Autoimmune diseases are generally considered as complex (and/or multi-factorial) diseases. Genetic background confers susceptibility to or protection from disease onset, but it is neither sufficient nor causative for disease development. While numerous similarities between conditions are being identified 1
, the etiology of the majority of autoimmune diseases remains largely unknown. Although strong genetic bases have been found by recent genome-wide association studies 2
, these studies fail to demonstrate the presence of a unique genetic mechanism underlying immune tolerance breakdown and, moreover, the significant genetic associations identified are found only in relative small proportion of patients.
The largely incomplete concordance rates of autoimmune diseases in monozygotic twins () strongly support other complementary mechanisms involved in gene expression regulation ultimately causing overt autoimmunity. Based on these observations, the use of novel strategies focusing on the analysis of histone modifications and DNA methylation supports the notion that epigenetic alterations may play a role may play a crucial role in triggering autoimmunity. Epigenetics (from the Greek επí-(epi) over and γενετικóς-(genetics)) studies mechanisms that determine and/or perpetuate heritable genomic functions without changes in DNA sequence. Epigenome and/or epigenotype is, thus, considered as a cell specific and stable pattern of gene expression induced by such epigenetic mechanisms. Functionally, epigenetic mechanisms are, indeed, crucial for cell type development and differentiation, being able to induce stable expression or repression of genes. Epigenetic mechanisms are, also, able to confer a metabolic plasticity to cell, thus allowing the cell to adapt itself to environmental changes.
Pairwise concordance rates (CR) of autoimmune diseases in monozygotic (MZ) and dizygotic (DZ) twin sets were calculated as n of concordant sets/n of studied sets.
The potential role of epigenetics in environmental/genetic interactions, where environmental changes produce modifications in gene expression, has been suggested by some intriguing experimental studies.
Firstly, a seminal study investigated the use of a specific dietary regimen, i.e. foods rich in methyl donors, in order to modify coat color in agouti
pregnant rodents. Such regimen led the offspring to manifest a specific coat color compared to mothers fed with a standard diet. This observation has been explained by an altered DNA methylation process that is the most thoroughly studied epigenetic mechanism. Such process silences the intracisternal A particle (IAP) retroviral insertional element, ultimately limiting the appearance of agouti
alleles. A second major example came from Dutch individuals who were exposed to famine during intrauterine life and childhood during the World War II. The DNA methylation analysis of the region regulating the insulin-like growth factor 2 (IGF2) expression constitutes a major example of epigenetic imprinting by demonstrating subjects a well conserved hypomethylation status in exposed compared to non-exposed subjects 3
Recent observational studies have shown association of DNA methylation profiles with several environmental factors including exposure to prenatal tobacco smoke 4
, alcohol consumption 5
, and environmental pollutants 6,7
. Based on these observations, it is becoming clear how epigenetic mechanisms should be considered as the new frontier in the interaction between genome and environment, thus well conjugating the adagio
stating that complex diseases ensue from ‘bad genes and bad luck’. This was strongly supported by the experimental data proposed by Dr. Fraga and colleagues who demonstrated how epigenetics may well explain the discordance of autoimmune diseases in monozygotic (MZ) twins3
. Phenotypic differences significantly increased along with age of the twins in a trend coined as “epigenetic drift”, which occurs during life according with the different expositions to environmental stressors 8
The present article will first illustrate the major epigenetic mechanisms under investigation and then will discuss available data in the field of autoimmune diseases.