Atlas of Science

Tag: allergy

  • The allergies go marching on: the atopic march and the temporal relationship of allergic diseases

    The allergies go marching on: the atopic march and the temporal relationship of allergic diseases

    Atopic/allergic family of diseases affects >20% of the global population and encompasses allergic asthma, hay fever, food allergy, atopic dermatitis, and allergic rhinitis. Frequently, individuals with an allergic condition develop another allergic disease. The atopic march theory summarizes this relationship, which often starts with childhood atopic dermatitis that proceeds to allergic asthma and/or allergic rhinitis.

    Allergic sensitization occurs when innocuous agents known as allergens trigger immune cells, namely helper T cells and B cells, to produce antibodies, that bind to the surface of mast cells. When next exposed to the allergen, binding to the antibodies activates mast cells to release factors that cause symptoms of allergies. This allergic response, when prolonged promotes tissue changes due to continual activation of local inflammatory cells. In the atopic march, it is postulated that changes in the skin of suspectable individuals facilitates allergen and pathogen entry, which triggers an allergic response and subsequent systemic sensitization. Murine models have shown that mice sensitized to an allergen in the skin will eventually mount a response in the airways when the same allergen is inhaled.

    Atlas of Science. The Allergies go Marching On: The Atopic March and the Temporal Relationship of Allergic Diseases.
    Fig. 1. Atopic Dermatitis Features Associated with Allergic Asthma Development, adapted from Aw et al, 202016. Legend: IgE – immunoglobin E, AD – Atopic Dermatitis.

    Numerous epidemiologic studies demonstrate a progressive between common atopic diseases. In a population-based birth cohort, early-onset atopic dermatitis ( less than 1.5 years old) was associated with persistent wheezing at age 6. Similarly, a population-based study in Tasmanian found that early-onset atopic dermatitis (onset less than 2 years old) doubled the odds of developing allergic asthma. The Dampness in Building and Health study followed 3000 children (aged 1-2) for 5 years and reported that children with atopic dermatitis had a 3-fold increased odds ratio of developing allergic rhinitis. The German mass allergen study studied 942 infants over 17 years and reported an increased prevalence of co-morbid allergic asthma or allergic rhinits from ages 3-7 with an age dependent decrease in the atopic dermatitis prevalence.

    The atopic march model may be oversimplified as only 3.1% of children follow the typical model (atopic dermatitisàallergic asthmaàallergic rhinitis); this increases to approximately 10.5% when associating atopic dermatitis with other atopic condition. Nonetheless, there are risk factors that favour atopic march progression (Fig. 1). Genetics play a major role. Children with an atopic family history are 5 times more likely to develop early persistent atopic dermatitis. There is a 0.3-0.4 phenotypic correlation with allergic asthma, of which 80% is attributable to genetics. Specifically, patients with filaggrin mutations, an integral epithelial protein, are predisposed to developing atopic dermatitis and allergic asthma. A metanalysis of 24 human studies showed that filaggrin mutations increased the odds of developing allergic asthma by 1.5 fold and 3 fold if the subjects also had atopic dermatitis. Furthermore, early onset atopic dermatitis which was persistent and severe increased the risk of developing asthma. Similarly a strong association between early-onset atopic dermatitis and asthma during a 5 year follow-up, but no association between late-onset atopic dermatitis and asthma has been reported. A prospective Canadian birth cohort study showed that the odds of developing allergic asthma or allergic rhinitis the age of 7 was significantly greater for children with early-onset persistent atopic dermtitis. Notably, only a third of patients with eczema have any allergen-specific IgE sensitization. Several longitudinal studies have found a strong relationship between IgE-associated atopic dermatitis and asthma which further implicates this phenotype.

    As the global prevalence of allergic disease rises, so does its impact on population health. Epidemiological evidence supports the progression of allergic disease as seen through co-morbidity and temporal prevalence changes. Understanding the role of age, severity, family history, phenotype, and genetic traits all give a clearer picture as to how atopic dermatitis may progress into allergic airways diseases.

    Michael Aw 1, Hermenio Lima 2, Roma Sehmi 3
    1Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
    2Division of Dermatology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
    3Division of Respirology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada

    Publication

    Atopic March: Collegium Internationale Allergologicum Update 2020
    Michael Aw, Jeremy Penn, Gail M Gauvreau, Hermenio Lima, Roma Sehmi
    Int Arch Allergy Immunol. 2020

  • Antigen-expressing regulatory T cells can protect against allergic reactions

    Antigen-expressing regulatory T cells can protect against allergic reactions

    Our immune systems are designed to protect us from dangerous foreign invaders, like viruses, bacteria or parasites. However, sometimes we respond to usually harmless foreign materials, e.g. pollens or food, the results of which can be mild to life threatening. These are manifestations of a series of events collectively termed “allergy” from the Greek word “allos” (“other” or different) with “ergon” (activity). So when such a material (called an “antigen” or “allergen”) enters the body via any surface or passageway, we react as if a parasite had invaded us. At first, little is noticed, but the next time, you encounter that allergen, you may develop itching, hives, a runny nose, or even shortness of breath, as in anaphylaxis. In the latter extreme case, death could occur.

    Atlas of Science. Antigen-expressing regulatory T cells can protect against allergic reactions
    Fig. 1. Cartoon depicting the putative interactions between antigen (Ag)-expressing Treg with specific B cells or mast cells with bound IgE specific for that Ag. (Figure courtesy of Dr. Maha Abdeladhim)

    Most allergies are due to the immune system making a type of antibody, called immunoglobulin E or IgE. IgE doesn’t neutralize the invader per se, but rather is captured by a specific type of blood and tissue cell called a mast cell. Mast cells have a receptor on their surface that loves to bind to IgE, any IgE. And mast cells are filled with granules containing many potent mediators, such as histamine, prostaglandins or leukotrienes, that are released when the IgE bound on the mast cells interacts with the specific inciting allergen. Boom! The granules are released into the circulation and you have various allergic symptoms, possibly anaphylaxis. Systemically in anaphylaxis, there may be a rapid drop in body temperature, which is one way to evaluate this strong allergic response.

    The main treatment for allergies is symptomatic relief with anti-inflammatory drugs, which are non-specific. Specific ways to treat allergies are an unmet need. Our laboratory has focused on developing specific therapies to induce non-responsiveness, or immune “tolerance”, using a group of immune cells called T regulatory cell or Tregs. Their job is to limit and control adverse immune responses. We have previously engineered Treg cells to express what is called a CAR or chimeric antigen receptor, which have been utilized effectively in cancer therapy. Thus, we designed a CAR that would target the specific precursors of IgE secreting cells, the B cells, as well as the mast cells that have bound the same specificity IgE. We called these cells, BAR Tregs, for B-cell Antigen Receptor). Our hypothesis was that BAR Tregs that expressed the antigen of choice (in our case, an egg protein called ovalbumin) would be recognized by and interact with ovalbumin specific B-cells or mast cells bearing ovalbumin specific IgE. This would block the antibody response to ovalbumin and subsequent mast cell degranulation leading to anaphylaxis, which we measured by a drop in temperature (hypothermia).

    We first immunized mice for a month with ovalbumin to induce an IgE response thus creating ovalbumin “allergic” mice. These mice were treated with ovalbumin-expressing or unrelated control Tregs and then “challenged” with the same antigen to induce anaphylaxis. Hypothermia was observed in control recipients, but these symptoms were blunted in mice that received ovalbumin BAR Tregs. This demonstrated a specific suppression of the allergic response in these mice.

    Anaphylaxis can also be induced in non-immunized mice by injecting serum containing IgE, a process called “passive anaphylaxis”. In this case, the anti-ovalbumin IgE will bind to mast cells in the mouse and anaphylaxis can be induced by injecting a high dose of ovalbumin. When we injected ovalbumin-BAR Tregs into these passively immunized mice, hypothermia was again blocked. This suggests that the target of this therapy was the mast cell!

    Our results provide proof of principle that engineered allergen-specific T-regulatory cells can provide clinical protection against severe allergic reactions in individuals already IgE-sensitized to an allergen.  We are expanding these studies to BAR Tregs engineered to express other allergens, such as peanut protein; we call these “peanut BARs”. Importantly, since patients often are allergic to several antigens, we need to determine whether the engineered Tregs will reduce symptomatic relief to multiple antigens; these experiments are in progress in research supported by the U.S. National Institutes of Health.

    David W. Scott
    Uniformed Services University, Bethesda, MD, USA

    Publication

    Engineered ovalbumin-expressing regulatory T cells protect against anaphylaxis in ovalbumin-sensitized mice
    Maha Abdeladhim, Ai-Hong Zhang, Laura E. Kropp, Alyssa R. Lindrose, Shivaprasad H. Venkatesha, Edward Mitre, David W. Scott
    Clin Immunol. 2019 Oct

  • Interleukin-18: Critical molecule in promoting allergic diseases

    Interleukin-18: Critical molecule in promoting allergic diseases

    First interleukin was discovered in 1977 from monocyte and termed as interleukin (IL)-1. Interleukins are the secreted proteins that bind to their specific receptors with leukocytes. They are recognized as a family of cytokines based on sequence homology and their functional properties. Most current information indicates that almost 38 interleukins, including interferon-γ are already discovered. IL-18 is a member of the IL-1 family that is expressed by a range of cell types, including keratinocytes (epithelial cells) and antigen presenting cells such as macrophages, Kupffer cells and dendritic cells. Similar to the receptor for IL-1 molecules, the IL-18 receptor is a complex of a primary IL-18Rα protein that binds IL-18 with low affinity, and an accessory protein IL-18Rβ with high-affinity. We recently found an important role for IL-18 in the generation and maturation of granulocytes including mast cells, eosinophils, neutrophils and basophils from bone marrow precursors (ancestors).

    Fig. 1. IL-18 role in innate and adaptive immunity. Diagrammatical representation of IL-18 role in a number of inflammatory cells differentiation and activation that promote autoimmune and allergic diseases. The presented summary indicates that IL-18 is involved in natural killer T cells activation, induces B cell differentiation, and conversion of naïve T cells to Th2 cells and produce Th2 cytokines that promotes autoimmune and allergic diseases.

    Bone marrow from naive mice cultured with stem cell factor (SCF) and IL-18 differentiate these inflammatory cells, which are critical in promoting allergic diseases like asthma, colitis, eosinophilic esophagitis, dermatitis, rhinitis including several gastrointestinal disorders. A study of fatal asthma indicated that IL-18 is strongly induced in lung that enhances effector T cells expansion. IL-18 was first described for its ability to induce a Th1 response, resulting in the production of IFN-γ and subsequently inhibiting a Th2 response. It is now appreciated that IL-18 can have opposing effects on the balance of Th1 and Th2 activation and cytokine production. Th1 cells abundantly express IL-18Rα while there is little expression on Th2 cells, and IL-18 can also accelerate but not induce differentiation of Th1 cells. When administered with IL-12, IL-18 stimulates Th1 activity and inhibits IgE production in an IFN-γ dependent manner. When administered alone, IL-18 increases IgE levels independent of IFN-γ. Dendritic cells-derived IL-18 was demonstrated to activate invariant NKT cells that have the capacity to release both Th1 and Th2 cytokines. We earlier showed that direct exposure of IL-18 to iNKT cells in vitro releases eosinophilia-promoting cytokines like IL-4, IL-5 and IL-13, and promotes eosinophilic inflammation in tissues and IL-18 overexpression in tissues promotes pulmonary and gastrointestinal eosinophilic disorders presumably via this iNKT activation.  IL-18 has been linked to increased ECP levels, increases the eosinophil-inducing cytokine IL-5, can induce eotaxin-dependent eosinophilia, and increases IL-8 expression by eosinophils. We showed increased levels of the IL-18 receptor transcript in humans and demonstrated induction of IL-18 and its receptor in a mouse model of eosinophilic esophagitis (EoE). We have also demonstrated correlations between IL-18 and eosinophilia in human EoE patients in addition to the previously mentioned results of iNKT cells. Hypersensitivity allergic reactions are often atopic, or in response to routine allergens and dependent on IgE sensitization, and a few disease states are classically associated with atopic allergy: urticaria, asthma, rhinitis, and dermatitis, as well as the life-threatening acute reaction anaphylaxis. Food and drug hypersensitivities are also common classes of allergy. Anaphylaxis is a life-threatening allergic reaction mediated by mast cells and basophils. Many reserve the term to only describe IgE-dependent mechanisms, but other “anaphylactoid” reactions can be IgG and IgM mediated as well. IL-18 has the ability to increase levels of IgE, IgG, and IgM, and as such IL-18 could play a role in these life-threatening reactions. There is not substantial evidence covering the role of IL-18 in anaphylactic and anaphylactoid reactions. However, IL-18 polymorphisms have been shown to be associated with latex and penicillin allergies Additionally, activation of the NLRP3 inflammasome is known to increase IL-18 and IL-1β processing, and functional NLRP3 polymorphisms are linked to food-induced anaphylaxis. Several reports speculated on the possible therapeutic applications of monoclonal IL-18 antibodies or IL-18 binding protein, the endogenous antagonist of IL-18, to treat autoimmune conditions, boost immune function for chemotherapy. However, given the many dichotomous effects of IL-18, the numbers of unintended consequences from IL-18 blockade still need to be studied.

    Anil Mishra
    Endowed Chair and Professor of Medicine, Tulane Eosinophilic Disorders Center, and
    Section of Pulmonary Diseases, Tulane University School of Medicine New Orleans, LA, USA

     

    Publications

    Role of interleukin-18 in the pathophysiology of allergic diseases.
    Sanders NL, Mishra A
    Cytokine Growth Factor Rev. 2016 Dec

    Involvement of interleukin-18 in the pathogenesis of human eosinophilic esophagitis.
    Niranjan R, Rajavelu P, Ventateshaiah SU, Shukla JS, Zaidi A, Mariswamy SJ, Mattner J, Fortgang I, Kowalczyk M, Balart L, Shukla A, Mishra A
    Clin Immunol. 2015 Apr

    Allergen-induced interleukin-18 promotes experimental eosinophilic oesophagitis in mice.
    Dutt P, Shukla JS, Ventateshaiah SU, Mariswamy SJ, Mattner J, Shukla A, Mishra A
    Immunol Cell Biol. 2015 Nov

  • Chronic rhinosinusitis patients with gastroesophageal reflux disease have a significantly higher prevalence of atopy and asthma

    Chronic rhinosinusitis patients with gastroesophageal reflux disease have a significantly higher prevalence of atopy and asthma

    An association between chronic rhinosinusitis ( CRS ) and gastroesophageal reflux disease ( GERD ) has been previously reported. GERD shares several similarities with the pathophysiology of CRS and atopy. CRS and GERD both can present with local infiltration of eosinophils. Furthermore, pro-inflammatory cytokines and eotaxins are highly expressed in both GERD and CRS. Despite these observations, the pathophysiological links between GERD and CRS remain to be clarified. Moreover, the association of GERD with CRS phenotypes has not been previously evaluated.

    Patients with CRS and GERD have higher BMI, age and percentage of females as well as higher prevalence of allergic
    Fig. 1. Patients with CRS + GERD have higher BMI, age and percentage of females as well as higher prevalence of allergic rhinitis and asthma compared to CRS without GERD.

    This study was structured to assess the association of GERD and CRS using both prospective and retrospective approaches. The retrospective study comprised a large cohort of CRS cases. In the prospective study, a group of CRS cases treated in the allergy or otolaryngology clinics were recruited . A group of age-, gender-, and BMI- matched controls visiting the same clinics were recruited as control subjects. CRS was diagnosed based on guidelines of the American Academy of Otolaryngology–Head and Neck Surgery Chronic Rhinosinusitis Task Force.

    Of 1006 CRS patients, 112(10.5%) had GERD. Among CRS patients, GERD was associated with higher BMI, higher age, and female gender. The odds ratios (OR) (95%CI) for asthma and atopy in the GERD+CRS group compared to the non-GERD CRS group were 2.89 (1.905-4.389) and 2.021(1.035-3.947). Furthermore, GERD was associated with a greater duration of CRS.
    Results of the Prospective Arm: 90 CRS cases and 81 controls were enrolled in the study. CRS cases showed a trend towards increased GERD (15.6% vs 7.4%, p=0.071). In the CRS group, GERD was associated with asthma with an OR of 4.77 (1.27-18.01). Furthermore, CRS cases with GERD had a trend towards a higher prevalence of atopy, with an OR of 3.19 (0.84-12.13). CRS cases with GERD had a longer duration and a lower age of onset of CRS. In controls, there was no association between GERD and asthma (OR 0.67[0.09-5.19]) or atopy (OR 0.35[0.05-2.59]).

    The current series illustrated significant association of GERD with asthma and allergic rhinitis, younger age of onset and greater duration of disease in CRS patients. One potential explanation is that the inflammatory response, in association with GERD, could be further aggravated in the setting of pre-existing eosinophilic inflammation due to atopic airway disease, and play a role in the pathogenesis of CRS. GERD is a treatable condition, and proactive identification and treatment, especially in atopic patients, could have a significant role in preventing more advanced inflammatory diseases of the airways. However, this important area merits further research to investigate the mechanisms underlying the association of GERD and atopy in CRS patients.

    Mahboobeh Mahdavinia
    Department of Immunology and Microbiology, Allergy/Immunology Section,
    Rush University Medical Center, Chicago, Illinois, USA

     

    Publication

    Prevalence of allergic rhinitis and asthma in patients with chronic rhinosinusitis and gastroesophageal reflux disease.
    Mahdavinia M, Bishehsari F, Hayat W, Codispoti CD, Sarrafi S, Husain I, Mehta A, Benhammuda M, Tobin MC, Bandi S, LoSavio PS, Jeffe JS, Palmisano EL, Schleimer RP, Batra PS
    Ann Allergy Asthma Immunol. 2016 Aug

  • Vitamin D may contribute to development of asthma

    Vitamin D may contribute to development of asthma

    Asthma is a chronic inflammatory airway disease, which development mechanism has not been fully investigated yet. Despite the progress of medical science in asthma field, morbidity of this disease remains high worldwide. Scientists raise hypothesis that vitamin D may be involved in development of asthma. Vitamin D is a fat-soluble nutrient, which is the best known as key factor in bone mineralization. However, scientific literature reveals wider role of vitamin D.

    Fig. 1. Vitamin D concentration in serum from patients with asthma and healthy subjects **p less than 0.01 compared to control group
    Fig. 1. Vitamin D concentration in serum from patients with asthma and healthy subjects
    **p < 0.01 compared to control group

    We aimed to compare serum vitamin D level between asthma patients and healthy subjects and assess correlation between vitamin D level and allergic and smoking status, lung function and body mass index in asthma patients.

    Our study involved 158 individuals over 18 years old. Out of them, 85 patients were asthmatics and 73 healthy individuals. For the evaluation of vitamin D level, measurement of concentration of 25(OH)D3 has been chosen because it shows a store of vitamin D in the body more accurately than an active form of vitamin D and is metabolised only in the liver. Blood samples for vitamin D measurement were collected during late autumn and winter (October, November and December) in order to avoid influence of sun exposure.

    We found that all studied subjects had a lower vitamin D level than recommended norms. Vitamin D level was significantly lower in asthmatics than in healthy individuals, but it did not differ between allergic and non-allergic asthmatics as well as between smokers and non-smokers with asthma. We estimated that low vitamin D level increases asthma risk 1.2 times. In asthma group vitamin D levels did not correlate with lung function and allergy markers (eosinophil count and total immunoglobulin (Ig) E level). We estimated that body mass index had impact on vitamin D level: high body mass index was related to low vitamin D level.

    Our study reveals that vitamin D level is significantly lower in patients with asthma than healthy subjects and has a link with body mass index, but a lack of this vitamin is not related to allergic status of these subjects. We can suggest that lack of vitamin D increases risk of asthma development in 1.2 times. Thereby data from our research suggest that vitamin D may play an important role in development of asthma.

    Dr Laura Tamasauskiene
    Department of Pulmonology and Immunology, Lithuanian University of Health Sciences, Lithuania

    Publication

    Evaluation of vitamin D levels in allergic and non-allergic asthma.
    Tamašauskienė L, Gasiūnienė E, Lavinskienė S, Sakalauskas R, Šitkauskienė B
    Medicina (Kaunas). 2015

  • Medicines – allergic reactions to antiepileptic drugs

    Around 1% of the global human population – ca. 65 million – suffer from epilepsy – a chronic neurological disease with one of the most prominent symptoms being so called epileptic seizures. With a range of antiepileptic drugs (AEDs) available, it is possible to mitigate the seizures and the majority of patients (70%) display a good control over epilepsy. However, there are patients in whom AEDs cause unwanted, and often dangerous, adverse side-effects. These include, among other things, dizziness, gastric problems, depression, impaired cognition and allergic skin reactions, which will be discussed in more detail here.

    Adverse skin reaction are the direct consequence of hypersensitivity to AEDs. They can range from mild skin rashes and changes in skin pigmentation to extremely severe and potentially lethal conditions (such as Stevens-Johnson syndrome, DRESS – drug rash with eosinophilia and systemic symptoms or TEN – toxic epidermal necrolysis). The morbidity rate in patients who develop these severe symptoms is estimated to be about 10%.

    The reasons for allergic reaction have not yet been determined unequivocally. Currently, there are several hypotheses about the source of hypersensitivity of epileptic patients. According to some studies, due to a varied mechanism of action, certain AEDs are more likely to induce severe allergic reactions (e.g. SJS/TEN) than others. Another identified cause can be related to genetics –it has been discovered that the presence of the antigen (HLA)-B*1502 in various Asian populations (particularly South-Eastern Asian,  e.g. Han Chinese) is linked with hypersensitivity. Similar associations have also been found between the severe skin reactions and the occurrence of the antigen (HLA) –A*31:01 in Japanese and European populations. Other theories assumed that certain disorders (SJS/ TEN) could be reactions of the immunological system. Among other factors that may trigger negative allergic reactions are patients’ gender, hormones, drug dosage schedule and administering two or more types of drugs simultaneously (co-medication). There have been reports that a negative reaction to one AED may trigger hypersensitivity to a different one, previously tolerated. Age can be yet another risk factor for allergic reactions, due to age-related differences in drug metabolism – certain forms of hypersensitivity are more likely to affect children than adults. Also, drug dosage schedule and starting dose can play a role here– it has been found that higher starting doses of some AEDs are more likely to increase the risk of adverse skin reactions.

    As mentioned earlier, the allergic reactions can vary in intensity, from quite benign and harmless, like rashes or pigmentation change, to potentially deadly, with failure of internal organs and severe skin damage. Such hypersensitivity reactions are difficult to diagnose as they induce a broad range of clinical manifestations. In addition, different AEDs cause different reactions.

    The first step to take when such allergic symptoms occur is the immediate cessation of therapy that employs the specific AED. It is recommended that patients with hypersensitivity to one type of AEDs ( e.g. aromatic) switch to the drugs with a different mechanism of action. If no alternative to the drug is available, then it is suggested to perform desensitization using antihistamines or steroids. However, it must be stressed that desensitization is usually efficient in benign cases. When serious allergic conditions are developed, clinicians recommend to treat such patients in hospital burn units to ensure proper care.

    Modern AEDs provide a good control over epileptic seizures and enable normal functioning of patients. However, certain percentage of them may experience a broad range of negative reactions that can seriously impact their health condition and quality of life.

    Barbara Blaszczyk
    Faculty of Health Sciences, High School of Economics, Law and Medical Sciences, Kielce, Poland
    Private Neurological Practice, Kielce, Poland

     

    Publication

    Antiepileptic drugs and adverse skin reactions: An update.
    Błaszczyk B, Lasoń W, Czuczwar SJ
    Pharmacol Rep. 2015 Jun

  • The inflamed skin in atopic eczema contributes to the disrupted skin-barrier

    The inflamed skin in atopic eczema contributes to the disrupted skin-barrier

    Atopic dermatitis, also known as atopic eczema or neurodermitis, is a chronic allergic skin disease affecting 15 – 30 % of children and 2 – 10 % of adults in industrialized countries. Patients suffer from inflamed, red and dry skin and strong itch. In many patients, the skin-barrier seems to be disturbed and an increased water-loss through the skin can be measured. Genetic mutations that lead to a weakened skin-barrier cannot explain this picture in total, since being detected in some, but not all patients.

    In our research project, we were interested in the question, whether the ongoing skin inflammation leads to the weakened skin-barrier. Inflamed skin cells are able to produce a bouquet of small biologically active compounds. A recently discovered one has been termed Interleukin-33 (IL-33).

    Fig1-RoesnerWe found that when skin cells had contact to IL-33 in the petri dish, they intended to produce less of the protein filaggrin, also often referred to as the skin´s glue. We observed the same when we applied IL-33 to human skin biopsies and looked for filaggrin: a strong reduction in this major skin-barrier protein became visible. To finally mimic the situation in the patient, where IL-33 most probably is present over days and weeks, we bred artificial skin in the petri dish with or without IL-33. While the artificial skin developed nicely under our test conditions, we found massive differences regarding the skin-barrier. First, the protein filaggrin was nearly absent, and second, the skin was much more permeable for a test allergen from peanut. This implies, that allergens may enter the inflamed skin easily, leading to an even stronger inflammation, creating a vicious circle.

    Overall, with this study we highlight that the inflammation in atopic dermatitis may sustain itself and that an early intervention is beneficial. IL-33 may therefore represent an interesting target for new therapy strategies.

    Lennart M. Roesner
    Hannover Medical School (MHH), Department of Dermatology and Allergy
    Division of Immunodermatology and Allergy Research
    Hannover, Germany

     

    Publication

    IL-33 impacts on the skin barrier by downregulating the expression of filaggrin.
    Seltmann J, Roesner LM, von Hesler FW, Wittmann M, Werfel T.
    J Allergy Clin Immunol. 2015 Jun

  • Bad news for people with a penicillin allergy

    There are over 500,000 hospitalizations annually in the U.S. in which patients will have a reported allergy against first line antibiotics. Beta-lactams are the largest group of antibiotics which include penicillins, cephalosporins, and carbapenems. These antibiotics are the first line treatment against most serious bacterial infections; however, they are also the class of antibiotics to which patients are most commonly allergic. Patients labeled as allergic to one of these antibiotics are often prescribed second line antibiotics. Previous studies have shown that the use of second line antibiotics are more expensive, result in more adverse events, and longer hospital stays.

    We theorized that patients labeled as penicillin, cephalosporin, or carbapenem allergic treated with non-beta-lactams would have higher rates of clinical failure, but lower rates of allergic reactions, than patients treated with beta-lactams. Analysis of the data revealed that patients treated with non-beta-lactams did indeed have higher rates of clinical failure. Unexpected findings of the study were the low number of new allergic reactions which occurred in 16 patients, less than 3% of the study population.

    The study showed that patients with a history of beta-lactam allergies are more likely to experience treatment failure when treated with a non-beta-lactam and no less likely to experience a hypersensitivity reaction. The findings of this do not support the practice of avoiding all beta-lactam antibiotics for patients with an allergy to penicillins, cephalosporins, or carbapenems. While the use of an antibiotic in the same class of allergy should continue to be avoided, clinicians can utilize this data to improve clinical outcomes by providing the most appropriate antibiotics.

    In an effort to combat the overutilization of second line antibiotics, clinicians must critically assess the validity of patient reported allergies and, when possible, update allergy data within the patient’s medical record. Additionally we need to identify methods in which clinicians can safely remove beta-lactam, particularly penicillin, allergy labels from a patient’s medical records. Research describing effective systems that would disseminate the updated allergy information to all prescribers is also needed.

    Meghan Jeffres1 PharmD, Prasanna Narayanan2 PharmD
    1Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy
    and Pharmaceutical Sciences, Aurora, Colo.
    2Department of Pharmacy, Mayo Clinic Hospital-Rochester, Rochester, Minn.

     

    Publication

    Consequences of avoiding β-lactams in patients with β-lactam allergies.
    Jeffres MN, Narayanan PP, Shuster JE, Schramm GE
    J Allergy Clin Immunol. 2015 Dec 11

  • Zinc supplementation and allergy

    Zinc supplementation and allergy

    Zinc is an essential trace element and an important factor of approximately 300 human enzymes.  It plays an important role in cellular growth, differentiation, and apoptosis. The immune system with its fast growing rates is especially dependent from available zinc since many studies have shown that insufficient levels of zinc increase the risk of developing infectious diseases, autoimmune disorders, and allergies. Especially the development, differentiation, and activation of antigen-specific T cells, part of the adaptive immune system, are zinc-dependent processes. The antigenic stimulation of T cells results in the differentiation of T helper (Th) cell subpopulations.  Th1 cells induce cellular responses against intracellular microbes and are interferon(IFN)-gamma-producing cells.  Th2 cells mediate humoral immune responses against worms, and produce the cytokine interleukin (IL)-4, which triggers IgE antibody production.  Regulatory T cells (Treg) suppress Th1 and Th2 mediated immune reactions by producing IL-10 and other cytokines, and control the peripheral tolerance. Treg highly express CD25 (IL-2 receptor alpha-chain), the transcription factor forkhead box p3 (Foxp3), and cytotoxic T-lymphocyte antigen (CTLA)-4. Even though T helper cells regulate and co-ordinate immune responses, they are also associated in the development of autoimmune diseases (Th1) as well as in the induction of allergies, which are Th-2 driven diseases.

    Fig. 1. The response to pollen allergens results in enhanced proliferation of T cells and increased Th2 cytokine releases. The presence of zinc plus allergen reduces T cell growth, induces Treg and switches the Th2-driven response into a Th1 cytokine milieu by releasing IFN-gamma, and TNF-alpha. Therefore, zinc supplementation may be a benefit for allergic patients.

    Zinc deficiency and allergic hyperresponsive reactions are often accompanied.  Treg are also affected by allergy, but some studies reveal that allergen immunotherapy in rhinitis and asthma is associated with the induction of Treg leading to clinical improvement. To investigate the influence of zinc on allergen reactions, allergen-induced cell growth, Treg cell numbers and cytokine expression in non-atopic and atopic subjects were compared. Peripheral blood mononuclear cells (PBMC) from non-atopic and atopic subjects were treated with timothy-grass (Phleum pretense)-derived allergen and pre-incubated with or without zinc. Exposure with timothy grass pollen is one of the major causes of allergic rhinitis in many parts of the world. The response to pollen allergens results in enhanced proliferation of T cells and increased Th2 cytokine releases. By using 50 µM zinc sulfate in combination with allergen, a significant reduction of PBMC proliferation of atopic subjects was observed.  50 µM zinc sulfate plus allergen enhanced Th1 cytokine responses shown by increased IFN-gamma / IL-10 ratios as well as increased tumor necrosis factor(TNF)-alpha release. Additionally, zinc supplementation and allergen increased Foxp3+ Treg, and upregulated the mRNA expression of Treg specific CTLA-4 mRNA in atopic subjects. Interestingly, 50 µM zinc sulfate alone led to an increase of CD25high+ Th cells in atopic and non-atopic subjects indicating a zinc-dependent effect on Treg growth, generally.

    Taken together, the application of zinc and allergen leads to suppressed proliferation, the induction of regulatory T cells, and to a Th1 cytokine production (Fig. 1). Th 2-driven responses by timothy-grass (pollen) allergens can be altered by zinc supplementation. Therefore, zinc might be able to dampen allergic reactions by switching the Th cell response and decreasing proliferation. In addition, Treg may be therapeutic targets for zinc-induced modulation of the allergic immune reaction.

    Lothar Rink
    Institute of Immunology, RWTH University Aachen, Medical Faculty, Aachen, Germany

     

    Publication

    Zinc enhances the number of regulatory T cells in allergen-stimulated cells from atopic subjects
    Rosenkranz E, Hilgers RD, Uciechowski P, Petersen A, Plümäkers B, Rink L.
    Eur J Nutr. 2015 Nov 20

  • Allergic mechanisms of Eosinophilic oesophagitis

    The concept of eosinophilic oesophagitis (EoE) as a food allergy seems foreign to many patients, and even physicians, since EoE does not exhibit the typical symptoms associated with allergic reactions such as hives, swelling, pruritus, wheezing or anaphylaxis. Instead, it affects only the esophagus and causes symptoms such as swallowing difficulty (especially solid foods), food impaction, refractory reflux symptoms, pain and feeding problems.

    We normally do not experience allergic reactions with food because there is a mechanism in our immune system that prevents hypersensitivity reaction to foods (a.k.a. oral tolerance). In patients with EoE, trigger food proteins circumvents the oral tolerance mechanism, and causes inflammation in the esophagus. The inflammation is predominantly driven by a specific type of white blood cells known as eosinophils, hence the name eosinophilic oesophagitis. Eosinophils are recruited to the esophagus through a complex network of signaling molecules and mediators.  In our review paper, we summarize the important lessons learned from animal and human studies, and dissected the roles of the key inflammatory mediators. Based on current evidence, we proposed the allergic mechanism of EoE.

     

    Publication

    Allergic mechanisms of Eosinophilic oesophagitis.
    Leung J, Beukema KR, Shen AH
    Best Pract Res Clin Gastroenterol. 2015 Oct

  • Allergy: the latest technology in vitro in the service of an appropriate diagnosis

    The countless and various allergen sources from both the plant kingdom is to the animal kingdom constantly stimulate our immune system.So the allergy diagnostics laboratory is evolving using new technologies such as molecular biology, nanotechnology to highlight the “cross-reactivity” and “polisensibility “.

    The cross-reactivity between allergens is a detectable phenomenon in vitro that allows to highlight the presence of antibodies formed after the sensitization to common molecules present in different substances, whether these pollens or foods, for example, reactivity between birch and apple or those that can be found between different shellfish or between different fish . Therefore the association between pollen allergy and food allergy can manifest clinically both locally, involving the respiratory (rhinitis), skin (conjunctivitis, urticaria), digestive (colic, diarrhea, itching of the pharynx and edema labile), both at the systemic level (angioedema).In patients with food allergy the polisensibility is almost always constantly present and we recommend a thorough diagnostic investigation in order to identify, exclude and remove all sources allergenic.Often the results obtained with the in vitro diagnostic allergologic traditional highlight multiple positive, but only with the use of “molecular diagnostics ” you can get and show whether we are facing a “true allergy” or if the patient has many positivity caused structural homology between different proteins.These molecular allergens are grouped into different families according to their molecular conformation and also perform different activities : enzymatic, metabolic, structural or storage causing clinical reactions of varying severity. One of the first cross reactivity highlighted is that between the “birch pollen” and some fruits and vegetables.

    In fact the most studied and most common allergenic molecules in the plant world are those of the birch and those present in pollens of plants in the family including fagacee (hazel, alder, hornbeam) and in plant foods such as apple, carrot, celery, cherry, pear. Allergic patients have clinical manifestations frequently report mild local and a good tolerance for cooked food and commercial fruit juice. The food allergy is an allergic disease immune-mediated in different ways: it can be IgE- mediated, non-IgE mediated, mixed IgE and non IgE mediated, cell- mediated. The food intolerance is non immune-mediated: the cause is enzymatic, such as lactose intolerance, or drug such as biogenic amines, or toxic such as sgombridis and idiopathic. Each food originating from plants contains allergenic proteins stable and heat-labile, easily degradable to heat and digestion while each food originating from animals is mostly characterized by allergenic proteins with stability to heat and digestion.

    Among the most common food allergies of animal origin is that the egg, especially the albumen sensitivity in pediatric patients showing clinical dermatological conditions like widespread eczema skin.

    Human milk, with more than 40 proteins, can also cause moderate allergic reaction and these proteins are heat sensitive and normally the individual develops tolerance within four years. The milk of various ruminants buffalo, cow, sheep, goat is the same or very similar proteins to those of human milk, sharingfeatures structural, functional and biological properties.

    The major allergen of shrimp, positive in 80 % of those allergic to shellfish, it is present in the muscle tissue of all living beings that explains the cross-reactivity between the different species: shrimp, prawns, lobster, crab, oysters, snails, squid. The same molecule has a high structural identity even to other invertebrates, such as dust mites and cockroaches. For patients allergic to mites and cockroaches are responsive to the same molecule without coming into contact with fish, so the patient vaccinated for mites likely to become sensitive to shellfish.

    One of the most important vegetables that cause allergy is soybeans. Used as nourishment or as flour, flakes, soy milk or squeezed to get the oil, for purposes pharmaceutical, cosmetics and industrial and is also an allergen that causes occupational asthma. The main difficulty in making the diagnosis of true allergy to soya is in being able to distinguish the real positive from the cross reactivity with birch and cross reactivity with peanuts.

    Reactions to wheat are connected to a storage protein responsible of severe immediate reactions or phenomena of anaphylaxis induced by exercise, within 4 hours after ingestion and when the body temperature has risen significantly; in winter such episodes occur less easily.

    The clinical utility of the assay of this protein is to be able to identify both patients at risk of anaphylaxis to wheat in relation to physical exercise both patients (adolescents) at risk of developing severe and immediate reactions to wheat.

    So when you suspect that a food borne allergen is causing allergic reactions, more or less strict, we must remember the different allergenic components, the cross reactions associated with food / pollen and cross reactions between foods.

    Dr F. Barocci, Dr M. De Amici, Dr S. Caimmi, Prof. G. L. Marseglia

    Publication

    Molecular evolution in food allergy diagnosis.
    Barocci F, De Amici M, Marseglia GL.
    Minerva Pediatr. 2015 Jun 19