Assignment: Summary Milk Allergy

Assignment: Summary Milk Allergy ORDER NOW FOR CUSTOMIZED AND ORIGINAL ESSAY PAPERS ON Assignment: Summary Milk Allergy Read each article and summary each article in 1 page (1 article/summary 1 page). This summary is one page (250 words/around 1/2-1 page, type double-spaced). Total 2 articles that you have 2 summaries. Please include title, author, where and when the article was published as shown in the following example. Assignment: Summary Milk Allergy Submit a hard copy in class. Please attach the original article to your summary. Example : Title of article : Safety Questions Over Ephedra Spark Clash Between FDA, Industry Officials Article published in : the Marketplace section of The Wall Street Journal Date published : Aug. 9, 2000 Article written by : Sarah Lueck, Staff Reporter cow_milk_s_allergy.pdf test_in_cow_milk_allergy.pdf Methods 66 (2014) 22–33 Contents lists available at ScienceDirect Methods journal homepage: www.elsevier.com/locate/ymeth Cow’s milk allergy: From allergens to new forms of diagnosis, therapy and prevention Heidrun Hochwallner a,?, Ulrike Schulmeister b, Ines Swoboda a,1, Susanne Spitzauer b, Rudolf Valenta a a b Division of Immunopathology, Department of Pathophysiology and Allergy Research, Medical University of Vienna, Austria Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria a r t i c l e i n f o Article history: Available online 15 August 2013 Keywords: Milk allergy Recombinant allergens Diagnosis Therapy Microarray a b s t r a c t The ?rst adverse reactions to cow’s milk were already described 2000 years ago. However, it was only 50 years ago that several groups started with the analysis of cow’s milk allergens. Meanwhile the spectrum of allergy eliciting proteins within cow’s milk is identi?ed and several cow’s milk allergens have been characterized regarding their biochemical properties, fold and IgE binding epitopes. The diagnosis of cow’s milk allergy is diverse ranging from fast and cheap in vitro assays to elaborate in vivo assays. Considerable effort was spent to improve the diagnosis from an extract-based into a component resolved concept. There is still no suitable therapy available against cow’s milk allergy except avoidance. Therefore research needs to focus on the development of suitable and safe immunotherapies that do not elicit severe side effect. Ó 2013 The Authors. Published by Elsevier Inc. Open access under CC BY license. 1. Introduction 1.1. History of cow’s milk allergy The introduction of cow’s milk (CM) into alimentation has a very long tradition. It is reported that animal milk was included into the human diet approximately 9000 years ago. The domestication of cattle provided meat and milk as important components of our diet [1]. The production of cheese started with the ancient Greeks and Romans [2]. At the same time people in Northern Europe lost their lactose intolerance. Therefore lactase activity, a genetic trait, and animal husbandry, a cultural trait, represent an example for gene-culture co-evolution [3]. The ?rst adverse reactions to CM that were described by Hippocrates (prior to 370 B.C.) were skin and gastrointestinal symptoms after CM consumption [4]. Five hundred years later, the Greek medical researcher Galen of Pergamum mentioned a causal relationship between these symptoms and milk consumption [5]. At the beginning of the ? Corresponding author. Assignment: Summary Milk Allergy Address: Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, AKH 3Q, Waehringer Guertel 18-20, 1090 Vienna, Austria. E-mail address: heidrun.hochwallner@meduniwien.ac.at (H. Hochwallner). 1 Current address: Molecular Biotechnology Section, University of Applied Sciences, Campus Vienna Biocenter, Vienna, Austria. 1046-2023 Ó 2013 The Authors. Published by Elsevier Inc. Open access under CC BY license. http://dx.doi.org/10.1016/j.ymeth.2013.08.005 20th century observations of adverse reactions to CM became more frequent. The ?rst reports mentioning diarrhea, growth retardation as well as anaphylactic shock after milk consumption were mainly published in the German literature [6–9]. The Swedish clinician Wernstedt proposed the term ‘‘idiosyncrasy’’ for this phenomenon [10]. 1.2. Prevalence of cow’s milk allergy Today CM is among the ?rst foods introduced into an infant’s diet and accordingly is one of the ?rst and most common causes of food allergy in early childhood. In fact, the term ‘‘allergic March’’ describes the typical early appearance of food allergy which precedes the subsequent development of respiratory allergy in children [11]. The reported prevalence of cow’s milk allergy (CMA) varies dramatically between studies which may be attributable to different methods used for diagnosis or differences in the ages of the studied populations [12]. Furthermore, geographical factors may in?uence the rates for prevalence. In general, the frequencies of self-reported adverse reactions to CM are much higher than the medically con?rmed diagnoses, not only in children but also in adults [13]. A meta-analysis of relevant original studies since 1990 by Rona et al. [14] showed a variation in self-reported prevalence of milk allergy between 1.2% and 17%, whereas the prevalence in studies using a double-blind placebo controlled food challenge or an open challenge varied between 0% and 3% and in studies based on skin prick testing (SPT) and IgE assessment frequencies were between 2% and 9%. H. Hochwallner et al. / Methods 66 (2014) 22–33 Nowadays, it is reported that 0.6–2.5% of preschoolers, 0.3% of older children and teens and less than 0.5% of adults suffer from CMA [13]. The prevalence of CMA is increasing which may be explained by a decrease in breast feeding and an increased feeding with cow’s milk-based formulas [15]. Several factors which may increase the risk for developing CMA are described such as genetic predisposition for allergy (i.e., atopy), early ingestion of small amounts of CM and also factors related to the intestinal microbiome [16]. Assignment: Summary Milk Allergy Interestingly, the majority of CM allergic infants outgrow their CMA. One study reports that 45–50% grow out at 1 year, 60–75% at 2 years, and 85–90% at 3 years of age [17]. Although another study did not con?rm exactly these numbers and the time course for the development of tolerance, it is reported that CMA resolved in 19% of the children by 4 years of age, in 42% by 8 years of age, in 64% by 12 years of age and in 79% by 16 years of age [18]. The mechanisms underlying the development of clinical tolerance are not fully understood. Several factors may be involved in the development of tolerance. They may include a decline of IgE antibodies due to avoidance, the development of blocking IgG antibodies due to regular intake of CM and/or the presence of IgE antibodies against mainly conformational epitopes and not against sequential epitopes [19–21]. One study has shown that reactions to less than 10 ml of milk during an oral food challenge and large wheal size reactions in SPT predict a higher risk for persistence [22]. Several other studies have con?rmed that low levels of milk-speci?c IgE and small wheals during SPTs are good indicators for resolution [23–25]. A recent observational study considered the severity of atopic dermatitis (AD) for the natural course of milk allergy and came up with a web-based calculator for the prognosis of milk allergy for infants younger than 15 months that is based on milkspeci?c IgE levels, SPT wheal sizes and severity of AD [26]. 1.3. Spectrum of symptoms and immune mechanisms in CMA The clinical symptoms of CMA may be elicited by different mechanisms. The immediate and IgE-associated mechanisms are responsible for approximately 60% of cow’s milk-induced adverse reactions. They may affect one or more organs. Typical IgE-associated symptoms appear immediately or within 1–2 h after CM ingestion and affect the skin, the respiratory system, the gastrointestinal tract and/or appear as systemic anaphylactic reactions in severe cases [13,27]. The IgE-mediated reactions affecting the skin comprise urticaria, angioedema, pruritus, rashes and ?ushing. Atopic dermatitis is usually T cell-mediated but T cell activation may be enhanced by IgE-facilitated allergen presentation [28]. Respiratory symptoms that appear immediately after CM ingestion are rhinoconjunctivitis, wheezing, coughing, asthma exacerbation and laryngeal edema [2,13]. Acute gastrointestinal symptoms include oral itching, abdominal pain, nausea, vomiting and diarrhea. Assignment: Summary Milk Allergy CM is the third most common food component after peanuts and tree nuts that causes anaphylactic reactions, accounting for 10–19% of all food-induced anaphylactic cases [27,29] with cardiovascular collapse, syncope or incontinence as the most severe characteristics [13]. Furthermore, food-dependent exercise-induced anaphylaxis is reported to appear in infants who outgrew their allergy or after an oral immunotherapy [30,31]. Several mechanisms leading to the initial sensitization to CM proteins are discussed. One hypothesis is that sensitization may occur before birth: In this context it has been shown that small amounts of food proteins consumed by pregnant women can reach the foetus via the placenta [32]. In fact, it has been speculated that IgE may be already produced by foetuses in early pregnancy and can be detected in cord blood [33]. 23 The other possibility is sensitization early after birth through intake of CM. However, it is still controversially discussed if the early contact with CM proteins leads to sensitization or to clinical tolerance to CM. There is still an ongoing debate if babies should be exclusively breast fed [34–36]. Interestingly, also sensitization to human milk has been reported [37]. Oral intake or other mechanisms of sensitization such as sensitization via the skin or by inhalation have also been considered [38]. Usually clinical reactions start very early in life, after breastfeeding is stopped and CM is introduced in the diet, whereas only in rare cases symptoms appear already during lactation [27,37,39]. Besides IgE-associated mechanisms also non-IgE-mediated mechanisms of cow’s milk hypersensitivity do occur but they are dif?cult to diagnose [40]. Non-IgE-associated symptoms are characterized by a delayed onset, around 2 h to several days after CM consumption. Patients suffering from this form of hypersensitivity lack circulating CM protein-speci?c IgE and they show negative results in skin prick tests [27,41–44]. It is estimated that around 0.5% of all infants suffer from non-IgE-mediated CMA [45] whereas it seems to be more common in adults. The clinical symptoms affect mainly the gastrointestinal system including enterocolitis, proctitis, proctocolitis, enteropathy, irritable bowel syndrome, eosinophilic esophagitis and constipation [13,27,46]. The role of milk allergens in gastroesophageal re?ux (GER), infantile colic and constipation is still under debate and needs further investigation [27]. Delayed respiratory symptoms include pulmonary hemosiderosis, chronic cough, tachypnea, wheezing and rales. Sometimes atopic dermatitis appears as a chronic symptom after CM ingestion. Hypersensitivity to CM in infants may be associated with pulmonary hemosiderosis and present chronic symptoms such as recurrent fevers, weight loss and failure to thrive [2,27,47,48]. The precise mechanisms leading to non-IgE mediated forms of CMA are still under debate. In principle, several immunological mechanisms may be responsible for non-IgE-mediated reactions to CM proteins [49]. Symptoms may be caused by cow’s milk-speci?c T cell responses, antibody-mediated mechanisms may involve Type II or Type III hypersensitivity mechanisms such as ADCC (antibody-dependent cell-mediated cytotoxicity) or complement activation [49,50]. Furthermore, Th1/Th2 imbalances are assumed to have an impact [51]. While atopy patch testing which measures CM allergen-speci?c T cell responses may be useful to assess T cellmediated reactions neither the measurement of CM allergen-speci?c IgG nor IgA are useful for diagnosis of non-IgE-associated CMA [52–54]. It is also possible that patients suffer from mixed manifestations, elicited through IgE- and non-IgE-mediated reactions. Both humoral and/or cell-mediated mechanisms may induce symptoms, including acute and chronic manifestations. The clinical manifestations may appear as atopic dermatitis and eosinophilic gastroenteropathies (esophagitis and gastroenteritis) [27]. Assignment: Summary Milk Allergy 1.4. The spectrum of cow’s milk allergens Cow’s milk contains around 30–35 g of proteins per litre and includes more than 25 different proteins but only some of them are known to be allergenic. Table 1 provides a short summary of the known CM allergens and their characteristics. Through the acidi?cation of raw skim milk to pH 4.6 at 20 °C two fractions can be obtained: the coagulum containing the casein proteins which accounts for 80% and the lactoserum (whey proteins) representing 20% of the total milk proteins [55–57]. The casein fraction (Bos d 8, Bos domesticus) consists of four proteins which account for different percentages of the whole fraction: aS1-casein (Bos d 9, 32%), aS2-casein (Bos d 10, 10%), b-casein (Bos d 11, 28%) and j-casein (Bos d 12, 10%) with aS1-casein being the most important allergen of the casein fraction [58]. Allergens found in the whey fraction are 24 H. Hochwallner et al. / Methods 66 (2014) 22–33 Table 1 Main characteristics of cow’s milk allergens, adapted from Jost [62] and the IUIS allergen nomenclature (http://www.allergen.org) [21,59,61–66]. Whey (20%) (5 g/L) Allergen name Protein Conc. (g/L) Size (kDa) No. of aa/ molecule pI Prevalence (% of patients) Microarray results (% of patients) [21] Allergenic activity (% of patients) [21] Bos d 4 Bos d 5 Bos d 6 a-Lactalbumin 14.2 18.3 66.3 123 162 582 4.8 5.3 4.9– 5.1 0–67 13–62 0–76 63 50 4 12 19 1 80 23.6 703 199 0–35 65–100 5 49 3 26 35–44 44 35 35–41 30 26 Bos d 7 b-Lactoglobulin Bovine serum albumin Immunoglobulins Bos d 9 aS1-casein 1–1.5 3–4 0.1– 0.4 0.6– 1.0 0.09 12–15 Bos d 10 aS2-casein 3–4 25.2 207 Bos d 11 b-Casein 9–11 24 209 Bos d 12 j-Casein 3–4 19 169 Lactoferrin Whole casein (80%) (30 g/L) 160 12–36 a-lactalbumin (Bos d 4), b-lactoglobulin (Bos d 5), immunoglobulins (Bos d 7), bovine serum albumin (BSA, Bos d 6) and traces of lactoferrin (Bos d lactoferrin). a-lactalbumin and b-lactoglobulin are the most important allergens of the whey fraction, accounting for 5% and 10% of the total milk proteins [55,59]. There are only few reports describing allergies to minor whey proteins such as immunoglobulin, BSA or lactoferrin [60]. A major problem of CMA is the fact that the human IgE response to CM proteins is characterized by a great variability and that no single allergen or particular structure has been identi?ed that accounts for a major part of allergenicity in milk. Sensitization to several proteins occurs in approximately 75% of patients with CMA, with a great variability of the IgE response in speci?city and intensity. The most frequently recognized allergens seem to be those which are most abundant in CM, namely caseins, b-lactoglobulin and a-lactalbumin [21,61]. For the de?nition of the clinically most relevant allergens it will be necessary to conduct extensive IgE binding studies in large populations of clinically well-de?ned CM allergic patients and an assessment of the allergenic activity of the individual allergen components [21]. At present there is still a lot of controversy about the prevalence of IgE reactivity to certain CM proteins. Assignment: Summary Milk Allergy One of the reasons for this might be that study groups were selected based on different criteria and often were very small [21,59,61–66]. 1.4.1. Allergens in the casein fraction The four caseins (aS1-, aS2-, b- and j-casein) form ordered aggregates also termed micelles [67]. These complexes bind essential minerals, such as calcium phosphate, that would otherwise precipitate and would not be easily ingested [68]. Casein micelles are spherical aggregates with diameters ranging between 100 and 300 nm [69]. The a- and b-caseins form the interior of the micelles while j-casein is located on the surface. The four casein molecules have little primary structure homology but they are all phosphorylated proteins and share biophysical features such as heat resistance. So far it has not been possible to resolve the three-dimensional structure of the individual caseins due to their highly rheomorphic structure. CM allergic patients are normally sensitized to several of the different casein proteins. Furthermore, there are amino acid sequence homologies of up to 90% between caseins from different mammals, like goat and sheep, and accordingly extensive cross-reactivity but there are also reports of selective sensitizations to caseins from certain animals [70–72]. Allergenic features were investigated in detail for aS1-casein, the major CM allergen which was expressed in recombinant form in Escherichia coli. CD spectroscopy analysis showed a primarily b-fold structure that kept its structure even upon heating up to 8.7 4.9– 5 5.2– 5.4 5.1– 5.4 5.4– 5.6 55 °C. However, caseins are easily digested in the gut which is a rather unusual feature for important allergens [73]. Using synthetic peptides and recombinant fragments epitopes of the major and minor CM allergens can be mapped. In contrast to respiratory allergens, that contain mainly conformational epitopes, several linear epitopes have been identi?ed for food allergens [58,74–76]. Several sequential epitopes are distributed along aS1-casein. However, experiments showed that mainly intact aS1-casein or larger IgE-reactive fragments thereof are responsible for the induction of allergic reactions [58]. aS2-casein, ß-casein and j-casein were characterized regarding their epitope distribution but data on allergenic activity are rare [77–81]. 1.4.2. The whey allergens b-Lactoglobulin is a major whey protein of most mammalian species but is not found in the milk of rodents and human. It is a small protein with a molecular weight of 18.3 kDa, consisting of 162 amino acids and it naturally occurs in a dimeric form. Assignment: Summary Milk Allergy The structure determination by X-ray crystallization as well as by NMR techniques [82–87] revealed a globular shape that is built up by an 8-stranded, antiparallel b-barrel with a 3-turn a-helix on the outer surface and a ninth b-strand ?anking the ?rst strand [88]. The function of this milk protein is not yet known but it belongs to the lipocalins, a protein superfamily, that binds hydrophobic ligands like cholesterol and vitamin D2 [82,88]. There are two major isoforms of beta-lactoglobulin, the genetic variants A (BLGA) and B (BLGB), which differ in amino acids 64 and 118 (aspartic acid and valine in BLGA, glycine and alanine in BLGB). It has been shown that two disulphide bonds account for high stability against proteases and acidic hydrolysis [55]. The allergenic potential of this molecule has been attributed to its high stability and the fact that blactoglobulin is not present in human milk [55,89]. However, recent data indicate that a-lactalbumin is the more important whey allergen [21]. a-Lactalbumin is a small (14 kDa), acidic, Ca2+ binding, monomeric protein that is stabilized by four disulphide bridges. It acts as a regulatory component in the galactosyltransferase system that synthesizes lactose [90] and it may interact with lipid membranes [91], stearic acid and palmitic acid [92]. A multimeric form of alactalbumin can induce apoptosis in tumor but not in normal cells [93–95]. a-Lactalbumin has become one of the best described and characterized molecules in protein science because of its ability to convert into a molten globule state under acidic pH [90] and in the apo-state (calcium-depleted state) under elevated temperatures. This was ?rst described by Dolgikh in 1981 [96] as a compact state with ?uctuating tertiary structure. H. Hochwallner et al. / Methods 66 (2014) 22–33 Sequence analysis showed a high degree of homology between the a-lactalbumin amino acid sequences from cows to human subjects and rodents, ranging at approximately 75% identity [97]. Furthermore, a-lactalbumin shows high thermal stability and refolding capacity [97]. Similar to the pollen allergens Aln g 4, Bet v 3, Bet v 4, Phl p 7, the ?sh allergen parvalbumin and the cockroach allergen Bla g 6, alactalbumin belongs to t … Get a 10 % discount on an order above $ 100 Use the following coupon code : NURSING10