Mechanisms of peripheral tolerance to allergens
This article has been published in September 2012 in «Allergy - European Journal of Allergy and Clinical Immunologie».
The immune system is regulated to protect the host from exaggerated stimulatory signals establishing a state of tolerance in healthy individuals. The disequilibrium in immune regulatory vs effector mechanisms results in allergic or autoimmune disorders in genetically predisposed subjects under certain environmental conditions. As demonstrated in allergenspecific immunotherapy and in the healthy immune answer to high-dose allergen exposure models in humans, T regulatory cells are essential in the suppression of Th2-mediated inflammation, maintenance of immune tolerance, induction of the two suppressive cytokines interleukin-10 and transforming growth factor-b, inhibition of allergen-specific IgE, and enhancement of IgG4 and IgA. Also, suppression of dendritic cells, mast cells, and eosinophils contributes to the construction of peripheral tolerance to allergens.
This review focuses on mechanisms of peripheral tolerance to allergens with special emphasis on recent developments in the area of immune regulation. Immune answers are strictly regulated to protect the host from exaggerated signals that may cause tissue injury by establishing a state of immune tolerance. Certain environmental and genetic factors disturb this fine balance of immune regulation, leading to diseases such as allergic or autoimmune disorders. Although allergens are ubiquitously distributed in the environment, the normal response to allergens in healthy individuals is either absent or results in antigen-specific immune tolerance. The immune system must recognize pathogenic stimuli and respond appropriately. Under nonallergic conditions, soluble proteins do not induce a vigorous immune response. Sensitization to a specific antigen is a prerequisite for the onset of atopic diseases in predisposed individuals, which is dependent on the potential of the allergen to prime the Th2 cell response in which interleukin-4 (IL) and IL-13 drive immunoglobulin E (IgE) class-switch in B cells (1–3). An allergen should induce both early- and late-phase clinical reactions. There are unique functional and structural features of allergens. There are several crossreactivities among allergen families due to IgE and T-cell epitope sharing. Particularly, food allergens possess structural cavities and tunnels that bind ligands for resistance to heat and proteolysis. Also, repetitive structures, aggregates, and glycation increase immunogenicity. A high number of disulfide bonds and occasionally disordered structures designed for protein stability and mobility have been observed (4). The amount of allergen in the extract, increased transepithelial allergen delivery, activation of airway epithelial cells, and suppression of local defense mechanisms by the allergen or other substances released from the allergen carrier might contribute to the allergenicity of the protein.
«Davoser Mäss 2012» – Allergy testing for Davos residents
The 9th «Davoser Mäss» was held in the Davos Congress Centre from 16 to 18 November 2012. Under the patronage of Academia Raetica, the partner institutions introduced themselves to the public. In set time slots, 150 Davos residents were able to have a skin prick test and received personal advice about reactions to the five most common allergens. Hochgebirgsklinik Davos and CK-CARE informed interested visitors about the benefits of cooperation between research and specialist clinic, especially in the area of allergies.
28. Continuing Education Congress on Allergology, Dermatology, Pneumology and Immunology
The 28th Continuing Education Congress on Allergology, Dermatology, Pneumology and Immunology, chaired by Professor Johannes Ring, was held in Davos from 12th to 15th September 2012.
In a collaboration between the Department of Dermatology and Allergology am Biederstein, Technical University of Munich, Hochgebirgsklinik Davos-Wolfgang and CK-CARE, 140 German-speaking participants were offered a broad and diverse programme. The daily case presentations and the optional parallel workshops and seminars allowed for a lively exchange between the different professional groups and provided the ideal forum for communicating the latest research findings. The interdisciplinary symposium «Zauberberg 2012» focused on modern diagnostics in the area of allergies, respiratory diseases and rehabilitation and formed a highlight of the conference programme.
Improved diagnostics for insect venom allergy
Up to 3.5% of the population reacts to bee or wasp stings with acute symptoms of the immune system (anaphylaxis). Very severe anaphylactic reactions can lead to permanent physical damage or prove fatal. Allergen-specific immunotherapy, also known as hyposensitisation, can nowadays protect over 90% of sufferers against further systemic reactions to renewed bites or stings.
In order to diagnose an allergy to insect venom, allergy specialists take a patient’s history but also use routine tests such as skin or blood tests to identify specific immunoglobulin E (IgE) antibodies to all insect venoms. These tests can sometimes elicit a positive result for bee and wasp venom even though only one of the two insects triggers the dangerous reaction in the sufferer. This means the doctors often do not know which insect venom should be the subject of the hyposensitisation.
To make the decision-making easier and avoid unnecessary immune therapies with both insect venoms, researchers led by Prof. Bernadette Eberlein, Prof. Markus Ollert, Prof. Ulf Darsow and Prof. Dr. med. Dr. phil. Johannes Ring from the Department of Dermatology and Allergy Biederstein, TU Munich, from research area C of CK-CARE, have developed new test methods. On the one hand, the scientists used a cellular test with basophilic granulocytes (a subgroup of white blood cells). This test enabled them to judge the dose-response curves and, by calculating a specific ratio between quantity of venom and degree of cell activation, they were better able to assess the reactivity to bee or wasp venom in relation to the clinical reaction. In addition, they used new recombinant allergens for determination of specific IgE antibodies.
The improved tests make it easier to identify the allergy-causing insect venom and mark a major advance towards successful immunotherapy of this life-threatening form of allergy. The tests are already being employed as standard at the Department of Dermatology and Allergy Biederstein in patients with suspected allergy to insect venom.
CK-CARE, in collaboration with aha! Swiss Allergy Centre, the Federal Office for Meteorology and Climatology (MeteoSchweiz)and the Swiss Society for Aerobiology (SGA), offer this app to healthcare professionals and people with allergies as a useful tool for making a diagnosis.
Acting as an electronic log, the «e-symptoms» app helps allergy and asthma sufferers to observe, quantify and document their symptoms easily. In a daily test run-through, the relevant symptoms are noted and any medication taken and lifestyle habits are recorded. In addition to the test questions, photographs of the skin can be documented, for example in the case of neurodermatitis (atopic dermatitis).
The data are accessible to sufferers in convenient graphical form. Before a consultation, a compilation of the symptom data can be sent to the treating physician at the touch of a button. This overview is supplemented by recorded data on pollen count, air pollution and rainfall to provide the doctor with additional information. The app perfectly supports diagnostics and communication between affected persons and their doctors.
The advice section contains basic information and tips for the allergy sufferer. The regional pollen forecast allows hay fever sufferers to make an initial assessment of the situation.
- Test questions for the daily symptoms log
- Photo function for taking pictures of skin changes
- Statistics functions
- Log transmission to doctor
- Practical guide to coping with allergies
- Record of treating physician’s contact details
- Personal data protection function with PIN
- Languages: German, French, Italian, English
Interleukin 17 a crucial messenger in various inflammatory skin diseases
In Research Area C, experiments on expression of the cytokine interleukin 17 in various inflammatory skin diseases were conducted in the working group of Kilian Eyerich. Interleukin 17 belongs to the class of tissue-signalling cytokines, which are centrally important to the immunity of the epithelial surface. Where relevant defects are present, severe chronic infections may develop, e.g. chronic mucocutaneous candidiasis, as previously found by co-workers from Research Areas A and C.
The working group has now studied 298 skin samples taken from patients with more than thirty different, common inflammatory skin diseases, using modern immunohistochemical methods. They found characteristic patterns of in situ IL 17 expression for various inflammatory skin diseases, particularly in terms of the type of positively marked cells, namely whether mainly T-lymphocytes, neutrophilic granulocytes or both were involved. Acute bacterial and fungal infections showed pronounced marking for interleukin 17- positive lymphocytes and granulocytes. In granulomatous diseases (such as sarcoidosis or granuloma annulare), it mainly involved lymphocytes. In lichen ruber, very few interleukin 17-positive cells were found, while psoriasis was characterised by the presence of interleukin 17-positive lymphocytes and granulocytes. In the case of eczema, again only lymphocytes were positive.
These different expression patterns of such an important inflammatory cytokine might gain significance in the diagnosis but also the treatment of different inflammatory skin diseases.
Project – Ambrosia in climatic chambers
The pollen of the common ragweed (Ambrosia artemisiifolia) has so far been one of the most potent allergy triggers and it can very quickly cause allergic reactions such as asthma. This aggressive neophyte from North America is spreading increasingly in Europe and is being sighted more and more frequently in Germany. Ambrosia grows mainly on wasteland and on disturbed soil. The aim is to investigate the influence of different natural and anthropogenic environmental and climatic factors (CO2, ozone, NO2, air pollution and soil contamination) on induction of potentially allergenic components in ambrosia pollen.
In our climatic chambers we are able to grow ambrosia under controlled climatic or environmentally relevant conditions, which means all the parameters such as temperature, light, air humidity and watering are controlled and we can additionally feed in different harmful gases. Our previous studies at the transcript and protein level showed that a rise in NO2, just like CO2 and drought stress, leads to an increase in Amb a 1 (the principal allergen). Similarly, various stress proteins are activated, some of which are also known to be allergens. An increase in the ozone concentration has virtually no effect on the allergen quantity of Amb a 1, but it does result in activation of stress proteins. Another factor that can lead to increased allergenicity is the potential nitrosylation of allergens which we have detected. Based on our current knowledge, «more aggressive» ambrosia pollen may be expected as environmental pollution increases.
Dr. med. Ulrike Kanter and Dr. med. Dietrich Ernst, Institute for Biochemical Plant Pathology, Helmholtz Centre Munich, German Research Centre for Health and Environment
Pollen in Winter
A study launched by Swiss doctor Markus Gassner attracts strong interest in the «New England Journal of Medicine». It demonstrates that the non-native Spaeth’s alder (Alnus spaethii) has been flowering as early as Christmas for the past three years, which is proven to cause immune reactions in children. The study was carried out in cooperation with MeteoSchweiz (Regula Gehrig) and the Allergy Unit of the University Hospital of Zurich (Peter Schmid-Grendelmeier).
Changing patterns of allergic sensitization to pollens have been noted around the world among schoolchildren. the group reports one associated with unusual winter allergic symptoms in Switzerland. They have gathered information on allergic symptoms and serologic findings among 15-year-olds attending school in Grabs, a village in eastern Switzerland, from 1983 through 2007. They measured IgE antibodies to 103 molecular allergens (using ImmunoCAP ISAC) in serum samples obtained from 54 students in1986 and from 46 students in 2006. In 2010, 12 of the former students (then 39 years old) who in 1986 had had positive IgE antibodies to inhalant allergens from birch trees, grass, house-dust mites, or cats were retested. IgE antibodies against the main allergen of alder trees (Aln g 1), which were not detected in any child in 1986, were found in 10.9% of unselected healthy schoolchildren. This increased prevalence of sensitization was not seen with pollen of other trees, such as birch, hazel, ash, or plane. Among the 12 former students who were tested at the ages of 15 and 39 years, 3 (25%) showed newly detectable IgE antibodies to alder pollen in 2010.
Although none of the schoolchildren reported having had allergic symptoms in December from 1983 through 1986, 6 students had such symptoms in 2006; all were sensitized to alder pollen. Because allergic symptoms are thought to be uncommon in winter, it seems likely that the rhinoconjunctivitis in these children might have been attributed to a common cold. Just over a decade ago, 96 hybrid trees with high winter resistance (Alnus x spaethii: A. japonica x A. subcordata ) were planted along a main boulevard in Buchs, where children walk or ride the bus on their way to school in Grabs. This leads to almost daily pollen exposure during the flowering season, which for alders in this region of Switzerland is in December. Near Christmas of 2011, large amounts of alder pollen were noted in the trap. It seems likely that this newly introduced plant species, along with changing temperatures and street lighting, may have influenced the release of pollens in winter, which led to the allergic sensitization to alder and to many children of a runny nose at Christmas.
A summary of the study findings was published in the edition of 23
January 2012 of the «New England Journal of Medicine». It is accessible to the public free of charge in the Online-Edition.