Epigenetic alterations and autoimmune disease

Abstract

Recent advances in epigenetics have enhanced our knowledge of how environmental factors (UV radiation, drugs, infections, etc.) contribute to the development of autoimmune diseases (AID) in genetically predisposed individuals. Studies conducted in monozygotic twins discordant for AID and spontaneous autoimmune animal models have highlighted the importance of DNA methylation changes and histone modifications. Alterations in the epigenetic pattern seem to be cell specific, as CD4+ T cells and B cells are dysregulated in systemic lupus erythematosus, synovial fibroblasts in rheumatoid arthritis and cerebral cells in multiple sclerosis. With regard to lymphocytes, the control of tolerance is affected, leading to the development of autoreactive cells. Other epigenetic processes, such as the newly described miRNAs, and post-translational protein modifications may also be suspected. Altogether, a conceptual revolution is in progress, in AID, with potential new therapeutic strategies targeting epigenetic patterns.

DNA Methylation in Systemic Lupus Erythematosus

“…In addition to cytokines, intra-and extracellular signaling molecules can be regulated through DNA methylation, some of which exhibit alterations in T and B cells from SLE patients (Table 1). Reduced methylation of regulatory regions of genes encoding for costimulatory molecules, including TNF ligand superfamily member 7: TNFSF7 (CD70/CD62L) [56], cluster of differentiation 6: CD6 [57], integrin α L: ITGAL (CD11A) [58], TNF ligand superfamily member 5: TNFSF5 (CD40L/CD154) [59,60] in T cells, and cluster of differentiation 5: CD5 [54] in B cells has been documented [6,7,11,[61][62][63]. Reduced DNA methylation in SLE T cells results in expression of usually CD8 + T celland NK cell-specific perforin (PRF1 gene) in CD4 + T cells, likely contributing to increased T cell mediated cell death of monocytes and macrophages [64,65].…”

“…Unfortunately, currently available drugs act in an untargeted way on the entire genome and may therefore result in deregulation of previously unaffected genes. Furthermore, DNA hypermethylation (reversible by these drugs) only occurs at a relatively small number of genes in lymphocytes from SLE patients, which tend to be hypomethylated [6,7,11,15,[61][62][63]. Target-directed and gene-specific epigenetic modifiers are currently unavailable, but may be required to reverse disease-causing or disease-modifying epigenetic alterations in SLE.…”

Serum thymosin α 1 levels in patients with chronic inflammatory autoimmune diseases

“…Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammation and tissue damage due to circulating autoantibodies and immune complexes depositing in different tissues . The aetiology of such diseases is still uncertain, although the role of genetic and epigenetic factors has been emphasized . The pathophysiology of RA, PsA and SLE implies an intricate cytokine network participating in inflammation and in perpetuation of disease by positive feedback loops including abnormal T cell signalling and unbalanced T helper type 17 (Th17)/regulatory T cells (T regs ) ratio (but may involve the overall cytokine milieu), thus promoting systemic disease .…”

Modificaciones epigenéticas en neurología: alteraciones en la metilación del ADN en la esclerosis múltiple

“…Su etiología es aún desconocida, aunque se presume un origen autoinmune y multifactorial, en la que se han descrito varios factores de susceptibilidad genética y ambiental. Teniendo en cuenta la complejidad de la enfermedad y la participación de diversos mecanismos etiológicos, tanto genéticos como ambientales, es lógico suponer que pueda existir una alteración en la regulación epigenética que participe en su desarrollo 12,13 .…”