Linda Cross 0. Development and Treatments. of Allergies. Linda Cross. BIOL 1503, section 2

Transcription

1 Linda Cross 0 Development and Treatments of Allergies Linda Cross BIOL 1503, section 2

2 Linda Cross 1 Allergies have been used to describe various ailments in the past, but have come to describe a specific pathological category, one of immune stimulations triggering specific proteins to react. Nevertheless, allergies are truly a modern affair. In the early twentieth century, the realization that clinical conditions may be a result of common pathology sparked immense biomedical research (Jackson 2008). Thus, most allergy developments and treatments are fairly recent. Today, up to million Americans are affected by allergies (American Academy of Allergy Asthma & Immunology 2009). Treatment developments cannot be understood without knowing what allergy really means. Allergy is commonly defined as a hypersensitivity reaction to an antigen. In some people, certain environments trigger lymphocytes to identify non-threatening proteins as threatening. This identification first activates a sensitizing exposure, in which B-cells produce antibodies which attach to mast cells and basophils, subsequently causing an imbalance of histamine. Antibodies produced (immunoglobulin E, IgE) during a sensitizing exposure will cause complement proteins to bind to the site when the same environment is encountered again. The complement proteins cause the mast cells and basophils to be destroyed, leading to histamine (and various other substances) being released, causing allergic reactions such as sneezing, itching, watery eyes, and possibly even anaphylactic shock (Eckley 2004). Various stimulations of the immune system trigger allergies. Food allergies tend to be the most diverse cause of allergic reactions. People can develop food allergies while young. Some children may even be allergic to their mother s breast milk, while other food allergies increase in prevalence as age increases (Jarvis et al. 2008). In England, there was a 2.4% increase in people who reported exposure to specific foods made their asthma worse in year olds

3 Linda Cross 2 versus under 16 year olds (Jarvis et al. 2008). Drug allergies are believed to be developed as a cause of drug resistance. Drugs cause bacteria to mutate to keep from dying out, but some of those mutations trigger the over-production of antibodies in certain people, eventually leading to an allergic reaction. Drug allergies can become serious. Allergies to penicillin have caused 400 deaths in a year via anaphylactic reactions (American Academy of Allergy Asthma & Immunology 2009). Environmental allergies can develop after short or long term exposure to allergens. For example, seasonal allergies result from a developed hypersensitivity to pollen in person s environment, and animal allergies usually result from too much dander introduced into a person s environment. These allergies are exacerbated by the increase of modern-day indoor living, as people spend less and less time outdoors and more time around pets and the house dust mite (Jackson 2008). People who do not get enough light exposure to allergens are then exposed heavily to the allergen, causing an influx of antibody production. Their body does not know how to handle the allergen and thus classifies it as attacking the body (Jarvis et al. 2008). The development of those allergies results from various factors. Food allergies stem from the improper digestion of foods. Food allergies are present in at least 3% of adults and have been reported in about 3 million children a year, but only cause deaths per year (American Academy of Allergy Asthma & Immunology 2009). In the last few decades of the twentieth century, studies by the World Health Organization surfaced showing increased allergic disorders in countries that were beginning to undergo industrialization (Jackson 2008). This is because better living conditions caused people to be less exposed and thus more sensitized to allergens. Geographical and temporal trends in allergies are also influenced by genetics, but not as much as the influence of environment and lifestyles. The risk of allergies has been contributed to by such diverse factors as genetic determinants of disease, bodily and mental characteristics,

4 Linda Cross 3 environmental and occupational factors, and various lifestyle triggers such as diet, smoking, levels of exercise, alcohol consumption and hygiene (Jackson 2008). Greater atmospheric concentrations of pollen create an increase in allergy trends (Jackson 2008). Jarvis et al. (2009) refutes these triggering factors, citing that there was no association of symptoms of neonatal infectious disease or infectious disease in children exposed early to infections and low hygiene. Such a range of possible triggers means cures for specific allergies are hard to pinpoint. Instead, treatments target allergies method of attacking the immune system. Besides environmental and lifestyle factors, genetics play a role in allergies. Meyers et al. (1991) investigated 42 nuclear families, segregating factors such as sex and age. Following traditional Mendelian inheritance patterns and skin sensitivity tests, they found that a high IgE level can be inherited as a recessive allele (Figure 1). The gene is at its own locus, meaning genetic linkages could be studied. 42% of men tested positive for allergens, while 27% of females did (Meyers et al 1991). This study does not consider if two loci are involved in allergic sensitivity. Figure 1 illustrates genetic outcomes between major locus IgE levels in two separate nuclear families. There is a genetic connection because select members tested skin test positive (ST+) for certain allergens.

5 Linda Cross 4 Figure 1. Two families showing segregation of total serum IgE levels in ng/ml at the major locus. Figure generated by Meyers et al. (1991). The most obvious way to control allergies is to remove the environmental stimulant by stopping exposure to the allergen. People who are allergic to specific foods can usually just change their diets to exclude that specific food. People with drug allergies, such as to penicillin, can take alternate drugs that perform the same function. Prevention is more effective than treatment. In cedar pollen-induced rhinitis, IgE can be prevented from being bound to its receptor using a method called H 1 receptor blockade (Almqvist 2009). This prevents Th2 (a T- helper cell affecting specific lymphocytes) inflammation and effects, showing that blocking signals may yield an effective allergy treatment. Corticosteroids function by blocking receptors, proving to be highly effective in the approach to preventing IgE antibodies attaching in the first place. These studies are supported by mucosal sites showing sensitizations to allergy tolerance (Almqvist 2009). Prevention measures would cause histamine to not be released in the first

6 Linda Cross 5 place, as IgE-allergens wouldn t be able to bind. An example of this occurrence would be IgG, specific immunotherapy-induced and allergen-specific, altering IgE s structure and thus the ability for allergens to bind to it (Almqvist 2009). The IgE antibody would not attach to mast cells and basophils, so allergens would not be able to destroy them. An imbalance of histamine in the body would not occur (Eckley 2004). Treatments of allergies otherwise target the effects of the released histamine and other substances in the body. Nevertheless, developing allergy treatments depends on what research has discovered about allergy mechanisms. The reaction of IgE is associated with different polypeptide chains, so that research is challenging. Allergies function via antigens stimulating large amounts of immunoglobulin E antibodies, so scientists have begun identifying which polypeptide chains are connected with which specific allergen. This will allow antibodies to be targeted (Almqvist 2009). Desensitization and antihistamines, bronchodilators and corticosteroids have their place in allergy treatments. Antagonistic drugs prevent proteins from being acted upon by antigens. These drugs usually treat just the symptoms of allergies (these are over the counter medications like antihistamines and nasal decongestants). Newly developed antihistamines do not enter the brain from the normal blood flow, thus keeping the proper balance of histamine in the brain to continue proper function (Kazuhiko et al. 2006). The main problem with antagonistic drugs is that they only provide short term relief. On the other hand, immunotherapy vaccines build immunity to allergens, providing long term solutions. Immunotherapies in general intend to reduce IgE production and block IgG antibody production. Immunotherapy vaccines include antibody injection and sublingual immunotherapy. Recent developments in these methods include developing a balance of the amount and timing of

7 Linda Cross 6 a dose of allergen injected into a person. Eventually, the doses are large enough to equal an unintended ingestion of a food. The person does not exhibit negative effects after gradually being exposed to increasing doses of the substance, usually every 2-4 weeks for 4-6 months and then in increasing intervals (Leiberman 2007). Considerable recent developments have been made identifying proteins associated with allergies. Most are aimed at preventing the mechanisms of each allergen s action. The first attempts at allergy medications arose in the mid-twentieth century with the introduction of antibiotics. Since then, many proteins associated with allergic reactions have been identified, which have helped the production of allergy drugs (Kazuhiko et al. 2006). Most allergists focus on inhibiting IgE, but there are several proteins that can be targeted to dilute the effects of allergies (Jackson 2008). Recent research identifies T cells role in atopic disease pathogenesis. An experiment by Bateman, et al. (2008) found that an HLA- DQB1*06 (a common allele found in the control group and patient groups) restricted epitope in B1-20 (a specific peptide) is highly probable due to the higher response from DQB1*06-positive derived B1-20-specific T cells than from DQB1*06 negative target cells. These results stem from the discovery of an HLA-DQB1*06-restricted epitope present in the B1-20 peptide (Figure 2) and recognized by CD4 T cells. Allergen-specific CD4 T cells circulate with a different frequency and phenotype (Bateman 2008) in atopics than in non-atopics. When treating atopic dermatitis, targeting CD4 T cells would be more effective than targeting them in non-atopics. This has to do with the specificity of allergens binding on cells. Recent research on epitopes being blocked by different antigens has proved that Fel d 1 (a major cat allergen) has an immunodominant region recognized by CD4 T cells. This would cause immune responses to be centered around those cells. Also, most atopic individuals have the HLA-DQB1*06 and HLA-

8 Linda Cross 7 DPB1*0401 epitopes restricted because DQ and DP are common alleles (Bateman, et al. 2008). Interferons (which produce different glycoproteins) in the patient group responded to B1-20 by increasing IL-4 (a protein causing mast cell production) response but decreasing IFN-y (which triggers a signal pathway) response as compared to the control group (Figure 3). Figure 2. (a). Illustration of B1-20 response being restricted by HLA. (b). Further determination of responses using multiple B1-20 peptides. Figure from Bateman et al. (2008).

9 Linda Cross 8 Figure 3. Response to B1-20 peptide from various interferons produced in HLA-DQB1*06. Figure from Bateman et al. (2008). Even though there has been a great deal of research trying to determine all the pathways and mechanisms of allergies, the field of allergy studies has much unanswered. Some treatment research difficulties include which HLA alleles differ between ethnic groups (Jackson 2008). This means more connections between epitopes needs to be further researched. The present and the future hold great incentives for developing better allergy treatments. Allergies put a strain on the health care system, costing an estimated $18 billion dollars annually and becoming the sixth leading cause of chronic disease (Georgiev 2009).

10 Linda Cross 9 Future research could include investigating responses through the complex pathways of the epithelium. Minimal research has been devoted to pathways of allergens through epithelial cells. These cells use a leukotriene D 4 -induced pathway, decoy receptors, and are fast-growing, making them suitable candidates for research of treatments (Almqvist 2009). Mouse models demonstrate immune mechanisms, which may be helpful for understanding how to treat allergies. They test various allergic conditions to determine the effectiveness of different treatment methods. T-cell mediated mechanisms have not been fully researched. Complex-peptide compounds stimulate T-cell receptors, creating a histocompatibility in which some cells only survive in the presence of others. This means that hypersensitivity may have an even larger role in the trigger of allergies (Schnyder et al. 2009). Further implications of each drug thus needs to be tested. Since several possible treatments have been developed, they stand to be tested in combinations and the down sides of each treatment weighed. A combination of antihistamines and leukotrienes would normally work efficiently because the antihistamines would inhibit allergic reactions while leukotrienes would stem the inflammatory response. The efficiency of each treatment has not been thoroughly tested. In fact, antihistamines may even make people more sensitive to allergies and reduce allergen-specific immunotherapy s effectiveness (Johansen et al. 2008). Johansen et al. s (2008) experiments found IgG2a production decreased and macrophages exhibited a histocompatibility. This results in T-cells secreting IL-4, which somewhat counteracts the effects of the antihistamine. It is difficult to determine how effective allergy treatments are. According to Almqvist et al. 2009, because there remains no reliable regulatory T cell marker in humans, in the future, it will be important to identify alternate markers of protective T cell responses if we

11 Linda Cross 10 are to determine whether new treatments for allergic disease could be beneficial. This contributes to the fact that extensive research has not yet gone into allergy treatments. The several access points of allergic reactions cause it to be an ever-growing field, hindered only by the economics of research and obtaining enough resources to test each possible cause of allergies. Because there are several different types of allergies, this task and further results remain elusive.

12 Linda Cross 11 Works Cited "Allergy Statistics." AAAAI - American Academy of Allergy Asthma and Immunology - American Academy of Allergy Asthma & Immunology, Web. 9 Apr < Almqvist, C., P. B. Bradding, J. Chakir, D. Ebo, C. Grattan, H. H. Kariyawasam, E. Savilahti, G. K. Scadding, S. Vieths, A. J. Wardlaw, and J. Woodfolk. "Developments in the Field of Allergy in 2008 through the Eyes of." Clinical & Experimental Allergy (2009): Academic Search Complete. Web. 20 Feb Bateman, E. A. L., M. R. Ardern-Jones, and G. S. Ogg. "Identification of an immunodominant region of Fel d 1 and characterization of constituent epitopes." Clinical & Experimental Allergy (2008): Academic Search Complete. EBSCO. Web. 20 Feb Eckley, Kirsten. "Allergies." Lock Haven University, Sept Web. 9 Apr < Georgiev, Vassil St. National Institute of Allergy and Infectious Diseases, NIH. Vol. 2. Totowa, N.J: Humana, Electronic. Jackson, Mark. Allergy: the History of a Modern Malady. London: Reaktion, Print. Jarvis, Deborah, Seif Shaheen, and Peter Burney. Allergy Frontiers. Ed. Ruby Pawankar, S. T. Holgate, and Lanny J. Rosenwasser. Vol. 1. Tokyo: Springer, Print. Johansen, P., Senti, G., Maria Martínez Gómez, J. and Kündig, T. M. Medication with antihistamines impairs allergen-specific immunotherapy in mice. Clinical & Experimental Allergy, 38 (2008): Kazuhiko Yanai, et al. "Brain histamine H 1 receptor occupancy of orally administered antihistamines measured by positron emission tomography with ¹¹cdoxepin in a placebo-controlled crossover study design in healthy subjects: a comparison of olopatadine." British Journal of Clinical Pharmacology 61.1 (2006): Academic Search Complete. EBSCO. Web. 9 Apr Lieberman, Phil L., and John A. Anderson. Allergic Diseases: Diagnosis and Treatment. 3rd ed. Totowa, NJ: Humana, Electronic. Meyers, D. A., Beaty, T. H., Colyer, C. R., Marsh, D. G., Vogler, G. P. and Rao, D. C. Genetics of total serum IgE levels: A regressive model approach to segregation analysis. Genetic Epidemiology, 8 (1991):

13 Linda Cross 12 Schnyder B, Pichler WJ. Mechanisms of drug-induced allergy. Mayo Clin Proc 2009; 84: