Thursday, January 8, 2015
Update on Epigenetics in allergic disease
Chronic inflammatory diseases, including allergies and asthma, are the result of complex interactions between the genetic predisposition and environmental factors. Epigenetics comprises the umbrella of such biochemical reactions and mechanisms including DNA methylation and chromatin modifications on histones and other structures. In their review, Harb and Renz review the recent developments in this context with emphasis on allergy and asthma research (J Allergy Clin Immunol 2015; 135: 15-24) .
There are many different epigenetic modifications affecting the status of the transcription of genes. For example, epigenetic modifications of T-cells start very early during the activation/differentiation program with naïve non-committed precursors during fetal immune development. DNA methylation is a biochemical process by the addition of a methyl group to the DNA nucleotides cysteine or adenine. This process leads mainly to gene silencing and subsequently to the inhibition of gene transcription. Histones are highly alkaline proteins found in eukaryotic cells nuclei that package and order the DNA into structural units called nucleosomes. Histone modifications range from gene activation to gene silencing and can have some DNA repair functions as well. The authors have previously shown that allergen sensitization and development of the TH2 immune response is closely linked to epigenetic programming of the previously naïve T-cell during development of the effector status. Moreover, house dust mite can also elucidate epigenetic modifications in asthmatic patients. Furthermore, environmental microbes are also considered to play an important role in shaping the immune response particularly early in life. For example, regulatory T-cell function was shown to be more efficient with farming exposure and was associated with demethylation of the FOXP3 promoter in offspring of mothers with farm milk exposure compared to controls. On the other hand,tobacco smoke has also been shown to impact epigenetic programming of different cell types.
There are many studies suggesting that different diet and nutrients exert their effect through epigenetic mechanisms, such as folic acid and vitamin B12 which are prominent methyl donors and can affect the DNA methylation status universally. In addition to that, fish oil is the main source of Omega-3 fatty acids that are precursors of a large number of anti-inflammatory mediators including defensins and resolvins, and recent data provides mechanisms toward an altered expression of NF-KB affecting important inflammatory regulatory pathways through deacetylation. The authors discuss a variety of examples indicating a role of epigenetic alteration as a mechanism linking obesity and the effect on altered gene expression leading to an asthma phenotype. Moreover, stress represents an additional environmental factor through epigenetic modifications, with evidence of altered gene expression that modifies the allergic phenotype.
The authors emphasize that questions remain on the role of different epigenetic regulator mechanisms in various areas. More clinical studies are needed to unmask the exact mechanism of epigenetic modifications and their role in disease development. Other questions relate to the regulation of gene-specific epigenetic modifications and the control of the events through the underlying enzymatic machinery. Reversibility and stability of these effects also require further attention together with the question about the inheritance of different epigenetic marks.