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Epigenetics of autoimmune disorders

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This is an old revision of this page, as edited by Aspillutla (talk | contribs) at 19:30, 4 May 2022 (Added to Graves' disease section). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.


Sandbox of Emily Breach, Aamani Pillutla, Oliver Myers

Emily: DNA methyaltion, Intro, Psoriasis, MS, Sjorgen's, SLE

Oliver: Non-coding RNA, Myansthenia Gravis, DLE, Rheumatoid Arthritis, Systemic Sclerosis

Aamani: Histone Mods, Type I Diabetes, Hashimoto's, Celiac, Graves'

Trevor's comments in magenta

Epigenetics of Autoimmune Disorders

Autoimmune disorders are a diverse class of diseases that share a common origin. These diseases originate when the immune system becomes dysregulated and mistakenly attacks healthy tissue rather than foreign invaders. These diseases are classified based on if the immune system is primarily attacking a single body system or if it is causing systemic damage that affects multiple organ systems. Whether someone develops an autoimmune disorder is dependent on genetics as well as environmental components. Some families show genetic predisposition for these conditions, however genetics alone is not definitive of whether or not someone will develop the condition. Environment plays an important role. Smoking, stress, and diet can produce epigenetic modifications to the genome that alter the regulation of immune system specific genes leading to the onset of these conditions. In this article, we outline the different types of epigenetic modifications as well as how these modifications play a role in the onset and symptoms of different systemic and local autoimmune diseases[1].

Mechanisms of Epigenetic Modifications

DNA Methylation

DNA methylation is an epigenetic modification that interferes with transcription and causes decreased levels of gene expression. The addition of methyl groups to DNA nucleotides inhibits transcription by creating a surface that transcription factors are unable to bind. Additionally, DNA methylation recruits methyl-CpG-binding domain proteins that signal for the formation of co-repressor complexes that alter chromatin structure and further inhibit transcription. A hypermethylated DNA state is associated with gene silencing while a hypomethylated DNA state is associated with increased levels of transcription and gene expression. DNA methylation is carried out by DNA methyltransferases (DNMTs) which attach methyl groups at the 5th position of a cytosine nucleotide. In vertebrates, gene expression is modulated in particular by methylation within a region of the genome known as a CpG island, a region near a gene's promoter that contains a high percentage of cytosine and guanine nucleotides[2]. DNA demethylation is carried out by Ten-Eleven Translocation (TET) enzymes which convert 5-methylcytosine (5mC) into hydroxymethylcytosine (5hmC), leading to the demethylation of that segment of DNA and an increase in gene expression. TET inhibitors have been identified as potential treatments for autoimmune diseases, particularly rheumatic ones[3]

Histone Modification

Histone modification, resulting in conformational changes to protein binding sites, is implicated in autoimmune disorders. Histone acetylation leads to increased transcription factor binding. This involves a more relaxed version of condensed heterochromatin, facilitating increased gene transcription. <- I think I see what you're going for here, but I think it's inaccurate to describe histone acetylation as a version of heterochromatin. Normally, histone deacetylases (HDACs) serve to remove acetyl groups from the lysine residue of the histone decreasing gene expression.*4* Histone modification can give rise to rheumatic, endocrinological, and gastrointestinal autoimmune disorders. Suberanilohydroxamic acid (SAHA), also known as Vorinostat, inhibits the activity of HDACs. Histone modification leads to either activation or repression of gene expression depending on context. <- What's the context here? Vorinostat has shown promise as a treatment for immune system dysfunctions.[3] <- Writing here is a little bit jumbled since there's a random sentence that breaks up your two sentences about Vorinostat.

This is pretty surface level. Histone acetylation is the only modification you mention here, which is very limiting for the discussion that you want to have. You don't have to describe every modification in detail, but clarifying euchromatic vs heterochromatic modifications and their associated functions should be done at a minimum here.

Probably a good idea to at least bring up the interplay between DNA methylation and histone modifications since these are pretty intimately connected. 

*4* Really jumps around form this point on. Introduce HDACs then tell us can modifications in general can cause disorders then jump to a drug. I would end this paragraph with the can give rise to autoimmune disorders sentence. Then start a new paragraph to talk about drugs (one paragraph per drug is probably an even better idea). Be sure to deal with Trevor's comments.

Non-Coding RNAs

Micro-RNAs (miRNAs)

Micro-RNAs (miRNAs) are small RNA fragments, 18-23 nucleotides in length, that act to regulate gene expression post-transcriptionally[3]. miRNAs play a critical role in modulating the immune response since they influence whether or not the mRNA transcribed from specific immune related genes will go on to be translated into protein or not. Alteration of different miRNA levels is associated with autoimmune disease pathogenesis and symptoms. Depending on the disorder, up regulation or down regulation of a specific type of miRNA is observed. miRNAs negatively regulate gene expression by binding to complementary mRNA sequences within the 3' untranslated region(3' UTR)[3]. This process of miRNA activity begins with the synthesis of pri-miRNA in the nucleus by RNA polymerase II which is then converted into pre-miRNA. This pre-miRNA exits the nucleus and is cut by Dicer into a double stranded RNA with one of the strands binding to the RISC complex. This binding leads to the association of the miRNA with its target mRNA sequence and encourages the degradation of the mRNA or represses translation of the mRNA, decreasing gene expression[4]. miRNA can also affect gene expression via the binding of RNA-induced transcriptional silencing (RITS) complex. The binding of the RITS complex to miRNA allows for post-transcriptional histone modifications such as methylation to be made further altering gene expression[1].

Long non-coding RNAs (lncRNAs)

Long non-coding RNAs have also been identified as playing an important role in gene expression. These lncRNAs are RNAs that are more than 200 nucleotides in length but are not transcribed into any functional protein and have been identified to play a role in the epigenetics of diseases such as Discoid Lupus Erythematosus and Rheumatoid Arthritis. Currently, not much is know about the specific mechanism these lncRNAs use to regulate gene expression[3].

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. Global DNA hypomethylation is a hallmark of Rheumatoid Arthritis and is observed in the early stages of this disease and is the start of the degeneration [3].Those who suffer from RA have a global level of hypomethylation where the targeted DNA promoter regions show the overexpression of various genes associated with the disease, such as ITGAL, CD40LG, PRF1, and more. Taking a closer glance at those who suffer from RA, it can be observed that within the synovial cells, there is a level of hypomethylation which is proposed to cause the expression and overproduction of the cytokines which perpetuate the inflammatory response causing inflammation within the synovial fluid, which is the fluid that exists between the joints[5]. Patients with RA often display anti-cyclic citrullinated peptide (anti-CCP) antibodies and have hypomethylation of the retrotransposon gene L1, as well as decreased methylation at the Il6 and ERa promoter [6].. 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 [3]. The RA development from demethylation of histones in the patient can lead to expression of high levels of IL-6 which causes destruction in the joints [3]. miRNAs also play an important part in rheumatoid arthritis developement as well, partciulalry the upregulation of miRNA-146a and miRNA-150. Although more research is needed, lncRNAs have been implicated to play a role in this disease since current treatments used for this disorder show altered expressio of 85 different lncRNAs in RA patients on tocilizumab and adalimumab [3].

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 causing wide-spread inflammation and tissue damage across many organ systems. 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[5]. 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 twin possessing the condition shows 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. It has been suggested that inhibition of DNMT1 produces the loss of methylation observed in those afflicted by systemic lupus. DNMT1 is a DNA methyltransferase that maintains methylation patterns across the process of DNA replication, ensuring that new copies of DNA contain the methylation pattern observed on the original parent strand. Inhibition of DNMT1 causes methylation patterns to be lost across DNA lines and epigenome-wide hypomethylation is observed as a result. In particular, it has been observed that DNMT1 expression is lower in immune T-cells [7]

Systemic Sclerosis (SSc)

Systemic sclerosis (SSc) is an autoimmune disease characterized by system wide excessive collagen deposits. It causes the patient’s skin and connective tissues to tighten and harden due to the uncontrolled accumulation of extracellular matrix proteins on the joints and various internal organ system which can lead to premature death in patients[5]. Hypermethylation of CpG islands in the Fli1 promoter region inhibits collagen production, as Fli1 is a transcription factor that regulates collagen. This is observed in SSc patients and is associated with collagen build-up and an overproduction of the fibrous connective tissue, leading to joint damage, scarring, and thickening of the skin. When there is less Fli1 transcribed, it can be observed that the production of collagen thus increases, helping to outline the role of the inhibitory function of the expression of Fil1. Patients with SSc are also observed to have decreased levels of DNA methyltransferases (DNMTs) in their CD4+ T cells suggesting a correlation of this reduced methylation to the progression of SSc and its inflammatory effects, however more research is needed to further understand this implication[6]. Patients with systemic sclerosis also display hypomethylation of collagen genes COL23A1 and COL4A2, as concluded by a genome-wide analysis, which is also attributed to over-expression of collagen genes and overproduction of collagen characteristic to tissue fibrosis. The TGF-β signaling pathway and Wnt/β-catenin signaling pathway also play an important role in this disease. The TGF-β signaling pathway is involved in that activation of fibroblast which precedes fibrosis. The gene, ITGA9 which codes for alpha integrin 9 and is involved in this pathway, is hypomethylated in those with this condition leading to overexpression of integrins which leads to fibrosis as wells as provides feedback to this pathway further encouraging fibroblast activation[8].

Epigenetics of Local Dermatological Autoimmune Disorders

Discoid Lupus Erythematosus (DLE)

Discoid lupus erythematosus is a cutaneous disease characterized by an attack on healthy tissue by the immune system leading to lesions on the skin, inflammation, and rashes which can result in pigment changes and scarring of the skin as well as potential hair loss. Differential expression of lncRNAs and circRNAs, identified in a study by Xuan et al [9], alter the mucosa a key part in the pathology this disease[10]. Many transcripts for DLE were found to be expressed in affected tissue; IncRNA to a significant extent and circRNAs to a lesser extent lesser were more heavily expressed in DLE tissue compared to control nonaffected tissue. The pattern of expressed lncRNAs and circRNAs helps to discriminate against affected tissue of DLE and healthy nonaffected tissues establishing a useable pattern for reference[10] . 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 a key transcription factor responsible for influencing the regulation of many target genes involved in DLE [10].

Psoriatic Arthritois (PsA)

Psoriasis is an inflammatory skin condition characterized by T-cell activation and the development of scaly red patches on the skin caused by the overproduction of skin cells[11]. Psoriasis can be broken down into plaque psoriasis and psoriatic arthritis. Psoriatic arthritis differs from plaque psoriasis because the psoriatic skin lesions are also accompanied by inflammation, joint pain, and joint stiffness attributed to immune system complication produced by psoriasis[12]. Psoriatic arthritis patients secrete high levels of immune-regulated cytokines and chemokines. It has been shown that epigenetics modifications play a prominent role in the symptoms and pathogenesis of this condition. Alterations in miRNA expression levels are one of many epigenetic modifications that accompany the onset of this disease. In particular, miRNA-203 levels are decreased in those with psoriatic arthritis and this has been linked to psoriasis pathogenesis[3]. miRNA-203 is responsible for targeting suppressors of cytokine signaling 3 (SOC3) and ensures that the immune response is kept in check. However, when miRNA-203 levels are low, cytokine signaling occurs at a high level leading to a heightened immune response. Developing a treatment that can increasing miRNA-203 levels has been implicated as a way to decrease the inflammatory immune response observed in patients with this condition. Abnormal expression of HDACs and HATs have also been observed in patients with psoriasis[3]. Peripheral blood mononuclear cells, which are a collection of immune system cells, exhibit a global decrease in acetylation of histone 4 in psoriasis patients as well as increased HDAC-1 levels. HDAC inhibitors have been identified as a potential treatment for psoriasis as well as many other inflammatory autoimmune disorder[13] .

Sjogren's Syndrome

Sjorgen's syndrome is a dermatological autoimmune disorder that causes a decreased function of the lacrimal and salivary glands*15*. 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 [5][3]. <- Not sure what this sentence means. Of the miRNAs identified to play a role in this diseases, miRNA-16a's role in the 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 (this brief description of monocytes is the kind of thing I want to see throughout this article. Remember that Wikipedia generally attracts more of a lay audience that needs these brief descriptions to hold their attention. Anything that seems like jargon should be quickly explained/defined). In Sjorgen's patients, there is an over expression of this miRNA leading to increased ingestion by these monocytes*16*; targeting of this over-expression is thought to hold potential in treatment of this disease [3]. As described previously, Sjorgen's targets the salivary gland, particularly its epithelial cells which are show to be hypomethylated*17*. 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[3]. <- I don't quite understand this. 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 [14]. 


*15* Can you introduce this in a way that the readers understand that the innate immune system is active in salivary and lacrimal glands?Also somewhere can you tell us what decreased function of the glands means? I could see this meaning a reduced volume of tears or the same volume of tears but the tears might not have all of the expected components.
*16* Can you mention why this increased ingestion is a problem? Do they phagocytize the inappropriate cells?
*17* I am having trouble keeping track of the players. First you say that affects monocytes then you say that it particularly affects epithelial cells. Now, I think that I can guess or make up the connection between the two but you really don't want readers guessing how things are related. They usually guess wrong. Please sort this out by explicitly telling. How do B cells or monocytes in general affect salivary epithelial. Also in this paragraph you ping pong between methylation in epithelia cells and immune cells.

Epigenetics of Local Endocrinological Autoimmune Disorders

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”[15]. 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. Family-based linkage screens have determined the thyroglobulin (Tg) gene is a major autoimmune thyroid disease susceptibility gene. This susceptibility stems specifically from fourteen single-nucleotide polymorphisms within the exons of the Tg gene.[16] 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. Tg is a thyroid-specific gene. In specific, the transcription factor IRF-1 exclusively binds to the Tg promoter only when the disease-associated variant is present.

This binding of IRF-1 to Tg is impacted by modulations in histone methylation patterns. Of note 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.[15] Specifically, IRF-1 serves as a transcription factor for interferon alpha (INF⍺), which is a critical cytokine expressed during viral infection. INF⍺ is produced by cells in response to viral infection. The interaction of INF⍺ with Tg is dependent upon the disease-associated genotype.[17]

Additionally, skewed X chromosome inactivation has been found to be implicated in autoimmune thyroid diseases (specifically Hashimoto’s thyroiditis and Graves’ disease). This indicates that the level of X chromosome inactivation in females is an important factor in the risk of developing autoimmune thyroid diseases[18]. For example, the chromosomal abnormality termed Turner’s Syndrome is linked to autoimmune thyroid disease, in addition to X chromosome monosomy. In the study of autoimmune thyroid disease, skewed X chromosome inactivation is defined as greater than or equal to “80% of activation of one X chromosome in the same tissue.”[18] It has been shown that the skew of X chromosome inactivation is markedly higher in individuals with autoimmune thyroid disease in both Graves’ disease and Hashimoto’s thyroiditis. Though there is no definite mechanism by which skewed X chromosome inactivation influences autoimmune thyroid disease, one possibility being studied is that skewed XCI in the thymus may lead to a lack of thymic expression, ultimately leading to inadequate T cell deletion.[18]

Graves' Disease

Graves’ disease is an autoimmune disease involving thyrotoxicosis, in which the body is affected by the overproduction of thyroid hormone. *18* The overproduction of thyroid hormone is termed hyperthyroidism. Thyrotoxicosis can be caused by hyperthyroidism, thyroiditis, and other conditions like those normally due to hereditary mutations, or due to thyroid medication issues. This is generally due to the immunoglobulin antibodies that activate thyroid-stimulating hormone receptor.[19] Like Hashimoto’s thyroiditis, Graves’ disease is qualified as an autoimmune thyroid disease. The epigenetic processes involved in Hashimoto’s thyroiditis are also involved in Graves’ disease. Namely, these are the modification of histone methylation in Tg and skewed X chromosome inactivation. The viral infection possibility mentioned in reference to Hashimoto’s thyroiditis also applies to Graves’ disease[15]. In the specific case of Graves’ disease, discoveries have been made showing the involvement of abnormal DNA methylation at certain CpG sites. This abnormal DNA methylation leads to interferon signaling and other immune system-related processes in cases of Graves’ disease. Graves’ disease patients have exhibited hypomethylation in CpG sites in certain T cells, indicating the implication of DNA hypomethylation in the mechanism of Graves’ disease. For example, the hypomethylation of genes that regulate T cells in various ways are shown to be at play in autoimmune thyroid diseases like Graves’ disease. Furthermore, histone methylation in peripheral blood mononuclear cells is abnormal in individuals with Graves’ disease. This abnormality has been attributed to the deregulation of epigenetic modifier genes such as the CD3 gene family that regulate T cell behavior among other genes related to immune system function. Additionally, the differential expression of certain non-coding RNAs has recently been implicated in the development of Graves’ disease. These non-coding RNAs can serve as biomarkers for Graves’ disease diagnosis upon further study in the future.[19]

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. Though the pathology of Type I diabetes is still being studied, certain epigenetic mechanisms have been implicated in Type I diabetes. Type I diabetes is characterized by global hypermethylation. This global hypermethylation arises by the altered metabolism of homocysteine. Specifically, insulin and glucagon alter homocysteine metabolism by increasing homocysteine production by the cell. Subsequently, DNA methyltransferases catalyze methionine in cells, thereby leading to enhanced DNA methyltransferase activity, which leads to increased global DNA methylation.[5]

Type I diabetes is also determined by DNA demethylation, specifically in the environmental component of the disease. 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 immune response gene 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[6]. Recently, an enrichment of differentially variable CpG positions has been identified, which indicates the involvement of DNA methylation in Type I diabetes pathogenesis.[6] More study is needed on this front. 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[20].

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 are 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.*27* 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.[21] The regulation of certain microRNAs differs significantly in individuals with Celiac disease compared to individuals without Celiac disease. This significant difference was found to come in the form of downregulation of some microRNAs and upregulation of others.[22] *26*


Fill in a little more mechanistic detail, e.g. where is H3K27ac up? Is there a pattern in the function of the miRNAs that are differentially expressed? 

*26* 
'Please make the connections for me. How does exposure to gluten produce an autoimmune response? Step-by-step, tell people things and don't expect prior knowledge.

 ALSO tell me about the “Several epigenetic mechanisms”. It does not have to be in this paragraph, which is an introduction to the disease paragraph. It should go in a separate paragraph that follows.

 Also what causes the high rate of CpG methylation?

ALSO, check subject verb agreement (everywhere really).

*27* This sentence should go above the tumor sentence. This sentence introduces  pathogenesis so don't talk about pathogenesis before this sentence. But before talking about tumors I would like to understand whether epgenetics has anything to do with the initial autoimmune response. It might not. Perhaps when cells are attacked by the immune system lots of other things go wrong. Organize the paragraph from Cause of Celiac disease clearly telling us if there is an epigenetic component. Tell us the role of gluten – does it just aggravate things in people with the disease? Can it cause the disease? Then talk about specifics such as adenocarcinomas and other pathologies. All of these would work in a well organized paragraph.

The epigenetics can be probably be inserted throughout. However, if you have a lot to say about epigenetics then leave it out of the first paragraph and dedicate a second paragraph to just the epigenetics (this might appeal to you even if you don't have a lot to say). It will require minimal repetition.

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.[5] 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[2]. Another article [23] . <- ???

Mechanism unclear to me.

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. It is also imparative to understand that the expression of the CTLA-4 region is responsible for the regulation of T-Reg cells which are important for MG as they work to suppress an immune response affecting those affected with MG as the CTLA-4 is an essential negative regulator. When there is a blockade of the CTLA-4 region there will be a resulting T-cell activation further proving CTLA-4 to be a negative regulator, this relationship can be used to help treat a tumor-induced immune tolerance[24]. The expression of CTLA-4 region is associated with the potential inhibition of the immune system through T-Reg cells 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[24].

References

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  20. ^ Paul, Dirk S.; Teschendorff, Andrew E.; Dang, Mary A. N.; Lowe, Robert; Hawa, Mohammed I.; Ecker, Simone; Beyan, Huriya; Cunningham, Stephanie; Fouts, Alexandra R.; Ramelius, Anita; Burden, Frances (2016-11-29). "Increased DNA methylation variability in type 1 diabetes across three immune effector cell types". Nature Communications. 7 (1): 13555. doi:10.1038/ncomms13555. ISSN 2041-1723.
  21. ^ Gnodi, Elisa; Meneveri, Raffaella; Barisani, Donatella (2022-01-28). "Celiac disease: From genetics to epigenetics". World Journal of Gastroenterology. 28 (4): 449–463. doi:10.3748/wjg.v28.i4.449. ISSN 1007-9327. PMC 8790554. PMID 35125829.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  22. ^ Dieli-Crimi, Romina; Cénit, M. Carmen; Núñez, Concepción (2015-11). "The genetics of celiac disease: A comprehensive review of clinical implications". Journal of Autoimmunity. 64: 26–41. doi:10.1016/j.jaut.2015.07.003. {{cite journal}}: Check date values in: |date= (help)
  23. ^ Elsen, Peter J. van den; Eggermond, Marja C. J. A. van; Puentes, Fabiola; Valk, Paul van der; Baker, David; Amor, Sandra (2014-03-01). "The epigenetics of multiple sclerosis and other related disorders". Multiple Sclerosis and Related Disorders. 3 (2): 163–175. doi:10.1016/j.msard.2013.08.007. ISSN 2211-0348. PMID 25878004.
  24. ^ 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. {{cite journal}}: Check date values in: |date= (help)
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