Environmental triggers in systemic lupus erythematosus

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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect almost any organ in the human body. Despite significant advancements in our understanding of SLE over the recent years, its exact mode of onset and disease progression remains elusive. Low concordance rates among monozygotic twins with SLE (as low as 24%), clustering of disease prevalence around polluted regions and an urban–rural difference in prevalence all highlight the importance of environmental influences in SLE. Experimental data strongly suggests a complex interaction between the exposome (or environmental influences) and genome (genetic material) to produce epigenetic changes (epigenome) that can alter the expression of genetic material and lead to development of disease in the susceptible individual. In this review, we focus on the available literature to explore the role of environmental factors in SLE disease onset and progression and to better understand the role of exposome–epigenome–genome interactions in this dreaded disease.

Introduction

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with a diverse phenotypic expression and disease course. Our understanding of the etiology and onset of autoimmune diseases in general and SLE in particular remains limited [1]. Collectively, autoimmune diseases affect at least 7% of the population in the United States, and create substantial socioeconomic burden as a major health condition [1]. Although extensive research over the past few years has identified multiple genetic factors associated with autoimmune diseases, current research fails to explain sufficiently the variation of differential disease expression, age of onset, and progression of autoimmune diseases. There has been growing attention to the role of the environment to help explain such phenotypic differences of autoimmune diseases [2], [3]. Genome wide association studies have identified altered deoxyriboneucleic acid (DNA) regions and disease-related genes that may be responsible for the molecular basis of SLE [4], [5], [6]. Supported by twin studies, epigenetic changes, particularly differential DNA methylation, is considered important for SLE disease onset and progression [7].

Herein, we aim to review the complex relationship between genetic, epigenetic and environmental factors for the development of SLE. We searched the PubMed/Medline database for the last decade 2006–2016, using indexing (Medical Subject Headings, MeSH) terms “Gene–Environment Interaction”, “Lupus Erythematosus, Systemic”, “Environment”, “Air Pollution” and others, and searched through references of the articles identified to establish our current understanding of the role of environmental factors in SLE. A brief summary is presented in the Table.

The complex interaction between the “Exposome”, defined as all lifetime environmental exposures of a person, its relationship to the “Genome”, i.e., the genetic blueprint, and the subsequent modifications of the genome by the exposome, referred to as “Epigenome”, has been implicated as a potential pathway for SLE disease onset and progression [3].

An epigenetic change can be defined as a heritable modification of gene expression through changes of the chromosome without altering the DNA sequence itself [8], [9]. In response to external triggers epigenetic modifications are initiated and continued exposures or additional environmental triggers have the potential to maintain the change brought about [9]. Examples of epigenetic changes include altered DNA methylation, histone modifications, non-coding RNAs, and altered chromatin architecture. Of these, altered methylation of the DNA appears to be most significant [10].

Two of the four DNA nucleotides, cytosine (C) and adenine (A), can be methylated, while thymine and guanine cannot. Methylation of the DNA nucleotides results in a covalent addition of the methyl group at the 5-carbon of the cytosine ring, resulting in 5-methylcytosine (5-mC), also informally known as the “fifth base” of DNA. Adenine is similarly methylated to N6-methyladenine, as has been recently demonstrated [11]. These methyl groups project into the major groove of DNA and inhibit transcription.

The DNA of all mammals feature so-called “CpG islands”, i.e., stretches of DNA rich in CpG base pairs of typically greater than 200 base pairs in length with more than half being G–C [12]. While most CpG islands are located in promoter regions of genes, CpG islands also occur in the coding part of genes itself that can act as a promoter sequence. Supported by DNA methyl transferases (DNMTs) [13], [14], [15], methylation at CpG sites promotes further methylation of the promoter region and results in transcriptional down-regulation or even “silencing” of target genes [13], [16], [17].

Specifically, methylation of the promoter region of genes inhibit binding of transcription factor proteins [18]. So-called “methyl CpG binding domain proteins” can help recruit histone deacetylases, proteins that can modify histone proteins of the chromatin into compact heterochromatin, which then renders the genetic material essentially inactive [19].

In a study of five monozygotic twin pairs discordant with SLE, the affected twins had significantly lower methylation in 49 genes when compared to the healthy twins (Student’s t test β > 0.10, p < 0.05), including CD9 antigen (CD9, p = 0.0000898), homeobox B2 (HOXB2, p = 0.00024), Interleukein 10 (IL10, p = 0.000809), and interferon gamma receptor 2 (IFNGR2, p = 0.001607) among others [7]. Indeed, a tight association has been reported between global CD4+ T cell hypomethylation, overexpression of DNA methyltransferases, and the expression of SLE susceptibility genes such as Integrin Subunit Alpha L (ITGAL) [r = 0.477, p = 0.004], and Perforin-1 (PRF1) [r = 0.557, p = 0.001], highlighting the role of hypomethylation in the pathogenesis of SLE [20]. Hypomethylated DNA in B cells has further been shown to increase auto-reactivity, providing a vital area for targeted B cell therapy [21], [22], [23]. These reports are in line with a genome wide DNA methylation study of CD4+ T cells, which demonstrated that SLE patients show widespread reduced DNA methylation than healthy controls in other SLE susceptibility genes that encode the immune-modulatory gene CD9, matrix metalloproteinase-9 (MMP9), and platelet-derived growth factor receptor alpha (PDGFRA) [24]. Reduced methylation of naive CD4+ T cells has recently also been associated with the presence of malar rash and discoid rashes in SLE [25].

Low concordance rates among monozygotic twins with SLE at as low as 24% support that genetic susceptibility alone is insufficient to trigger onset of clinical manifestations of SLE [26] (Fig.). Further, large registries are reporting a higher incidence and prevalence of SLE [27], [28]. Together this suggests that, besides genetic risk factors, environmental influences are pivotal in the pathophysiology of SLE [29]. Air pollution has long been implicated in the development and progression of SLE but there is a strong need to study this association further. It is not surprising that the National Institutes of Health consider the identification of environmental exposures, gene environment interactions, and collaboration of investigators with expertise in environmental health and SLE as research objectives for future studies [30].

Section snippets

Ultraviolet radiation

Ultraviolet (UV) radiation is a short wavelength, high-energy component of the optical radiation spectrum. It ranges from wavelengths 100 nm to 400 nm and can be further subdivided into three major components: UV A (320–400 nm), UV B (290–320 nm) and UV C (200–290 nm) [31], [32]. UV B subtype is most biologically relevant and strongly associated with the development of skin cancers, sunburns and autoimmune states like dermatomyositis and SLE [31], [33]. The UV C component, although considered most

Conclusion

There have been significant insights in the mechanisms leading to development and progression SLE. It has been recognized that epigenetic changes secondary to environmental pollutant exposure are likely relevant to the development of clinical manifestations of SLE, including age at disease onset and severity.

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