. The structure of chromatin is regulated by epigenetic mechanisms, primarily DNA methylation and histone modifications. Several recent studies have demonstrated that disrupting the epigenetic regulation of transcription plays crucial roles in the development of autoimmune diseases. The main purpose of the “epigenetics session” at Brest, France, October 2, 2009 (http://www.sjogrensymposium-brest2009.org),was not only to present recent academic works, but also to obtain a more comprehensive view of the current state of epigenetics research in the international autoimmunity community.
Epigenetic modifications are changes in gene expression that can be maintained throughout a cell's life and be passed on through cell division, and thus can remain persistent in the organism without alterations in DNA sequences. Epigenetic factors are associated with a great number of diseases, including cancer, autoimmune disorders, heart diseases and skin diseases. Since drugs that can reverse aberrant gene expression profiles are readily available, the identification and subsequent modification of epigenetic markers involved in disease development may provide important novel therapeutic approaches for autoimmune disorders.
Section snippets
What are epigenetic modifications?
Epigenetic regulatory mechanisms comprise DNA methylation, a variety of histone modifications, of which the best characterized is acetylation, and microRNA activity; all of which act upon gene and protein expression levels [1], [2], [3]. In vertebrates, DNA methylation is defined as the postsynthetic addition of methyl groups to cytosine bases, generally only those in CpG pairs, at position 5 of the pyrimidine ring, and catalyzed by a DNA methyltransferase (DNMT). About 70% of CpG dinucleotides
Epigenetic modifications and autoimmune diseases
Continued efforts in the field of epigenetics have led to the discovery of associations between every epigenetic modification mentioned above and one or more autoimmune disorder. Specific epigenetic defects associated with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) and systemic sclerosis (SSc) were presented and are summarized below.
B and T cell autoreactivity
Yves Renaudineau (University of Brest, France) presented evidence detailing the contribution of DNA demethylation defects to the autoreactivity of B cells [22]. Indeed, testing the influence of IL-6 overproduction by SLE B cells, it was observed that IL-6 abrogates the ability of SLE B cells to induce DNMT1, and then to methylate DNA. This effect is reversed in the presence of a blocking monoclonal antibody to IL-6 receptor, and reproduced in B cells from healthy controls when the cells are
Concluding remarks
The “epigenetics session” of the 10th International Symposium on SS provided an opportunity to relate and discuss the latest research findings in the field of epigenetics. Participants candidly agreed on the creation of a worldwide epigenetic bank and to the development of gold standards in an epigenetic consortium. The momentum in the field is considerable, and all participants look forward to the “epigenetics session” that will take place during the Autoimmunity Congress in Ljubljana, May
Take-home messages
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Epigenetic regulatory mechanisms comprise DNA methylation, a variety of histone modifications, and microRNA activity; all of which act upon gene and protein expression levels.
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Increased activity and destructive potential of synovial fibroblasts in rheumatoid arthritis are due in part to the deregulation of epigenetic factors.
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Development of an epigenetic bank and the establishment of gold standards in an epigenetic consortium to analyse epigenetic modifications are needed.
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Epigenetic alterations
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