Priority Research Area Chronic Lung Diseases
Clinical and Molecular Allergology
Allergies are complex multi-organ diseases. In Germany, 12.3 Mio people are affected by allergy alone (asthma not included), and the prevalence is still increasing. Therefore, allergies nowadays are a widespread disease. Some allergies are life-threatening and/or pave the way for chronic diseases such as bronchial asthma as a sequel of a pre-existing allergic rhinitis (e.g. hay fever). These respiratory diseases are recurrent (like rhinitis), are prone to become a chronic illness, and affect the quality of life and overall activity. As a consequence, they lead to major socio-economic burden (Weißbuch Allergologie in Deutschland 2018).
Allergy is an immune reaction to substances of natural origin (from the natural environment) that are as such harmless. Allergies are partly driven by both, a genetic predisposition and environmental factors.
The Research Group Clinical and Molecular Allergology investigates the influence of allergen structure on sensitization/sensitization routes, the development of allergy and asthma, on the grade of symptom severity as well as on localization (lung, gastrointestinal tract, etc.) of allergic symptoms (Molecular Phenotyping).
Projects of the RG Clinical and Molecular Allergology
1. Identification and Characterization of Novel Allergens (CARE)
The identification of new allergens is a main focus of our research and shall lead to the establishment of biomarkers for clinical diagnostics and organ manifestation. Characterization of proteins in terms of structure, molecular weight, hydrophilic/lipophilic characteristics, function (e.g. protease activity) and binding to IgE antibodies from patients’ sera shall help to answer the question: What makes an allergen an allergen? What are the relevant adjuvant factors?
So far, the Research Group (RG) identified and isolated single allergens from plant sources which serve as marker allergens and seem to be associated with the severity of allergic symptoms. The identified allergens are: Cor a 8 (lipid transfer protein of hazelnut), Ara h 6 (storage protein of peanut), Ara h 9 (lipid transfer protein of peanut) as well as in 2015, Ara h 12 and Ara h 13 (peanut defensins) and Ara h 14 and Ara h 15 (peanut oleosins).
Investigations of blood from patients with mild and severe peanut allergy recently revealed that only those suffering from severe peanut allergy had IgE-antibodies against the oleosins. This points to their potential as marker allergens for symptom severity.
The determination of the interactions of allergens with the immune system and the induction of a pro-allergic immune response with resulting IgE antibody synthesis is achieved by partly cell-based structure-function analysis.
The isolated and characterized allergens are important tools for
- the elucidation of sensitization routes (CONTROL)
- the elucidation of disease development (CONTROL)
- the identification of biomarkers which shall allow for the improvement of diagnostic tests, treatment options as well as treatment management (CARE)
2. Investigation of Sensitization Routes (CONTROL)
Sensitization mechanisms of certain allergens and the development of allergic diseases associated with the commonly known symptoms are rarely investigated and not fully understood. In our hands, peanut allergy serves as a model disease for allergy research: Peanut allergy affects several organ systems including the respiratory tract. It is one of the most severe allergic diseases and can sometimes be fatal.
In terms of food allergies, in principle sensitization can occur at the interfaces such as a) the gastrointestinal tract (orally, also via breast feeding), b) the respiratory tract, c) the skin or even earlier d) in utero before birth. One of the main questions of allergology is if peanut exposure during breast feeding may act as a sensitization route or a vector that leads to tolerance induction to peanuts very early in life. Thus, one of our research topics is the investigation on the transfer of peanut allergens into breast milk.
Recently, we could show that marker allergens from peanut, the storage proteins Ara h 2 and Ara h 6 are transferred into breast milk.
Several single peanut allergens have been identified and isolated in the RG over the years.
Some peanut allergens are very stable molecules and can be transferred via air directly inducing bronchospasm after opening a bag with peanut snack. These single allergens shall now be used as tools to elucidate sensitization and elicitation mechanisms of allergy and asthma in projects funded by the German Center for Lung Research (DZL).
A special focus of our research lies on the interaction of lipophilic allergens and the lipids of the respective allergen source and its effect on allergenicity. In addition, we investigate whether lipophilic allergens are preferentially responsible for severe allergic reactions and asthma development and try to elucidate the various underlying mechanisms (Flagship Project Basic Science of the DZL, coordinator: Prof. Uta Jappe).
Apart from peanut as one of the most severe food allergies we purify single allergens from house dust mite and/or produce them recombinantly in order to determine individual sensitization profiles. We recently succeeded in the development of a serum-saving array for the detection of IgE-antibodies against several new house dust mite allergens.
These assays will enable us to identify those allergens that most probably act as “initiator allergens” in sera of very small children from atopic families (DZL-ALLIANCE-cohort) that are responsible for the primary sensitization.
After completion of the identification of these initiator allergens in the childrens’ cohort as well as those mite allergens, which are associated with a risk to develop ashma we would have in our hands a “cocktail” of clinically relevant single allergens which could be investigated for its potential to become an allergy vaccine rather than a component-based specific immunotherapy (Figure ).
3. Determination of Disease Development Mechanisms (CONTROL)
For the determination of the pathomechanism of immediate-type (type I) allergy it is crucial to elucidate how the individual production of allergy-mediating IgE antibodies is triggered by single allergens. Therefore, the specific interaction of allergens at interfaces (surface epithelium at the respiratory and gastrointestinal tract) is examined.
Our aim is to elucidate how allergens are processed and metabolized and if differences exist between allergic and non-allergic individuals. Moreover, we are examining potential disturbances during immune regulation which lead to sensitization and consequently to the clinically relevant allergic reaction. Determination of allergy pathomechanisms including the relevant adjuvant factors is the rational way to battle against allergic diseases.
4. Identification and Characterization of Biomarkers for Diagnosis and Therapy (CARE)
The identification of biomarkers in sera of allergic patients is another important field of research of our group. These biomarkers are, for example, a) metabolized and/or immunologically altered allergens, b) allergen-coupled carrier molecules, c) antibodies of the IgE isotype, but also d) other antibody isotypes like allergen-specific IgG and IgA, which may have anti-allergic effects. Here, certain IgE-binding motifs may serve as risk factors for the severity of clinical allergy symptoms. Also a certain allergen-specific IgE-antibody pattern (sensitization profile) may present a risk factor, e.g. a peanut-allergic patient with IgE against the storage proteins Ara h 1, 2 and 3 (see figure, panel 4) as well as the oleosins Ara h 14 and Ara h 15..
Determination of IgE antibodies against single allergens is a molecule-specific diagnosis, and its significance is strongly dependent on the allergen source and the clinical characterization of the single allergens.
This is only possible due to the close connection of the Research Group to the Allergy Outpatient Clinic at the Medical Clinic Borstel as well as the Interdisciplinary Allergy Outpatient Clinic at the University Hospital Schleswig-Holstein (UKSH), University of Lübeck (UzL), both headed by Prof. Dr. med. Uta Jappe.
The identification and characterization of clinically relevant single allergens, cloning and production of recombinant allergens as well as synthesis of peptides which are part of IgE epitopes puts us in the position to perform component-resolved diagnostics. This way, IgE antibodies specific for an allergenic protein or a certain sequential epitope can be identified and analyzed. Thus, individual sensitization patterns (“allergograms”) against different a) proteins, e.g. food allergens like peanut and lupine, house dust mite allergens, pollen, drugs like novel biological drugs, b) homologous (structurally related) proteins in different food and c) different antibody-binding motifs (IgE binding regions) of a single allergen are determined (precision diagnostics).
During the last years, we succeeded in the isolation of marker allergens for allergy severity from peanut, the oleosins. Since these allergens are not soluble in aqueous solutions, they are most probably not part of the solutions provided presently for routine allergy diagnostic tests or treatments.
At present we are working at the transfer of these lipophilic allergens into routine allergy diagnostic tests (transfer) and investigate their potential as therapeutic allergens and the according application routes.
Additionally, we have developed a multianalyte assay for the detection of delayed anaphylaxis to meat, a new entity called “the alpha-GAL syndrome”, which is already in use for the patients in the RG-associated allergy outpatient clinics. In some cases in which the routine diagnostic tests were negative, our multianalyte assay led to the correct diagnosis and therefore enabled the patients to re-evaluate their diet and reduce their risk of anaphylaxis (precision diagnostics).
In our project on immune reactions to target treatments (biologicals) we identified single epitopes which are most probably responsible for the loss of efficacy during treatment due to anti-drug-antibodies in patients’ sera (Proof-of-Principle).
We investigate sera from patients with hypersensitivity reactions to biologicals in order to develop assays that will allow the monitoring of anti-drug-antibodies during biological treatment and the switch to safe and effective alternative biologicals in the near future (individualized diagnostic, precision diagnostic).
5. Setup of Registries and Data Bases
Data which was acquired in registries and data bases is used for epidemiologic studies and serves as a tool for the detection of new allergies. Furthermore, the Research Group is involved in the setup of the infrastructure for and participates in biomaterial collection BioMaterialBank (BMB) Nord.
- Allergy Outpatient, Medical Clinic Borstel
- Interdisciplinary Outpationt Clinic, Dept. of Pneumology, University Hospital Schleswig-Holstein (UKSH), University of Lübeck (UzL)