Justin S Research Paper

Justin Moser
Dr. Rachel Robson
Morningside College
March 31, 2008
Immunological Aspects of Asthma
Asthma is an atopic disease that is very common around the world today. It is characterized by inflammation of the alveolar epithelial tissue, increased mucus production within the lungs, increased bronchial smooth muscle contraction, an influx in leukocytes, particularly eosinophils, CD4+ T cells, neutrophils and mast cells, and an increase in the expression of intracellular adhesion molecules 1(ICAM-1) [1][2][3][4]. It was recently thought that a molecule called Adam 33 Is Adam suppose to be in all caps? was also associated with asthma. However, it has been recently deciphered that ADAM 33 does not play a role in asthma.[5]. Asthma is also characterized by an unbalanced Th1 and Th2 response in which the Th2 response is favored.[6][7] Since it is an atopic disease, asthma is usually preceded or simultaneously occurring with other atopic diseases such as allergic rhinitis[8]. Challenges of allergic rhinitis with different chemicals like histamine can cause bronchial-hyper responsiveness, which is a characteristic of asthma. Interestingly, asthma is more predominate in western and developed countries that have a higher degree of cleanliness and healthcare. [8] [4]
As stated above, asthma is characterized by a Th2 dominated response. The Th1 response synthesizes interferon gamma (IFN-γ), inhibits the release of IgE, and blocks the development of Th2 cells. [4] Even though, there is generally not elevated levels of IFN-γ in asthmatics, Th1 responses can occur due to constitutively active jak-stat pathways in airway epithelial cells. [7] For some an unknown reason, the jak receptor sometimes phosphorylates a stat-1 molecule without IFN-γ being bound to it in people with asthma. From here, the phosphorylated stat-1 molecule dimerizes and translocates to the nucleus, where it acts as a transcription factor for ICAM-1, IRF-1, and stat-1 genes. The Th2 response is characterized by a release of IL-4, IL-5, and IL-13.[9][10] IL-4 is a cytokine that is important for B lymphocyte class switching to make IgE, it also increases airway epithelial cell expression of VACM-1 (Did you mean VCAM) , a cell adhesion molecule. Il-5 should it be IL-5?plays an important role in recruiting eosinophils and along with IL-4, promotes(should be promoting?) inflammation.
(Move down the sentence from above that pertains to this to make less confusion) The hygiene hypothesis is a hypothesis that attempts to answer the question, “Why is asthma more common in western and industrialized countries that are cleanlier and have better healthcare systems?” This hypothesis states that exposure to allergens and other exuberants of asthma early in life, before allergen sensitization, will help prevent the development of asthma.[10][11][6] This explains why asthma would be more prevalent in developed countries. There is less exposure to allergens at a younger age. This hypothesis also explains why people with asthma have a Th2 dominated response. People are born with a Th2 dominated response. [6]So the hypothesis explains that people are born with a Th2 dominated response? THe wording is confusing Bacterial and viral infections at younger ages can help establish a Th1 response.[6][3] Newborns getting microbial infections establish their Th1 response, which, as stated above, helps prevent the over development of the Th2 response. This prevents the Th2 response from becoming too great and offsetting the balance between the Th1 and Th2 response. Even though this hypothesis seems to explain why asthma is more prevalent is people with asthma, it is under some debate. (this sentence doesn't make sense) In the case of vitamin D, early exposure has been shown to increase the chances of developing asthma.
People with asthma usually show varying degrees of symptoms, depending on the situation they are in. Severe asthma symptoms are generally not seen unless something is exuberating one’s asthma. Exuberants can vary from person to person, and even throughout one’s lifetime. Typical exuberants include pollen, exercise, smoke, anxiety, and stress. The most common trigger of asthma is the rhinovirus. [12] The rhinovirus is a virus that can replicate in macrophages and causes the induction of pro-inflammatory cytokines and adhesion molecules (But earlier you said that exposure to viruses can decrease the risk for asthma??). When one’s body becomes infected with a virus, one of the molecules released is IFN-γ .[12] This molecule uses the jak-stat pathway described above to cause the release of pro-inflammatory cytokines, adhesion molecules, the recruitment of eosinophils and neutrophils, and the hyper contractility of smooth airway muscle. [12] Other viruses can also exuberate asthma. The dsRNA of some viruses can activate protein kinase receptor that inactivates IkB. This releases NF-kb, which translocates to the nucleolus of the cell and causes the expression of TNF-ά and IL-1. [13] [book] The activation of the protein kinase receptor by viral dsRNA also lead to IgE class switching of B cells and possibly the release of IL-4.[13]
Studies have also shown that some vaccines, like the ones for tetanus and Diphtheria pertussis diptheria & pertussis are two different diseases as well, can also increase the likelihood and severity of asthma.[3][11] [14]Vaccines do this by one of two mechanisms. One mechanism in which vaccines can increase the severity of asthma is by hindering the effects of Th1 promoting agents.[3] The second mechanism by which vaccines can cause asthma is by inducing a Th2 response. Both of these mechanisms tip the balance of the Th2 and Th1 receptor response towards the Th2 side, which stimulates asthma. However, it has also been shown that some vaccines can help protect the exuberation of by specific microbes. An example of this is a Pa immunization (What does Pa stand for) . This immunization can be given to people with asthma in order to help protect them from asthma exuberation caused by the B pertussis microbe[15].
Lipopolysaccarhide (LPS), a structural outer membrane component of gram negative bacteria, has also been shown to exuberate asthma.[10] Lipid A is a component of the LPS found in gram negative bacteria. This molecule, with the help of accessory proteins, binds to the TLR-4 receptor to generate an inflammatory response. Since ligand bound TLR-4 can interact with MYD-88 and TRIF, it is very effective at generating an inflammatory response, which makes it a good exuberant for asthma. [16] These exuberating effects of LPS can be counteracted by treatment with histamine. Histamine accomplishes this by causing down regulation of ICAM-1 and decreasing the release of inflammatory cytokines from dendridic cells. [17] Some studies have shown, however, that LPS can, in some cases, protect against the exuberation of allergic asthma. LPS does this by causing eosinophils to decrease their IL-10 production and by reducing the amount of eotaxin secreted. [10]
Another chemical know Known to exuberate asthma is estrogen. [18] This is believed to be the reason why asthma is very prevalent in women. It is also believed that this is why most female children do not have asthma or have mild asthma, but Aas they grow up they develop asthma or their asthma worsens.[18] Estrogen is released in higher amounts once during the onset of puberty, which usually occurs around the ages of 10 and 11. Studies have shown that estrogen can exuberate asthma through it’s interaction with estrogen receptors (ER) alpha and beta, which are found on mast cells. [18] Interaction between estrogen and ER alpha and beta has been shown to stimulate mast cell degranulation and the release of histamine and other cytokines into the body. The chemicals released from degranulation cause the exuberation of asthma. [18] Many environmental chemicals have regions that can act like estrogen and bind to the ER receptors. At very low levels, these environmental estrogen-like chemicals have been shown to stimulate degranulation and exuberate asthma.[18] Other things that have been shown to exuberate asthma include B. pertussis, Parietaria judaica, fungi, and rabbits. [11] [8][19] [20]
IgE is an immunoglobulin that plays a very big role in the creation development? of asthmatic symptoms. IgE is generally at higher levels in people with asthma and other atopic diseases such as rhinitis. [4] However, asthmatics generally have higher levels of IgE in response to different allergens, such as rabbit allergens, than people with just rhinitis. [20] This makes sense because IgE has been shown to be linked to bronchial hyperresponsiveness, which is a symptom of asthma. [21] IgE has been shown to interact with a FCέRI receptor on neutrophils, which causes the neutrophils to live longer.[22] Wildtype neutrophils have receptors on them that require accessory molecules in order to bind to IgE. However, neutrophils in asthmatics have the FCέRI receptor that can bind to IgE alone, without accessory molecules. [22] Interaction between IgE and the FCέRI receptor increases the intracellular levels of the mcl-1 protein within the neutrophil. This protein has antiapoptotic effects that work indepently independently? of the nl-Fas ligand expression mechanism.[22] IgE also has a survival effect on mast cells and monocytes. By increasing the life of the innate immune cells, the number of innate immune cells also increases, which makes the overall innate immune cell responses to forgien (spelling) antigens greater. IgE interaction with the FCέRI receptor on mast cells has other effects as well. In mast cells, IgE stimulation of the FCέRI receptor triggers the release and synthesis of prostoglandins and leukotrienes, as well as the transcription of inflammatory cytokines. [21] The release of these molecules causes hypersensitivity, mucosal edema, mucus production, smooth muscle contraction, and inflammation. In mast cells, the stimulation with IgE can have a late phase response that can occur four to six hours after the sensitization. IgE interacts with the CD23 receptor on B cells. This interaction increases the antigen presenting ability of B cells as well as activates B cells.[21] IgE’s interaction with CD23 also causes an increase in IL-4 secreation secretion from mast cells, expansion of Th2 cells, and an increase in IgE production from B cells. [21] One method for the treatment of asthma targets IgE, these drugs are called IgE blockers. IgE blockers do not help in the prevention/treatment or might be better than a "/" of chronic asthma, only acute asthma. IgE blockers prevent the binding of IgE to different innate immune cells by down regulation of the FCέRI receptor. [21]
Histamine is another molecule that is very important in asthma. Histamine can interact with two different histamine receptors, H1 and H2. Granulocytes in asthmatics exhibit a decreased H2 response. [23] Histamine interaction with the H2 receptor causes a negative feedback mechanism, while histamine interaction with the H1 receptor causes a positive feedback and an increase in cytokine production. [17] By having a decreased negative feedback response, asthmatics have an uncontrolled response, which causes the bronchial hyperresponsiveness. Histamine also interacts with H1 and H2 receptors on airway smooth muscle cells. Interaction with the H1 on airway smooth muscle cells causes constriction of the smooth muscle, and interaction with H2 cause smooth muscle relaxation. [23] The effect of histamine binding to the H1 and H2 receptors on airway smooth muscles cells in asthmatics is constriction of the airway muscles. This is caused by the decreased H2 response in smooth airway muscle cells that is also seen in granulocytes.
The vitamin D receptor is a receptor that is believed (I would not use believe) to be involved with asthma.[24] The vitamin D receptor has been shown to enhance the Th2 response, which is a characteristic of asthma. [25] The vitamin D receptor (VDR) bound to its ligand, vitamin D, has been found to decrease IFN-γ levels and increase IL-2 and IL-10 levels. [25] Not only does the VDR influence asthma, but the VDR gene also influences asthma as well. The VDR gene contains many places where there are single nucleotide variances between the genetic makeup of people within a population. These variances are called single nucleotide polymorphism (SNPs). The VDR gene contains many SNPs, all but one of which is found in introns.[25] Usually SNPs in introns do not have any effects since introns are removed removed from what? before mRNA moves from the nucleus to the cytoplasm and are translated. [26] However, in the case of the VDR gene and asthma, the SNPs in the introns do seem to can have an effect. It is believed that the intron of the VDR gene act as regulatory elements for genes that are associated with asthma. [25] It is not yet known if VDR gene introns normally are i would flip the words normally and are silencers and the SNP deactivated them, or if they are enhancers and the SNP deactivates them.You use "deactivated" which is past tense and in the same sentence you use "deactivates" which is present tense. Make your tenses agree. The one SNP that is located on one of the exons of the VDR gene can influence asthma. This SNP, however, does not affect the VDR that is translated from the mature mRNA. This is because the SNP is located on the 3rd position of the reading frame, so because of wobble, the SNP does not cause a change in amino acid sequence. [25] This SNP in the exon is believed to effect the 5’ splice site of one of the introns in the gene, and this is how it influences asthma. [25] This suggests that the introns that contain the SNPs that influence asthma may also influence asthma through a mechanism using the pre-RNA intron fragments as well.
Atrial naturetic peptides (ANPs) are more molecules that help tip the scales towards a Th2 biased response. [27] ANPs bind to atrial naturetic peptide receptors (ANPRs). The Binding of ANP to the ANPRs causes the release of cyclic GMP within the cell. These molecules (what molecules? cGMP?) then activate cyclic GMP protein kinases, which open ion channels located within the cell membrane and activates transcription factors. This increases the transcription and translation of inflammatory genes. [27] A treatment that can be used to target this mechanism of inflammation is small interfering RNA (siRNA). It has been recently determined that an Imiquimod cream can be used as a method of delivering RNA and DNA transdermally to the body. [27] The cream works because it protects nucleic acids from interacting with enzymes that would degrade it, do you need the word "it" here? can pass through layers of skin, and is easily degraded by the body into non-harmful products. As a treatment for asthma, the cream contains siRNA specific for the RNA of the ANPR gene. These siRNA anneal to the mRNA for the ANPR and either marks them for degradation by another protein, or if a stem loop is formed as a secondary structure of the RNA, the siRNA block the translation of ANPR RNA. [26]
(Awkward sentence) Along with the treatments for asthma to specific mechanisms as described above, more general treatments are also used. There is some debate weather whether these treatments are actually in accordance with scientific data[28]. AnFor example, of this is the treatment of asthma with AdvairTM. AdvairTM is a medication that contains two types of drugs: ICS, a drug that is slow acting and treats the chronic symptoms of asthma, and LABA, a fast acting drug that treats the exuberation of asthma.[29] AdvairTM is one of the most commonly used daily asthma medications. However, there is another drug, SymbicortTM , that is also an ICS and LABA drug all in one. The major difference between these two medications is that for the LABA component, AdvairTM uses salmaterol and SymbicortTM uses formoterol. [29] Studies have shown that if more formoterol is administered, it has a higher effect. This means that during times of high exuberation do you ingest it of inhale it? because i think you should say, an increase in ingestion/inhalation of this drug… **more of this drug will have greater effectswhat kind of effects?.[29] The LABA component of AdvairTM, at higher concentrations, does not cause a greater response. [29] Because of this, SymbicortTM is a better medication. This is not the case for AdvairTM; people taking AdvairTM ,during times of high exueration **exuberation, must use a separate medication to get higher effect. [29]
One reason why the normal treatments might not be up to date with scientific data is due to the difficulty in testing treatments. Asthma is not easily induced in Monkeys, a common model used infor studying asthma, are not easily induced to have asthma, so therefore treatments cannot easily be tested.[30]you use "easily" a lot in that sentence However a new method for making monkeys asthmatic requires far less time, so this problem could potentially be corrected.[30]
One type of medication that is frequently used to treat the exuberation of asthma is a glucocorticoid. Glucocorticoids can be used to prevent asthma exuberation before it happens and can also be used to help stop exuberation after transcription of inflammatory genes.[2] In mast cells, glucocorticoids alter the mRNA stability of inflammatory genes, specifically IL 1,3,4,5,6, and 8. After the mRNA stability is modified by glucocorticoids, the mRNA is rapidly degraded so it cannot be translated. In T cells, glucocorticoids alter the expression of lL-4 and 5 by stimulating the production of I-kb.[2] I-kb is a protein that blocks NF-kb from entering the nucleus where it acts as a transcriptional factor for inflammatory genes.
A different set of drugs that are commonly used to treat the exuberation of asthma are corticosteroids. Corticosteroids work to prevent/reduce exuberation of asthma by different mechanisms than glucocorticoids. One mechanism by which corticosteroids act is by inhibiting the GATA-3 transcriptional activator. [29] By inhibiting the GATA-3 protein, the production of inflammatory cytokines is inhibited. Another mechanism by which they act is by lowering the mcp-1 protein levels within the body. Mcp-1 is a protein that may be involved in stimulating histamine and leukotriene release from mast cells and basophils, and it is also an anti-apoptotic protein. [31] By inhibiting the anti-apoptotic protein mcp-1, corticosteroids lower the number of immune cells, as well as the overall severity of the response they can cause after stimulation with allergens. The last mechanism by which corticosteroids act is by reversing the acetylation of histone proteins around inflammatory genes.[9] When histone proteins become acetylated, the positive charge of the histone is reduced. This weakens the electrostatic interation the histone protein has with the negatively charged DNA, which means the DNA becomes more loosely wrapped around the histone protein. This allows the genes in the section of DNA around the protein to become transcribed. [26] By, reversing the acetylation, corticosteroids prevent inflammatory genes from being transcribed.
Asthma is a disease characterized by many things including and influx of lymphocytes, an unbalanced Th1/Th2 responsive, hyper-responsiveness to allergens, etc etc is probably not the best way to end the sentence. People with asthma generally do not have that severe of symptoms until something exuberates their asthma. Allergens, as well as other things such as microbes, can exuberate asthma by stimulating an abnormal immunological mechanism in asthmatics. This stimulation of the abnormal mechanisms is the target of many on the treatments of asthma. could possibly go into more detail with the conclusion

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