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[[Autoimmune disease|Autoimmune disorders]] are a diverse class of diseases characterized by the dysregulation of a person's immune system leading their body to produce an immune response in which there immune system incorrectly attacks their own healthy cells rather than foreign invaders, leading to the destruction of healthy cells. Depending on the condition, these diseases can effect all types of body tissue and are categorized based on whether or not the disease acts systemically or on a particular local system. Autoimmune disorders have both an environmental and genetic components as described by the fact that although these conditions show an increased prevalence amongst certain families, monozygotic twins are not both destine to develop a disorder and often only one twin is afflicted<ref name=":1" />. Research has elucidated genes associated with the conditions as well as associative epigenetic modifications observed in those sharing the same condition and causative epigenetic modifications produced as a result of environmental components. |
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== '''Epigenetics of Autoimmune Disorders''' == |
== '''Epigenetics of Autoimmune Disorders''' == |
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Revision as of 15:36, 5 April 2022
Sandbox of Emily Breach, Aamani Pillutla, Oliver Myers
Autoimmune disorders are a diverse class of diseases characterized by the dysregulation of a person's immune system leading their body to produce an immune response in which there immune system incorrectly attacks their own healthy cells rather than foreign invaders, leading to the destruction of healthy cells. Depending on the condition, these diseases can effect all types of body tissue and are categorized based on whether or not the disease acts systemically or on a particular local system. Autoimmune disorders have both an environmental and genetic components as described by the fact that although these conditions show an increased prevalence amongst certain families, monozygotic twins are not both destine to develop a disorder and often only one twin is afflicted[1]. Research has elucidated genes associated with the conditions as well as associative epigenetic modifications observed in those sharing the same condition and causative epigenetic modifications produced as a result of environmental components.
Epigenetics of Autoimmune Disorders
Autoimmune disorders are a diverse class of diseases characterized by the dysregulation of a person's immune system leading their body to produce an immune response in which there immune system incorrectly attacks their own healthy cells rather than foreign invaders, leading to the destruction of healthy cells. Depending on the condition, these diseases can effect all types of body tissue and are categorized based on whether or not the disease acts systemically or on a particular local system. Autoimmune disorders have both an environmental and genetic components as described by the fact that although these conditions show an increased prevalence amongst certain families, monozygotic twins are not both destine to develop a disorder and often only one twin is afflicted[1]. Research has elucidated genes associated with the conditions as well as associative epigenetic modifications observed in those sharing the same condition and causative epigenetic modifications produced as a result of environmental components.
Trevor's comments in magenta
Priya's comments in purple
Sienna's comments in green
Jonathan’s comments in orange
Mechanisms of Epigenetic Modifications
Comment: add section describing overview of mechanisms: Use these articles!!! [2][3][4][5],
DNA Methylation
Hypomethylation, a loss of DNA methylation, particularly hypomethylation of DNA promoters is heavily associated with multiple different autoimmune disorders, specifically rheumatoid arthritis and systemic lupus erythematosus; Next discuss procainamide and hydralazine induced lupus like condition an d how this relates to hypomethylation as underlying cause of many autoimmune diseases[6]. Here we would also discuss circRNA and how it is a regulator of methylation and the immune system and how this is tied into many autoimmune conditions[7] Next write about hypermethylation and its role in autoimmune diseases like Type 1 Diabetes. Include research from the Farh et al paper because this is a big deal in the epigenetic research as far as identifying causal loci via GWAS and iChip analysis[6].
#800080
Histone Modification
Recommend describing mechs more here to give better big picture [4]
Non-Coding RNAs
Micro-RNAs
Recommend describing mechs more here to give better big picture [4]
Epigenetics of Systemic Autoimmune Diseases
Systemic autoimmune diseases are those that effect multiple organ systems rather than targeting a single type of tissue or organ system.
Rheumatoid Arthritis (RA)
Rheumatoid arthritis is a degenerative autoimmune disease that damages and causes inflammation in a patient’s joint. It is characterized by hypomethylation of synovial cells and CpG island hypomethylation [3] . Patients with RA often display anti-cyclic citrullinated peptide (anti-CCP) antibodies and have hypomethylation of the retrotransposon gene L1, and decreased methylation at the Il6 and ERa promoter [8].. TET proteins, more specifically the TET1-TET3 enzymes and TET2 in T cells can demethylate DNA which helps to set and clarify the early stages of RA [4]. This early stage is more closely observed to be the formation by the TET proteins to cause aberrant global DNA hypomethylation which is the start of the degenerative property and hallmark of Rheumatoid Arthritis [4]. Furthermore, the epigenetic nature of RA is intertwined with the chronic inflammation and significant disability of the immune system in the body that leads to the aberrant histone modifications. The RA development from demethylation of histones in the patient has been observed to express high levels of IL-6 which causes destruction in the joints [4].
Systemic Lupus Erythematosus (SLE)
Systemic lupus erythematosus is the most common form of lupus and is a condition in which the immune system attacks healthy bodily tissue. Hypomethylation is observed across the epigenome in those with systemic lupus. The promoter regions of many genes including ITGAL, CD40LG, and CD70 are shown to be hypomethylated as well as the 18S and 28S ribosomal gene promoters. In particular, this DNA hypomethylation is thought to alter the chromatin structure of T cells enhancing the immune and inflammatory response observed in those with this condition[3]. Genome wide it has been shown that when comparing the epigenomes of pairs of identical twins in which one twin is afflicted by the condition and one is not, the twins possessing the condition show global decreases in methylation of their genomes. This hypomethylation causes genes that are traditionally repressed by methylation to be overexpressed particularly in CD4+ T cells. Recently, it has been explored which causative mechanisms are responsible for this genome-wide demethylation and inhibition of DNMT1 has been identified as a potential culprit. DNMT1 is a DNA methyltransferase that conserves methylation patterns from the parent DNA strand to a new copy of DNA during DNA replication. By inhibiting DNMT1 methylation patterns are lost across DNA lines and overall hypomethylation is observed as a result. In particular, it has been observed that DNMT1 expression is lower in immune T-cells. [1]
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Systemic Sclerosis (SSc)
Systemic sclerosis (SSc) is an autoimmune disease that causes the patient’s skin and connective tissues to tighten and harden due to the uncontrolled accumulation of Extracellular Matrix (ECM) Proteins[3]. These ECM Proteins are observed to impact the patient suffering from SSc by affecting the joints and various internal organ systems, even leading to premature death in patients. hypermethylation of CpG islands in Fli1 promoter leads to the overproduction of the fibers affecting the joints and skin thickness of the person suffering from SSC Decreased levels of DNA methyltransferases (DNMTs) in SSc CD4+ T cells suggesting a correlation of this reduced Methylation leading to the progression of SSc and its inflammatory effects, however more research is mentioned to be needed to help further understand this implication[8].
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Epigenetics of Local Dermatological Autoimmune Disorders
Discoid Lupus Erythematosus (DLE)
Discoid lupus erythematosus is the most common form of the cutaneous autoimmune condition in which the immune system attacks healthy tissue and is presented by lesions on the skin, inflammation, and rashes which can result in pigment changes and scarring of the skin even hair loss for those impacted. Here we will explore how differential expression of lncRNAs and circRNAs identified in a study by Xuan et alter the mucosa a key part in this disease[7]. In said study, many transcripts for DLE were found to be expressed in affected tissue incRNAs and to a significant extent but lesser circRNAs were expressed as compared to a control nonaffected tissue. The pattern of expressed incRNAs and circRNAs helps to discriminate against affected tissue of DLE and healthy nonaffected tissues establishing a useable pattern for reference[7] . Furthermore, the IncRNAs were found to be present in both X and also Y chromosomes giving reference to their inheritability and non-sex selective nature. It was found that through analysis of the function and expression of lncRNA that IncRNAs had various correlations with Il19, CXCL1, CXCL11, and TNFSF15 which all are related to an immune response helping to identify the pathway in which DLE is manifested genetically by the abnormal expression of IncRNA . Another key portion of the Xuan et alter study was the identification of STAT4 as being a key Transcription factor responsible for influencing the regulation of many target genes involved in DLE but this needs to be further investigated as mentioned in the article [7].
Psoriasis
Psoriasis is an autoimmune skin condition in which skin cells are generated too rapidly leading to a buildup of these cells producing scaly red patches on the patient's body. Keratinocyte hyper-proliferation, which leads to an overproduction of keratin, and T cell dysregulation play a key role in this condition. Decreased DNA methylation is observed in patients with psoriasis, particularly in CD4+ T cells. Additionally, miRNA dysregulation of miRNA-203, miRNA-31, miRNA-146a, and miRNA-210 is prevelant [9]. Acetylation also plays an important part in this disease and it has been shown that patient with psoriasis demonstrate abnormal expression of HDACs and HATs. HDAC-6 is hyper-methylated in CD4+ T-cells and HDAC-1 levels are shown to be increased in epidermal cells of those with psoriasis[4]. SIRT1 has been identified as a gene involved in negative regulation of keratocyte proliferation and it plays an important role in inhibiting E2F1 activity in order to prevent abnormal cellular proliferation. In psoriasis, HDAC SIRT1 is more heavily expressed leading to increased keratocyte proliferation. HDAC inhibitors show promise as a potential treatment of psoriasis as well as many other inflammatory autoimmune disorder [10].
Sjogren's Syndrome
Sjorgen's syndrome is a dermatological autoimmune disorder that causes a decreased function of the lacrimal and salivary glands. In terms of research on the innate immune system, it is characterized by over expression of certain miRNAs in salivary glands, in particular miRNA-16a and miRNA-146a [3][4]. Of the miRNAs identified to play a role in this diseases, miRNA-16a role in pathogenesis of this condition has been elucidated. miRNA-16a levels play an important role in phagocytosis by monocytes, white blood cells that target and remove infected cells. In Sjorgen's patients, there is an over expression of this miRNA leading to increased ingestion by these monocytes and targeting of this over-expression is thought to hold potential in treatment of this disease [4]. As described previously, Sjorgen's targets the salivary gland, particularly its epithelial cells which are show to be hypomethylated. This hypomethylation is hypothesized to be linked to activity by B cells since usage of a B cell depleting antibody has been shown to restore this methylation[4]. Epigenetic alterations in CD4 and T-cells in the immune system are also observed in this condition. Specifically, research has linked a decrease in expression of FOXP3 gene as well as CD70 promoter region hypomethylation to the development of Sjogren's syndrome [9].
Epigenetics of Local Endocrinological Autoimmune Disorders
Graves' Disease
Graves’ disease is an autoimmune disease involving thyrotoxicosis, in which the body is affected by the overproduction of thyroid hormone, a quality termed hyperthyroidism. Like Hashimoto’s thyroiditis, Graves’ disease is qualified as an autoimmune thyroid disease. The epigenetic processes involved in Hashimoto’s thyroiditis, namely the modification of histone methylation in Tg and skewed X chromosome inactivation, are also involved in Graves’ disease. The viral infection possibility mentioned in reference to Hashimoto’s thyroiditis also applies to Graves’ disease.[11] In the specific case of Graves’ disease, discoveries have been made showing involvement of abnormal DNA methylation in certain CpG sites leading to interferon signaling and other immune system-related processes in cases of Graves’ disease. In fact, Graves’ disease patients have exhibited hypomethylation in CpG sites in certain T cells, indicating the implication of DNA hypomethylation in the pathophysiology of Graves’ disease.[12]
Hashimoto's Thyroiditis
Hashimoto's thyroiditis is an endocrine disease in which a patient’s immune system attacks their thyroid gland. Hashimoto’s thyroiditis usually manifests via hypothyroidism, which is characterized by “lymphocytic infiltration of the thyroid and the production of thyroid autoantibodies”[11]. Research suggests a strong genetic susceptibility when it comes to autoimmune thyroid diseases like Hashimoto’s thyroiditis, and an epigenetic involvement in the pathology of Hashimoto’s thyroiditis. In association with autoimmune thyroid diseases such as Hashimoto’s thyroiditis, a change in histone methylation patterns in the thyroglobulin (Tg) promoter has been found in a genetic variant, wherein Tg is a thyroid-specific gene. In specific, the transcription factor IRF-1 binds to the Tg promoter exclusively only when the disease-associated variant is present. This binding of IRF-1 to Tg is impacted by modulations in histone methylation patterns. Something of note here is that in the Tg promoter, the susceptibility allele allows the binding of IRF-1 in the case of a viral infection, pointing to a potential environmental factor on the development of Hashimoto’s thyroiditis, rather than attributing epigenetic modifications restrictively to genetic sources.[11] In addition to histone methylation, skewed X chromosome inactivation has been found to be implicated in autoimmune thyroid diseases (specifically Hashimoto’s thyroiditis and Graves’ disease), therefore indicating that the level of X chromosome inactivation in females is an important factor in the risk of developing autoimmune thyroid diseases[13].
Type I Diabetes
Type I diabetes is an endocrinological disease in which the immune system’s T cells attack the beta cells of the pancreas, disrupting the production of insulin. Type I diabetes is characterized by global hypermethylation[3]. The demethylation of certain proteins is implicated in Type I diabetes such as HOXA9, a transcription factor whose demethylation has been reported in Type I diabetes. Additionally, increased DNA methylation in the Foxp3 promoter region has been observed in Type I diabetes. The increased DNA methylation of the Foxp3 promoter region leads to a reduction in the frequency of regulatory T cells, which suppress immune responses in the body, in the blood of Type I diabetics[8]. Increased DNA methylation variability in immune effector cells in Type I diabetes has shown the involvement in DNA methylation in other processes related to Type I diabetes’ pathogenesis as well[14].
Epigenetics of Local Gastrointestinal Autoimmune Disorders
Celiac Disease
Celiac disease is a disease in which the small intestine is damaged in those whose bodies are unable to process gluten. Celiac disease is an autoimmune disorder in which exposure to glutinous foods like wheat and rye is the primary environmental factor. Several epigenetic mechanisms have been found to be implicated in Celiac disease. A high rate of DNA methylation of CpGs contributes to the development of small bowel adenocarcinomas, which are malignant tumors, in individuals with Celiac disease. Furthermore, unusual methylation in the genes involved in the core NF-κB pathway is implicated in the pathogenesis of Celiac disease. There are also allele-specific gene methylations that impact phenotype in such a way that it can lead to Celiac disease, thus involving allele-specific methylation in Celiac disease predisposition. Additionally, an increase in histone acetylation, specifically H3K27ac, has been found in Celiac disease biopsies.[15] The regulation of certain microRNAs, which are a type of non-coding RNA, differs significantly in individuals with Celiac disease compared to control individuals without Celiac disease. This significant difference was found to come in the form of downregulation of some microRNAs and upregulation of others.[16]
Epigenetics of Local Neurological Autoimmune Disorders
Multiple Sclerosis (MS)
Multiple Sclerosis is an autoimmune disease characterized by neurodegeneration, causing damage to the myelin sheath of neurons leading to weakness, pain, and vision loss. Many miRNAs have been identified in the pathogenesis of this diseases. miRNA-326, miRNA-34a, and miRNA-155 are some of them miRNAs to be identified. miRNA-326 is upregulated in those with multiple sclerosis and is associated with flare-up in symptoms. It acts on Ets-1 which negatively regulates TH-17, a helper T cell, and its differentiation. In terms of miRNA-34a and miRNA-155 increased level of these miRNAs inhibits the CD47 signal in macrophages and leads to an increase in demyelination.[3] It has been shown that infection with Epstein-Barr Virus, vitamin D deficiency, and smoking are associated with alteration to epigenetic markers and MS pathogenesis. Epstein-Barr Virus causes up-regulation of DNMTs, vitamin D deficiency alters expression of histone modifiers, and smoking has been shown to effect all three mechanisms of epigenome modification[5]. Comment: another article to look at [2] .
Myasthenia Gravis (MG)
Myasthenia Gravis is an autoimmune disease-causing weakness and dysfunction in the affected patient’s skeletal muscles related to extensive neurological damage. It has been found in individuals who have Myasthenia Gravis have significantly higher levels of methylation in the CTLA-4 region and higher levels of expression of AchR-Ab and also E-Ach for those affected. The expression of CTLA-4 region is associated with the potential inhibition of the immune system in those affected by MG and the expression of the CTLA-4 generating cytokines regulating both AchR-Ab and E-Ach need further exploration for their mechanism of action[17]. Look for more mechanisms for the regulation of AchR-Ab and E-Ach and then expand on the impact of methylation of the CTLA-4 region[17].
COMMENTS
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References
- ^ a b c Long, Hai; Yin, Heng; Wang, Ling; Gershwin, M. Eric; Lu, Qianjin (2016-11). "The critical role of epigenetics in systemic lupus erythematosus and autoimmunity". Journal of Autoimmunity. 74: 118–138. doi:10.1016/j.jaut.2016.06.020.
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- ^ a b c d e f g Quintero-Ronderos, Paula; Montoya-Ortiz, Gladis (2012). "Epigenetics and Autoimmune Diseases". Autoimmune Diseases. 2012: 1–16. doi:10.1155/2012/593720. ISSN 2090-0422. PMC 3318200. PMID 22536485.
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- ^ a b Farh, Kyle Kai-How; Marson, Alexander; Zhu, Jiang; Kleinewietfeld, Markus; Housley, William J.; Beik, Samantha; Shoresh, Noam; Whitton, Holly; Ryan, Russell J. H.; Shishkin, Alexander A.; Hatan, Meital (2015-02-19). "Genetic and epigenetic fine mapping of causal autoimmune disease variants". Nature. 518 (7539): 337–343. doi:10.1038/nature13835. ISSN 0028-0836. PMC 4336207. PMID 25363779.
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{{cite journal}}: Check date values in:|date=(help) - ^ a b Fang, Ti-Kun; Yan, Cheng-Jun; Du, Juan (2018-05). "CTLA-4 methylation regulates the pathogenesis of myasthenia gravis and the expression of related cytokines". Medicine. 97 (18): e0620. doi:10.1097/MD.0000000000010620. ISSN 0025-7974.
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- ^ Long, Hai; Yin, Heng; Wang, Ling; Gershwin, M. Eric; Lu, Qianjin (2016-11-01). "The critical role of epigenetics in systemic lupus erythematosus and autoimmunity". Journal of Autoimmunity. A Comprehensive perspective on systemic lupus erythematosus. 74: 118–138. doi:10.1016/j.jaut.2016.06.020. ISSN 0896-8411.