User:Sarahtucker511/Week 4

In recent years, allergies have become much more common, so much current research focuses on understanding and treating allergies. It has been found that environmental factors can cause of allergies mediated by epigenetic changes to DNA. This results in genes being repressed that prevent allergies and genes that cause allergies being upregulated. Thus, future allergy treatments will likely manipulate the epigenome.

Allergies
Many organisms, including humans, have innate and adaptive immune responses. The innate immune response is built-in genetically, and the adaptive immune is acquired upon exposure to a particular pathogen, which creates a "memory" in the organism's immune system. Allergic reactions occur when an innate response triggers an adaptive immune response. The innate immune response reacts non-specifically to toxins or foreign substances (antigens) as a base level of molecular defense. These responses come in two forms: humoral and cellular. Humoral responses utilize antigen-specific antibodies in order to ward off infection and to help the cellular response. Antibodies, or immunoglobulins, are Y-shaped proteins that bind foreign proteins with the aim of killing bacteria, neutralizing viruses, etc. The humoral response uses antigen-specific antibodies, whereas the cellular response does not. The cellular response includes the recruitment of natural killer T cells, macrophages, mast cells, and more whose role is to kill and/or digest foreign organisms or substances. The innate immune response occurs swiftly when needed, and it helps trigger the slower but much more powerful adaptive immune response. The adaptive immune response begins when antigen-presenting innate immune response cells signal to adaptive immune response receptors. They do this by ingesting foreign substances and "displaying" small antigens on their surface to T-cells and B-cells. There are multiple strains of T-cells that can be created from the initial naive T-cell. This leads to the creation of different T helper cells. B-cells act as memory cells with the ability to produce the antibodies needed to fight off illness. The adaptive immune systems has a continuous memory response where the antigens are always ready to be used and reproduced. Innate immunity reacts to the first invasion but returns to a baseline memory level. If the same antigen returns, the innate immunity can react more quickly due to prior experience but still requires time to recall the past experience.

All the members of the group of atopic disorders, the most common types of allergy, are mediated by immunoglobin E (IgE). This group of disorders include common hypersensitivities to food and inhaled allergens. Atopy is the genetic tendency to develop allergies. Atopic disorders have a strong genetic factor. Non-atopic allergies are allergies that occur in people with no clear genetic disposition to develop hypersensitivity to food or inhaled allergens.

In societies with developed hygiene and public health systems, people tend so be more susceptible to environmental substances. This increase in the rates of hypersensitivity to allergens arises from decreased exposure to these substances during development. This absence of potential allergens prevents the body from recognizing them as harmless substances in later life. This process of adaptation to environmental agents occurs through an array of epigenetic mechanisms. An allergic reaction is simply an immune response to an otherwise harmless substance. The immune response induced by contact with the allergen results in an exaggerated, sometimes even deadly, inflammatory response.

Epigenetic Background
Each cell in an animal's body has the same genome, so the selective activation and repression of different genes is what gives rise to different types of tissue. Also, environmental factors such as stress during early years can have lasting effects on the expression levels of many genes. Epigenetics is the study of the mechanisms that underlie these selective changes in gene expression without causing alterations to the DNA sequence itself. Such changes can be inherited through the successive generations. Histones are often the physical substrate of epigenetic alterations. The approximately 6 feet of human DNA fit in the nucleus of a cell because it is wrapped around many histone proteins. The extent to which the DNA strand is condensed (compacted) by histones determines how easily proteins and other molecules can bind DNA, and hence how easily DNA can be transcribed into mRNA. Much of the regulation of gene expression occurs by either loosening the grip of histones on DNA (upregulation) or tightening it (downregulation). Downregulation can be induced in multiple ways such as by methylation–i.e. the addition of methyl groups to DNA or to histones. The repressive effect of methylation arises in part due to that it increases the electrostatic attraction of DNA to methylated histones. Also, methylated histones act as markings that eventually help recruit other repressive machinery. On the other hand, the addition of acetyl groups to histones, known as acetylation, often upregulates gene expression. Acetylation can cause the elongation of DNA strands into so-called euchromatin (as opposed to the densely packed heterochromatin) allowing for the DNA to be more easily transcribed as the bound transcription factors allow for recognition. Acetylation induces upregulation of transcription this through a variety of mechanisms, some of which include inducing the disassembly of long chains of nucleosomes that keep DNA inaccessible, as well as the recruitment of cellular machinery that further increases the accessibility or the transcription levels of that particular stretch of DNA.

Role of Epigenetics in Immune Response
While the full role of epigenetics in T-cells is still an area of active research, there is clear evidence that it plays an important role in the development of allergies. Environmental factors affect histones' methylation and acetylation patterns, partly determining the overall pattern of gene expression in an organism. For instance, methylation of the histones neighboring the genes that predispose an individual for a particular allergy may prevent the disorder from actually developing. The differentiation of T-cells is partly dictated by epigenetic modifications, as well as specific levels of particular cytokines in the cell's microenvironment. Abnormal epigenetic modification patterns can, thus, induce abnormal patterns of T-cell differentiation. T-cells play a role in the activation of the inflammation response, and changes in their gene expression have shown to have different effects on the appearance or lack of allergies. This effect may come from differential epigenetic marking at immunity-related genes. It may also come from abnormal marking on genes of proteins involved in the epigenetic marking itself. For example, excessive methylation of the regulatory region of a TET gene results in repression of the TET gene, which is one in a family of genes essential for DNA demethylation. Such repression can then result in abnormally low demethylation patterns, which itself leads to widespread increased repression of gene expression, which has been established as a risk factor for the development of allergies.

Epigenetic modifications mediate cells' ability to retain "memories" of antigens. Upon the first exposure to an antigen, genes coding for the antibodies that bind to that antigen change from heterochromatin (condensed, inaccessible DNA) to euchromatin (accessible DNA). As the DNA is now able to be transcribed, the cell can produce antibodies that will attack the antigen. The DNA for that particular antibody will remain as euchromatin, so that when the cell is exposed to the same antigen in the future, it will be able initiate a swift response against it.

Environmental factors can cause epigenetic modifications relevant in the development of allergies even before birth. If the maternal parent is exposed to environmental substances while pregnant, epigenetic alterations of the parents' DNA can prevent the expression of genes that enforce the development of allergies in the fetus by allowing for the expression of CD4, resulting in CD4+ T cells with epigenetic modifications that prevent the allergy from appearing. According to a study on methylation patterns in children, a 92-CpG methylation signature in CD4+ T cells distinguishes children who develop clinical food allergy by age 12 months, and is enriched in genes encoding MAP kinase signaling molecules. This signature was stable from birth until 12 months of age. This suggests that the children with that genetic mark were predisposed to disease since birth. MAP kinases (MAPKs) are proteins involved a number of signaling pathways, especially those related to acute responses to hormones. Specifically, MAPKs, upon being activated, promote the inflammatory response.

The differential methylation patterns found most often in allergic children may cause deficits in T-lymphocyte responses in early childhood. Such anomalous responses are presumably associated with the development of food allergies. Genetic predisposition is not necessary for the development of allergies, but it might make it easier for environmental factors to eventually cause an allergy. If early in childhood, the potential allergen the cell is predispositioned for is not encountered, the allergy may never develop.

Exposure to air pollutants results in increased likelihood of developing allergies and asthma. Polycyclic aromatic hydrocarbons exposure results in increased methylation of CpG islands located on the FOXP3 locus. The FOXP3 gene has been implicated in the suppression of immune responses to allergens. Thus, abnormally high levels of methylation near FOXP3 and the resulting suppression of expression can hinder the balance in signaling in response to allergens. This effect is more pronounced in asthmatic children. Maternal exposure to these compounds during pregnancy is a risk factor because it results in hypermethylation of the fetal genome. Though the role of widespread increases in methylation plays in the development of allergies is unknown, it has been established that people with this pattern of over-methylated CpG islands are more likely to experience asthma and prolonged wheezing. The effect of smoking on epigenetic changes is better understood. Smoking is known to alter methylation of DNA found in peripheral blood, but when exposed in utero, the fetal DNA methylation patterns are changed in buccal cells, fetal lungs, and placenta. On the other hand, hypomethylation can also play a role in the development of allergies. It has been found that genes involved in the immune response, such as IL13, RUNX3, and TIGIT, were hypomethylated in asthma patients. These genes are all expressed in T-cells, and abnormally high levels of their expression tend to be seen in allergic patients.

On the other hand, while the exposure to environmental factors can create allergies, it can also prevent them. The reason for the contrasting reactions stems from the type of factor. Different substances can evoke opposite epigenetic changes. For instance, drinking unprocessed cows milk can decrease methylation of FOX3P CpG islands as well as activate Treg cells, a regulatory T-cell. These effects contrast with those of polycyclic aromatic hydrocarbons.