User:Josiehar/Epigenetics of autoimmune disorders

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Systematic autoimmune diseases

Rheumatoid arthritis (RA)
Rheumatoid arthritis is a degenerative autoimmune disease that causes damage and inflammation to a patient's joint and can affect bodily systems involving the heart, lungs, nerves, eyes, bones, and skin. Global DNA hypomethylation is a hallmark of Rheumatoid Arthritis and is observed in the early stages of this disease, when joint degeneration begins. Those who suffer from RA have a global decreased level of methylation on many DNA promoter regions including those associated with normal immune system and joint function. This overexpression from hypomethylation is observed in various genes 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.undefined '''Typically, healthy joints have a thin layer of synovial tissue that lines the cavities of the joints. However, as an increase number of immune cells begins to penetrate the tissue, the synovial tissue begins to form a thick lining layer that consists of different macrophages and synovial cells.''' Hypomethylation of CD40LG, which will make the T-cells within the immune response, can lead to T-cell overexpression and becomes a contributing factor to how Rheumatoid Arthritis functions within an inflammatory response. 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.undefined 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. 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. miRNAs also play an important part in rheumatoid arthritis development as well, particularly 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 expression of 85 different lncRNAs in RA patients on tocilizumab and adalimumab.

'''As a systemic disease, RA can develop other complications and cause damage to tissues and organs besides the joints, which include the heart, lungs, bones, skin, and eyes. In regard to the heart, RA patients typically experience some form of heart disease such as pericarditis, myocarditis, and coronary artery disease. Because the synovial tissue and circulating immune cells release pro-inflammatory cytokines (TNF-α and IL-6), this leads to systemic inflammation and the overexpression of T-cell and B-cell lymphocytes. Autoantibodies, antibodies that react with self-antigens, in RA then affect the structures of the cardiovascular system, such as the myocardium and heart valves, thus leading to various forms of cardiovascular disease.  Osteoporosis is another common systemic disease that can occur along with RA. Systematic inflammation, autoantibody circulation in the body, and the secretion of pro-inflammatory cytokines work together to contribute to the bone erosion and fragility in RA patients. The inflammatory cytokines decrease osteoblastogenesis while promoting osteoclastogenesis, which is why bone loss is more likely to occur, especially around the joints of those who suffer from RA. Osteoblastogenesis refers to the process by which osteoblasts, the cells responsible for bone formation, are generated and differented to develop and maintain the bone. Meanwhile, osteoclasts, cells involved with the dissolution and reabsorption of old bone tissue, are involved in the process of osteoclastogenesis.'''

'''There are several environmental risks factors that also contribute to the development of rheumatoid arthritis through epigenetic modifications induced by external stimuli, which include smoking and air pollution. The main source of air pollution has come from heavy traffic, fuel burners, forest fires, and solid fuel combustion, which usually contain a mixture of particles and gases such as nitrate, sulfur dioxide, ozone, and carbon monoxide. These pollutants can release reactive oxygen species that can be easily inhaled into the respiratory tract to activate nuclear factor ƙappa B (NF-ƙB), an important regulator for pro-inflamatory cytokine production in RA. This process leads to an excess production of T helper lymphocyte type 1 (Th1) cytokines that migrate to tissues in the synovial joints, further promoting inflammation.  In addition, smoking has been found to be one of the most common environmental risk factor for developing RA as it affects the lung tissue and alters the expression of sirtuins (SIRT) in the body. SIRT is a deacetylase protein that is involved in modifying histone and non-histone proteins, and it is essential for the body's ability to adapt as it helps to maintain the stability of the genome when cells are using epigenetic mechanisms to respond to stress.  Other general risk factors for rheumatoid artithritis include sex, age, family history, and excess weight. Women are more likely to develop RA compared to men, and RA typically begins developing in middle-aged adults. '''

'''Because rheumatoid arthritis is caused by certain epigenetic mechanisms involved in regulating biological processes, these epigenetic alterations have been found to be reversible and could be altered by diet, drugs, and other environmental factors. This suggests that prevention and therapy of diseases that target the epigenetic mechanisms could help to treat chronic inflammatory diseases. Efforts have been made to create drugs that either change or restore the original epigenetic mechanisms that occur within the body, and some DNA methyltransferase inhibitors have already been used to treat inflammatory conditions such as pancreatitis.  However, more clinical trials and testing still needs to be done before the drugs can be approved.'''

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 epi-genome in those with systemic lupus. The promoter regions of many genes including ITGAL, CD40LG, and CD70 are shown to be hypo methylated as well as the 18S and 28S ribosomal gene promoters. In particular, this DNA hypomethylation is thought to alter T cells' the chromatin structure, enhancing the immune and inflammatory response observed in those with this condition. Genome-wide has been shown that when comparing the epi-genome 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 traditionally repressed by methylation to be over expressed, 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 methyl transferase enzyme 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 generations, and epi-genome wide hypomethylation is observed. In particular, it has been observed that DNMT1 expression is lower in immune T-cells. '''Levels of DNMT1 is partly regulated by the ERK signaling pathway in the body. In patients with SLE, ERK activity has been found to be reduced in lupus CD4+ T-cells. When ERK activity is suppressed, it causes there to be a reduction in DNMT1 expression and DNA hypomethylation levels increases. Because of this, the DNA of CD4+ T-cells in SLE patients becomes hypomethylated, which causes them to be autoreactive when encountering self-class MHC II molecules. Because it is a systematic disease, SLE can also affect many other body systems including the kidneys, brain, central nervous system, blood system, lungs, and heart.''' There is no cure for SLE but treatments aim to control inflammation, alleviate pain and damage to the joints, prevent disease flares, and minimize organ damage.

'''Several environmental factors such as smoking, viral infections, various chemicals, and UV light, have been found to induce oxidative stress that leads to inhibition or reduction of DNMT1 levels, which reduces DNA methylation in CD4+ T-cells and can prompt autoimmunity. In patients with SLE, the disease can be triggered or induced by exposure to UV light with its effects appearing to be dose dependent. UV-B light can induce apoptosis of dermal cells, and this can release large amounts of autoantigens and pro-inflammatory cytokines, which can trigger systematic inflammation. Additionally, vitamin D has been found to have a role in SLE activity. Vitamin D has a protective role in regulating the immune system and possibly in the regulation of gene expression important for SLE pathogenesis. Deficiency of vitamin D has also been shown to be associated with higher lupus disease activity as there seems to be a decrease in the proliferation and production of the IgG immunoglobulin. Although there is no clear association, smoking and drinking have also been been reported as potential environmental risk factors for SLE.'''

Systemic sclerosis (SSc)
Systemic sclerosis (SSc) is an autoimmune disease characterized by system wide excessive collagen deposits. It can affect several bodily systems including the skin, internal organs, lungs, heart, kidneys, musculoskeletal system, and the gastrointestinal tract. 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.undefined Fli1 is a transcription factor that negatively regulates collagen production such that the higher the Fli gene expression, the less collagen is produced. In SSc patients, hypermethylation of CpG islands in the Fli1 promoter region is observed, inhibiting transcription of the Fli gene and increasing collagen production beyond normal levels causing collagen build-up and an overproduction of fibrous connective tissue. This causes joint damage, scarring, and thickening of the skin. Patients with SSc are also observed to have decreased levels of DNA methyltransferases (DNMTs) in their CD4+ T cells which play an important role in the immune system. This reduced methylation is associated with immune dysfunction and the progression of SSc and its inflammatory effects, however more research is needed to further understand this implication. Patients with systemic sclerosis also display hypomethylation of the collagen genes COL23A1 and COL4A2. This overexpression of these collagen genes leads an 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 responsible for several cellular responses from cell differentiation and migration in developing cells to regulating homeostasis within an immune response in the body. 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 positive feedback to this pathway further encouraging fibroblast activation. An Integrin is a type of receptor that is a transmembrane receptor meaning it is able to communicate from cell to cell and help the cell attach and adhere to nearby cells.

'''There are several different types of environmental risk factors that can affect autoimmune diseases, some of which can be exposed from occupation. Frequency exposure to crystalline silica dust has been recognized as a risk factor for SSc. SSc patients with occupational exposure to silica has been shown to be a factor in the pathogenesis of the disease. Additionally, organic solvent exposure has been found to also be a risk factor for the disease, although the specific agents involved have no been identified. '''

'''Because epigenetics has been recognized as a contributor to SSc pathogenesis, epi-drugs have been tested as potential therapeutics for the disease. Drugs targeting certain miRNAs in SSc to replace or inhibit them have been found to reduce some fibrosis effects. However, several issues including inconsistent results of epigenetic modifications and problems getting the treatment to the proper tissues means that no definitive epi-drug has been created for the disease.  '''

Josie Edits:

Local dermatological autoimmune disorders

Local dermatological autoimmune disorders are those that effect skin and mucous membranes.

Discoid lupus erythematosus (DLE)
Discoid lupus erythematosus is one of the most common cutaneous diseases characterized by an attack on healthy epidermal tissue by the immune system leading to lesions on the skin, inflammation, and rashes. '''Localized DLE lesions will occur on the face, ears, and scalp. Disseminated DLE, below the neck lesions, is unusual if localized DLE lesions are absent. DLE lesions can result in pigment changes, scarring of the skin, potential hair loss, and rare occurrences of squamous cell carcinoma.'''

Differential expression, a significant observed difference in expression levels, of lncRNAs and circRNAs, identified in a study...

The mucosa serves as a key part in the pathology of this disease.



Sjogren's syndrome
Sjorgen's syndrome is a dermatological autoimmune disorder that targets exocrine glands  and attacks lacrimal and salivary glands causing a decrease in the secretion of tears and saliva. This results in inflammation, dry eyes, and dry mouth. Patients with this condition experience a buildup of white blood cells in the salivary glands known as lymphocytic infiltrate. The first confirmed case of Sjogren's syndrome was reported in 1892. Current research is largely focused on the innate immune system's role in the pathogenesis of this diseases. In Sjorgen's patients, miRNA-146a is upregulated in PBMCs and is associated with the pathogenesis of this disease. miRNA-146a plays an important role in regulating the immune system by providing negative feedback to toll-like receptor (TLR) signaling which is used to engage the innate immune response. When miRNA-146a is upregulated, this negative feedback to TLR signaling decreases leading to inflammation and a heightened immune response that can damage healthy cells such as those in the lacrimal and salivary gland. miRNA-150 and miRNA-149 are also upregulated in the salivary glands and lymphocytes of those with Sjorgen's. These miRNAs are targeted to mRNAs that play an important role in immune function and regulating pro-inflammatory cytokine levels. The overexpression of these miRNAs thus leads to a heightened and dysregulated immune response. Epigenetic alterations to the genes of CD4+ T-cell in the immune system are also observed in this condition. Specifically, research has linked hypomethylation of CD70, a T-cell costimulatory gene, to the development of Sjogren's syndrome. Decreased expression of the FOXP3 gene, which leads to DNA hypermethylation, is also observed in these CD4+ T-cells. This causes CpG hypermethylation leading to the downregulation of many cells that are essential for keeping the immune system in check.

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Alopecia Areata (AA)
'''Alopecia Areata is a dermatological autoimmune condition where the immune system attacks the immune system and causes patchy or total hair loss usually affecting the scalp and face but can cause hair loss on the whole body. The cause of alopecia areata is unknown and typically people with the condition have no other symptoms. Genetic and environmental factors, like stress, are believed to trigger an episode of the condition. This condition was described as “bite alopecia” over 3500 years ago by Cornelius Celsus. The modern term was not used until the early 1700s to late 1800s.   In a study done by Zhou et al., a significant increase in DNA methylation, specifically T-cells, was detected after the analysis of peripheral blood mononuclear cells in patients with AA compared to healthy control cells. Other areas of increased expression included DNA methylation-regulating enzymes, RANTES, E1A binding protein p300, and HDAC1. There were also decreased levels of HDAC2, HDAC7, and LSD1 expression shown in the peripheral blood mononuclear cells. A notable protein in patients with AA is the HDAC1 protein. It has become a more heavily studied protein because of a study with postnatal dermal cells in mice conducted by Park et al. that has shown that a HDAC inhibitor, that is known for upregulating genes that effect hair follicle pathways, is causing HDAC 1 dysregulation in AA patients. This dysregulation is causing patients with AA to have higher serum levels of HDAC1. '''

Celiac disease
Celiac disease also known as Coeliac, is a disease in which the small intestine is damaged due to the body being unable to process gluten because of a T cell response that is activated when gluten, from foods such as wheat or rye, is present in the intestine. Several epigenetic mechanisms are disturbed in celiac disease, such as DNA methylation, histone modification, and non-coding RNAs. These epigenetic mechanisms are involved in the pathogenesis of celiac disease as well as altered in those prone to celiac disease. Furthermore, unusual methylation in the genes involved in the core NF-κB pathway, organizes cellular resistance to invading pathogens, is implicated in the pathogenesis of celiac disease. A high rate of DNA methylation sequences contribute to the development of cancerous tumors in the small bowel, in individuals with celiac disease. This hypermethylation an increase in DNA methylation agrees to the loss of expression of the MLH-1 gene, which is involved in DNA repair. Furthermore, hypermethylation of the APC gene, a tumor suppressor gene, has been found to cause defects in the mismatch repair mechanisms. An increase in histone acetylation, specifically (H3K27ac), has also been found in celiac disease biopsies. When comparing the genes of three different cytokines in response to cytotoxic T lymphocytes in celiac biopsies, an increase in H3K27ac in the promoter and enhancer regions were found in the cytokine INFꞵ genes. The regulation of certain microRNAs differs significantly in celiac disease compared to individuals without celiac disease. These differences were found to come in the form of down regulation of some microRNAs and up regulation of others. This differential regulation likely occurs for microRNAs involved in modulating intestinal barrier function, though more study is needed specific to celiac disease. The only treatment plan for celiac is to follow a strict gluten diet for life along with dietary supplements.

Multiple sclerosis (MS)
Multiple sclerosis is a neurological disease where the immune system attacks and destroys the myelin sheaths that coat nerve fibers. Destruction of these sheaths leads to the slowing or loss of electrical transmission of messages across nerve cells. As a result, patients experience weakness, pain, and vision loss. It has been shown that vitamin D deficiency relates to alteration to epigenetic markers and the progression the disease has throughout the body called MS pathogenesis. Vitamin D plays an important role in suppressing autoimmunity, a process where the immune system attacks itself, and particularly Th17 autoimmunity. Th17 is a subset of T helper cells that secrete pro-inflammatory interleukin (IL)-17, causes local tissue inflammation by induction release of neutrophils simulating cytokine. Traditionally vitamin D suppresses transcription of IL17 via recruitment of regulator HDAC2 to the IL17A promoter, however in those deficient in vitamin D, IL17 transcription is increased leading to a raise in inflammatory immune response. Increased expression of inhibitor miRNA-326 goes in a blood cell with a single nucleus called PBMC cells it is also prevalent in those with Multiple Sclerosis (MS) and is known to encourage Th17 cell differentiation. Histone H3 citrullination, which alters the methylation of arginine residues and consequently chromatin structure and gene expression, has been shown to be increased in the brains of MS patients as well. Although more research is needed to understand the mechanism of how histone H3 citrullination contributes to a loss of myelin with relative preservations of axons called demyelination, research demonstrates that inhibitors of the enzymes involved in this citrullination a chemical process and improve the outlook and progression of this disease.

Myasthenia gravis (MG)
Myasthenia gravis is an autoimmune disease that causes weakness and dysfunction of the patient's skeletal muscles because of extensive neurological damage or nerve damage that destroys the communication between the nerves and the muscles. It has been found that individuals who have Myasthenia Gravis possess high levels of the [https://www.mountsinai.org/health-library/tests/acetylcholine-receptor-antibody#:~:text=Acetylcholine%20receptor%20antibody%20is%20a,signals%20from%20nerves%20to%20muscles. acetylcholine] receptor antibody, AchR-Ab, which is a protein found in blood and affects the nerve cells that sends signals from nerves to muscles and recruits the immune system to destroy the ACh receptors present at the terminal end of a motor nerve and a muscle. A significantly higher levels of methylation in the CTLA-4 region, a region to help keep the body in check and is observed in MG patients. CTLA-4 gene expression serves as a negative regulator of T-Reg cells and suppress the immune response. When expression is blocked of the CTLA-4 region, as is seen in those with MG, increased T-cell activation occurs, and a heightened immune response is observed. The expression of the CTLA-4 generating cytokines that regulate AchR-Ab autoantibodies require further exploration to better understand their mechanism of action. There are several treatment plans that help with the symptoms and are dependent on ages and how bad the disease is, for example surgery is an option but so is intravenous therapy as well as different medications.