Abstract
Autoimmune Addison's Disease (AAD) is an endocrine and immunological disease of uncertain pathogenesis resulting from the immune system's destruction of the hormone producing cells of the adrenal cortex. The underlying molecular mechanisms are largely unknown, but it is commonly accepted that a combination of genetic susceptibility and environmental impact is critical. In the present study, we identified multiple hypomethylated gene promoter regions in patients with isolated AAD using DNA isolated from CD4+ T cells. The identified differentially methylated regions were distributed evenly across the 10.5-kb-promoter regions covered by the array, and a substantial number localized to promoters of genes involved in immune regulation and autoimmunity. This study reveals a hypomethylated status in CD4+ T cells from AAD patients and indicates differential methylation of promoters of key genes involved in immune responses.
Highlights
Autoimmune disorders constitute a group of diseases that affect 5–10% of the population in western countries and around 3% worldwide (Shapira et al, 2010; Youinou et al, 2010)
Autoimmune Addison’s Disease (AAD) is primarily associated with class II Human leukocyte antigen (HLA) alleles, suggesting that activation of CD4+ T helper cells is a necessity for the disease to develop
By MeDIP combined with array hybridization, we identified 3373 regions that were differentially methylated between AAD patients and controls (Supplementary Table S1)
Summary
Autoimmune disorders constitute a group of diseases that affect 5–10% of the population in western countries and around 3% worldwide (Shapira et al, 2010; Youinou et al, 2010). Apart from a few autoimmune diseases caused by mutations in single genes (Michels and Gottlieb, 2010), the etiology of most autoimmune diseases is still unclear. It is commonly accepted that a combination of genetic susceptibility and environmental factors are at play, causing breakdown of the natural tolerance mechanisms (Costenbader et al, 2012; Gonzalez et al, 2011; Wing and Sakaguchi, 2010). The relative importance of environmental factors is illustrated by the facts that monozygotic twins show moderate rates of concordance for autoimmune disorders and that drug-induced autoimmunity is observed after medication with demethylating agents (Javierre et al, 2011). As the environment directly impacts the epigenetic code, the surrounding milieu of an individual will directly affect gene regulatory mechanisms and disease development. Bjanesoy et al / Molecular Immunology 59 (2014) 208–216 factors in T cell differentiation and function, such as the interferon gamma locus (Sawalha, 2008), and the transcription factors FoxP3 (forkhead box P3 (Lal et al, 2009) and AIRE (Kont et al, 2011)
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