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. 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. 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.

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.

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Local dermatological autoimmune disorders

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.

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 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. There is no cure for SLE but treatments aim to control inflammation, alleviate pain, damage to the joints, prevent disease flares, and minimize organ damage.

Local gastrointestinal autoimmune disorders

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.

Local neurological autoimmune disorders

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 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.