Environmental triggers in systemic lupus erythematosus
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.
References (106)
- et al.
Epidemiology of environmental exposures and human autoimmune diseases: findings from a National Institute of Environmental Health Sciences Expert Panel Workshop
J Autoimmun
(2012) Environmental influences on systemic lupus erythematosus expression
Rheum Dis Clin North Am
(2014)- et al.
CpG islands in vertebrate genomes
J Mol Biol
(1987) - et al.
Natural antisense transcripts regulate gene expression in an epigenetic manner
Biochem Biophys Res Commun
(2010) - et al.
Biological functions of methyl-CpG-binding proteins
Prog Mol Biol Transl Sci
(2011) - et al.
Altered patterns of epigenetic changes in systemic lupus erythematosus and auto-antibody production: is there a link?
J Autoimmun
(2012) Sunlight-induced pathogenesis in systemic lupus erythematosus
J Invest Dermatol
(1985)- et al.
The specificity of p53 mutation spectra in sunlight induced human cancers
J Photochem Photobiol B
(1995) - et al.
Ultraviolet B enhances DNA hypomethylation of CD4+ T cells in systemic lupus erythematosus via inhibiting DNMT1 catalytic activity
J Dermatol Sci
(2013) - et al.
Current status of cadmium as an environmental health problem
Toxicol Appl Pharmacol
(2009)
DNA methylation is differentially associated with environmental cadmium exposure based on sex and smoking status
Chemosphere
Increased frequency of delayed type hypersensitivity to metals in patients with connective tissue disease
J Trace Elem Med Biol Organ Soc Miner Trace Elem GMS
The cognitive impairment induced by zinc deficiency in rats aged 0∼2 months related to BDNF DNA methylation changes in the hippocampus
Nutr Neurosci
CD4(+) T cells epigenetically modified by oxidative stress cause lupus-like autoimmunity in mice
J Autoimmun
Environmental exposure, estrogen and two X chromosomes are required for disease development in an epigenetic model of lupus
J Autoimmun
Estrogen enhances immunoglobulin production by human PBMCs
J Allergy Clin Immunol
Bisphenol A (BPA) stimulates the interferon signaling and activates the inflammasome activity in myeloid cells
Mol Cell Endocrinol
Autoreactive responses to environmental factors: 3. Mouse strain-specific differences in induction and regulation of anti-DNA antibody responses due to phthalate-isomers
J Autoimmun
The plasticizer BBP selectively inhibits epigenetic regulator sirtuin during differentiation of C3H10T1/2 stem cell line
Toxicol Vitro Int J Publ Assoc BIBRA
Biomarkers of polycyclic aromatic hydrocarbon exposure in European coke oven workers
Toxicol Lett
1-Hydroxypyrene and 3-hydroxybenzo[a]pyrene as biomarkers of exposure to PAH in various environmental exposure situations
Sci Total Environ
Increased liver and lupus mortalities in 24-year follow-up of the Taiwanese people highly exposed to polychlorinated biphenyls and dibenzofurans
Sci Total Environ
Alcohol and inflammation and immune responses: summary of the 2006 Alcohol and Immunology Research Interest Group (AIRIG) meeting
Alcohol Fayettev N
Alcohol effects on the epigenome in the germline: Role in the inheritance of alcohol-related pathology
Alcohol Fayettev N
Environmental factors, toxicants and systemic lupus erythematosus
Int J Mol Sci
Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci
Nat Genet
The genetics of systemic lupus erythematosus and implications for targeted therapy
Ann Rheum Dis
Replication of GWAS-identified systemic lupus erythematosus susceptibility genes affirms B-cell receptor pathway signalling and strengthens the role of IRF5 in disease susceptibility in a Northern European population
Rheumatol Oxf Engl
Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus
Genome Res
Epigenetic alterations in autoimmune rheumatic diseases
Nat Rev Rheumatol
An operational definition of epigenetics
Genes Dev
Epigenetics: the science of change
Environ Health Perspect
DNA methylation on N(6)-adenine in mammalian embryonic stem cells
Nature
Critical role of DNA methylation in the pathogenesis of systemic lupus erythematosus: new advances and future challenges
Lupus
DNA methyltransferases: mechanistic models derived from kinetic analysis
Crit Rev Biochem Mol Biol
DNA methylation and differentiation: silencing, upregulation and modulation of gene expression
Epigenomics
Genome-wide conserved consensus transcription factor binding motifs are hyper-methylated
BMC Genomics
Epigenetics in systemic lupus erythematosus: leading the way for specific therapeutic agents
Int J Clin Rheumatol
Associations between the expression of epigenetically regulated genes and the expression of DNMTs and MBDs in systemic lupus erythematosus
PloS One
B-cell-targeted therapies in systemic lupus erythematosus
Cell Mol Immunol
B-cell targeted therapies in systemic lupus erythematosus: successes and challenges
BioDrugs Clin Immunother Biopharm Gene Ther
Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus
Epigenetics
DNA methylation patterns in naïve CD4+ T cells identify epigenetic susceptibility loci for malar rash and discoid rash in systemic lupus erythematosus
Lupus Sci Med
A revised estimate of twin concordance in systemic lupus erythematosus
Arthritis Rheum
The incidence and prevalence of systemic lupus erythematosus, 2002–2004: the georgia lupus registry
Arthritis Rheumatol Hoboken NJ
Population-based incidence and prevalence of systemic lupus erythematosus: the Michigan lupus epidemiology and surveillance program
Arthritis Rheumatol Hoboken NJ
The role of genetic factors in autoimmune disease: implications for environmental research
Environ Health Perspect
Ultraviolet radiation and systemic lupus erythematosus
Lupus
Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women
Arthritis Rheum
Cited by (42)
Genetic Component of Autoimmune Rheumatological Diseases
2022, Reumatologia ClinicaMethyl- rich diet ameliorates lupus-like disease in MRL/lpr mice
2022, ImmunobiologyCitation Excerpt :Genetic predisposition has undoubtedly an important role in the development of the disease as >60 genes have been defined as risk genes for lupus (Zeng et al., 2017). However, many studies have showed that genomic susceptibility is necessary but not sufficient for SLE to appear indicating that environmental factors are also key components in the disease onset (Relle et al., 2015; Gulati and Brunner, 2018). resulting in repression of gene transcription (Bernstein et al., 2007).
Systemic lupus erythematosus as a genetic disease
2022, Clinical ImmunologyWhat can we learn from DNA methylation studies in lupus?
2022, Clinical ImmunologySystemic lupus erythematosus, a disease conditioned by the environment
2021, Revista Colombiana de ReumatologiaCitation Excerpt :The conclusion is then that oral contraceptives can be safe in patients with stable SLE, but there may safety concerns in patients with antiphospholipid antibodies and the development thrombotic episodes. Ultraviolet (UV) radiation is a short, high-energy wave that is part of the spectrum of optical radiation.50 There are three types of UV radiation: UV-A (320 to 400 nm wavelength range), UV-B (290-320 nm wavelength range) and UV-C (200 to 300 nm wavelength range 290 nm);51 both UV-A and UV-B rays are biologically associated with immunosuppression states, UV-A rays represent more than 95% of the total UV radiation that reaches the earth's surface,52 but it is not absorbed by the atmosphere and has little uptake by proteins and nucleic acids, unlike UV-B rays that are strongly associated with the development of skin cancer, sunburn, and autoimmune states.53