environmental and epigenetic considerations in the formation of autoimmune diseases

8/22/2019 Environmental and Epigenetic Considerations in the Formation of Autoimmune Diseases

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Environmental and epigenetic considerations in the formation of autoimmune diseases

Abstract

Autoimmune diseases are often the result of multivariate interactions between suspect genes

(epistasis) and environmental factors. While the genes that lead to an increased risk of clinical

presentation of disease have been recently identified, gene consideration alone cannot account

for the total discrepancy in disease risk observed. Consequently, researchers have begun to

investigate the role environmental factors play in the formation of autoimmune diseases. Studies

of environmental factors roles in the formation of autoimmune diseases have led to the discovery

of several known triggers and the hypothesized involvement of several others. While the exact

mechanism of how environmental stimuli elucidate changes in a host’s immune system is under

investigation, epigenetic interactions between stimuli and genes are a primary suspect. This

article aims to offer a review of the genetic, epigenetic and environmental considerations in the

formation of autoimmune disease.

Outline

- Overview of Epigenetics

- DNA methylation

- Histone Acetylation

- Role in Multiple Sclerosis

- Conclusion



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Overview of Epigenetics

Epigenetics is defined as the “heritable alterations in gene expression caused by mechanisms

other than changes in DNA sequence”. Primary epigenetic mechanisms include; transcription

factors, miRNA, DNA methylation and histone modification (Bonasio et al., 2010). It is through

these epigenetic interactions that the high specificity of gene expression and thus cell identity is

made possible (Costenbader et al., 2012). Epigenetics also enables cells to maintain and form

new “memories” such as cell identity, with polycomb and trithorax proteins playing a prominent

role in this process (Ringrose and Paro, 2004). Additionally, DNA methylation is responsible for

gene imprinting and X-chromosome silencing in mammals and is mediated principally by DNA

methyltransferase-1 (DNMT1) (Song et al., 2011).

Figure 1 (figure taken from (Song et al., 2011)): Individual proteins and overall structure of DNA methyltransferase-1

(DNMT1) (Song et al., 2011).



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Histones are another epigenetic method of genomic regulation that determines the overall

chromatin structure by hyper/hypo coiling of DNA. This coiling can either expose or hide genes

for transcription. Compounding this, coiling also determines the proximity between genes and

their respective “genetic switches” that exist in the non-coding regions of DNA (Ecker et al.,

2012). Consequently, histone regulation plays a critical role in overall gene expression. The

methods of histone modulation are numerous and include “acetylation, methylation,

phosphorylation,

ADP-ribosylation,

ubiquitination,

sumoylation, etc.,”

(Cincarova et al.,

2012). Histone

acetylation is

mediated by histone

acetyltransferases

(HATs) and histone

deacetyltransferases

(HDACs).

Viral infections and Multiple Sclerosis

The possible genetic background and subsequent environmental triggers for multiple sclerosis

(MS) remains an area of great interest for researchers. While many genes have been identified

that increase the risk of developing MS, overall they only account for approximately 20% of

Figure 2 (figure taken from (Ecker et al., 2012)): DNA methylation and histone acetylation

are important mechanisms of epigenetics that enable exceptional diversity and control of

genomic expression and resultant cell function (Ecker et al., 2012).



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heritability of MS (Lin et al., 2012) (Thacker et al., 2006).

Figure 2 (figure taken from (Lin et al., 2012)): Various genes associated with developing multiple sclerosis. Taking into

consideration all of these genes still leaves about 80% of heritability of MS unaccounted for (Lin et al., 2012).

As with many autoimmune diseases, it is thought that the combination of both susceptible genes

and an exposure to an environmental irritant is needed to induce clinical expression of MS.

Currently, environmental sources of induction of disease are thought to be vitamin D levels, UV

radiation exposure, chronic smoking and most notably, exposure to Epstein – Barr virus (herpes)

(Lin et al., 2012). Herpes infections always result in permanent residence of the virus in the body

via infection of b-lymphocytes where it will modulate between active (infectious) and dormant

(asymptomatic) phases. During infection, herpes is coupled with epithelial cells or B-

lymphocytes by binding their receptor CR2 with major envelope glycoprotein gp 350 (Young et

al., 2008).



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Figure 4 (figure taken from (Levin et al., 2005)): Note: VCA indicates viral capsid antigen; EBNA, Epstein-Barr nuclear

antigen. The risk of developing MS when considering EBNA and EBNA-1 levels, an increase of EBNA levels by 4 fold

increases the risk of developing MS by 3 fold (Levin et al., 2005).

Herpes is able to achieve this lifetime residence through immune-modulating activities that can

cause the immune system to display irregularities associated with multiple sclerosis and

infectious mononucleosis (IM) (Santiago et al., 2010). The most notable immune modulating

function herpes employs is the up-regulation of inflammation cytokines IL-1β, TNF-α, and IL-6

(Costenbader et al., 2012). Ultimately it is this constant expression and up-regulation of these

cytokines that promotes demyelination and clinical expression of MS.

In an effort to counteract herpes role in triggering autoimmune diseases, anti-viral methods such

as vaccines and inhibitors are being proposed. Specifically, retroviral integrase inhibitor,

raltegravir (Isentress) has been used to induce remission in a patient with chronic idiopathic

urticarial (CIU), an autoimmune condition, by depleting memory b-cells and thus depleting the

available reservoirs for herpes to reside in (Dreyfus, 2011).



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Conclusion

Figure 5 (figure taken from (Costenbader et al., 2012)): A general overview of the role environmental factors play in

influencing genes through epigenetic interactions and the development of immune diseases (Costenbader et al., 2012).

The growing understanding of the specific and unique interactions that environmental factors

play in influencing epigenetic mechanisms offers a unique opportunity to exploit these

interactions in highly specific ways that should limit the side effects of treatment immensely in

relation to current immunosuppressant treatment standards. Overall it is clear that genes,

epigenetics, environmental factors and epistasis all play vital roles in the formation of the clinical

presentation of complex autoimmune diseases. The inclusive understanding of environmental

factors and epigenetics interactions is at its infancy and consequently the treatment of

autoimmune diseases still largely relies on treatments that broadly target the immune system as a

whole. While genomic makeup of an individual is largely fixed, epigenetics offers a window

through which modifications to gene expression can be made. Future research should focus on

developing treatments that target specific environmental irritants, such as the anti-viral integrases

currently being tested against herpes.



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environmental and epigenetic considerations in the formation of autoimmune diseases

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