ISAC Allergie Info

What are allergies?

Allergies are the immune system’s adverse reactions to a foreign substance. Exposure to what is normally a harmless compound, such as pollen, causes the immune system to react as if it were deleterious. Substances that cause allergies are called allergens.

Many substances can cause allergic reactions, including:

Tree- and grass pollens
Animal hair, tissue or feces (e.g., cat or dog)
Insects (e.g., mites) and insect venom (e.g., bee or wasp)
Foods of plant (e.g. vegetables) or animal (e.g., cow’s milk) origin
Chemical substances (e.g., drugs or preservatives)

Over the last 2 decades, the prevalence of allergic diseases has increased dramatically in the industrialized world. In Europe, one out of three is estimated to suffer from at least one of the many symptoms of allergy. Some scientists believe that this development is based on a dramatic life style change provoked by an increased daily hygiene or by the eradication of certain pathogens from our environment. Others state that the disease is triggered by increasing concentrations of pollutants in our environment. Apart from a likely environmental contribution, it has been shown in scientific studies that the development of allergy correlates to the presence of certain risk genes and this heritable component is particularly evident in families where both parents are affected, leading to an at least 50% chance for the offspring to develop the disease. Nevertheless, any genetic component only confers an increased risk whereas the actual development of the disease depends on a number of parameters, including the repeated exposure to elevated concentrations of allergens, amongst others. Food allergies are particularly common among children below 3 years of age, whereas the corresponding symptoms usually vanish with adolescence. In contrast to this, adults are especially prone to becoming sensitized to environmental allergens such as cat hair, mites or pollen.

What types of allergy are there ?

Scientists have described 4 types of allergic disesaes. The most common is the so-called Type-I or immediate-type allergy which is characterized by the presence of a particular class of antibodies in the immune system. Immediate type reactions occur not later than an hour after an allergen has entered the body of a patient and the corresponding antibodies can be used to trace the origins of the disease. Only immediate-type allergies can be diagnosed using ISAC.

The following is a typical classification of allergic reactions:

Inhalant allergies (e.g. to pollen or spores)
Food allergies (e.g., to fruits, vegetables or dairy products)
Drug allergies (e.g. to antibiotics)
Insect venom allergies (e.g. to bee or wasp)
Contact allergies (e.g. to metals)

How do allergies develop ?

After the primary contact with a particular biological source (e.g. pollen), a patient’s immune system develops so-called IgE antibodies against one or several allergen molecules. This is called sensitization. Upon the second encounter with the same allergen, sometimes years later, the immune system responds with a molecular chain reaction leading to the cross-reaction of IgE molecules bound to the surface of so-called mast cells. As a result, a vast number of mediators of inflammation are released (e.g. histamines) triggering the well-known symptoms of allergy.

What are the typical symptoms of allergy and how do they present ?

Allergy can affect different organs and tissues in the human body, leading to different symptoms.
The main symptoms of allergic diseases are:

(Chronic) rhinitis ⁄ hay fever
Hay fever, otherwise known as seasonal allergic rhinitis, is an allergic reaction to airborne substances such as pollen that get into the upper respiratory passages - the nose, sinus, throat – and also the eyes. The name hay fever is misleading because symptoms don't just occur in autumn when hay is gathered and never include fever. „Allergic rhinitis“ is the correct term used to describe this type of allergy. Rhinitis means „irritation of the nose“ and is a derivative of „Rhino“, meaning nose. Allergic rhinitis which occurs during a specific season is called ”seasonal allergic rhinitis“. Symptoms of allergic rhinitis, or hay fever, frequently include nasal congestion, a clear runny nose, sneezing, nose and eye itching, and tearing eyes. Hay fever is the most common of all the allergic diseases – about 15 per cent of the population in industrialized countries suffer from this condition. Symptoms usually appear in childhood first and then lessen by the age of 30 or 40. Perennial allergic rhinitis is a similar allergy that occurs all year round and is caused by things such as house dust mites and pets. However the predominant allergen changes from time to time.
Conjunctivitis
Inflammation of the conjunctiva (conjunctivitis) is often caused by allergens and it frequently presents in conjunction with rhinitis. Allergic conjunctivitis is common in people who have other signs of allergic disease such as hay fever, asthma and eczema. Conjunctivitis is often caused by antigens like pollen, dust mites or cosmetics. Symptoms include burning, discharge, dryness, itching, light sensitivity, eye pain or discomfort, stickiness, tearing and chemosis. Rubbing of the eye can possibly worsen symptoms.
Shortness of breath, asthma
In some allergic patients, asthma symptoms can be triggered by inhaling particular environmental triggers (e.g. allergens or other environmental pollutants) leading to an inflammatory reaction in the airways of the lung. Typical asthma-eliciting allergens include pet dander, dust mites, cockroach allergens, molds, or pollens. Asthma symptoms can also be triggered by respiratory infections, exercise, cold air, tobacco smoke and other pollutants, stress, food, or drug allergies. When an asthma attack occurs, the muscles surrounding the airways become tight and the lining of the air passages swell. This reduces the amount of air that can pass by, and can lead to wheezing sounds. Most people with asthma have wheezing attacks separated by symptom-free periods. Some patients have long-term shortness of breath with episodes of increased shortness of breath. Still, in others, a cough may be the main symptom. Asthma attacks can last minutes to days and can become dangerous if the airflow becomes severely restricted. Smoking or physical activities.
Allergic reactions of the skin
The skin is our most important barrier when protecting the body from getting in contact with pathogens or pollutants and therefore it is also a key contact point for allergens. Allergic contact dermatitis is an itchy skin condition caused by an allergic reaction to material in contact with the skin. It arises some hours after contact with the responsible material, and settles down over some days providing the skin is no longer in contact with it. Contact dermatitis should be distinguished from contact urticaria, in which a rash appears within minutes of exposure and fades away within minutes to hours. The allergic reaction to latex is the best known example of allergic contact urticaria. Allergic contact dermatitis is also distinct from irritant contact dermatitis, in which a similar skin condition is caused by excessive contact with irritants. Irritants include water, soaps, detergents, solvents, acids, alkalis, and friction. Irritant contact dermatitis may affect anyone, providing they have had enough exposure to the irritant, but those with atopic dermatitis are particularly sensitive. Most cases of hand dermatitis are due to contact with irritants.
Circulation problems, fatique
The response issued by the human body’s immune system in response to allergen contact (e.g. a local inflammation) can have a profound effect on the circulation or lead to a general fatigue. Frequently, these symptoms are caused by drugs such as anti–histamines.
Digestive symptoms
An allergy can also affect the the digestive system may cause in which case it may present with symptoms of stomach pain, nausea, vomiting or diarrhea.
Anaphylaxis
Anaphylaxis is a severe allergic reaction that affects the entire immune system simultaneously with possibly life– threatening results. Full-blown anaphylaxis includes urticaria (hives) and/or angioedema (tissue swelling) with hypotension (low blood pressure) and bronchospasm (asthma). Anaphylactoid reactions are clinically similar to those experienced in anaphylaxis. The only difference is that anaphylactoid reactions are non-IgE mediated and may be less severe. Severity of reactions from anaphylaxis can vary from mild symptoms to sudden death. In any case, medical attention should be sought immediately and appropriate treatment provided.

How are allergies diagnosed ?

The first step in the diagnosis of allergic diseases is the assessment of a patient’s symptomatic history by an allergologist (a practitioner specialized in allergy diagnosis). This is called anamnesis. Important elements of this examination include an evaluation of the nature, duration, and time course of symptoms; possible triggers for symptoms; response to medications; family history of allergic diseases; environmental exposures; occupational exposures; and effects on quality of life. Once the possible causes of allergy have been narrowed down, there are 2 possible ways of confirming the actual disease-eliciting allergens: One includes the direct exposure of the patient to the allergen(s) in questions (so–called in–vivo tests) while the other employs a patient’s sample (such as blood or serum) to detect specific antibodies present in the immune system.

Laboratory investigations

Diagnostic procedures conducted in a laboratory are based on detection of specific IgE antibodies in the blood or serum of allergic patients. Therefore, the corresponding methods can only diagnose Type-I allergic diseases. A major benefit of blood/serum testing is that a direct contact of a patient with allergen is avoided, which particularly relevant for the diagnosis of infants. Scientists have shown that the amount of total IgE present in the immune system of allergic patients is a reliable marker of allergy while it also indicates the severity of the disease. Typically, above average levels of IgE are reliable predictors of allergy. However, some patients don’t have elevated IgE concentrations although they are presenting with symptoms while others show high IgE levels but no history of allergic disease.

Once elevated IgE levels indicate allergy, possible disease-eliciting antibodies present in the immune system of a patient can be determined. Most conventional in-vitro diagnostic tests employ the well-known principle of solid-phase immunoassays to capture and quantify disease-related antibodies. In brief, allergen material (e.g. an extract from pollen, dust mites or cat hair) is immobilized on a solid substrate such as a microtitre plate or a nitrocellulose membrane. Subsequently, bound allergen material is incubated with patients’ serum in order to specifically capture and retain antibodies on the solid phase. In a washing step, excess serum components and unbound antibodies are removed. Afterwards, specifically retained IgE antibodies are detected using antibody conjugates carrying a fluorescence or radioactive label.

In-vivo testing

The most important diagnostic procedure employing a direct exposure of a patient to a particular allergen source is the so–called skin-prick test (SPT). For SPT minute amounts of defined dilution of an allergen extract is applied to the skin of a patient (in most cases the forearm). The skin is then pricked through the drop using the tip of a lancet. When the allergen is introduced into the skin on a previously sensitized individual, IgE molecules on the surface of a mast cell cross–link and mediators of allergy (e.g. histamines) are being released. With a positive reaction to an allergen the skin becomes itchy within a few minutes and then becomes red and swollen with a ”weal“ in the centre (very much like the reaction to a nettle sting). With SPT, a number of allergens can be tested simultaneously when applied to different sections of the skin. Skin prick testing is a cheap, rapid and accurate way of identifying the causative allergens in a patient. Although these tests are generally accurate, there are some medications that can affect the results. When taking antihistamines patients are normally asked to stop taking these at least 48 hours before the test. Some other medications such as antidepressants can also interfere with skin prick tests. More importantly, where there has been a clear anaphylactic (shock) reaction to a specific allergen then skin testing is not appropriate. For these reasons it is sometimes better to rely on laboratory tests for the determination of allergen-specific IgEs instead!

How are allergies treated ?

A simple way of treating allergic diseases is to avoid the contact with the disease-eliciting source. While this is sometimes possible in the case of certain food allergens, allergen avoidance is difficult to administer when a patient is plagued by pollen or dust mite allergies.

Nevertheless, a number of possible treatments are available. The goal of SIT is to “re-program” the immune system, therefore gradually diminishing the allergic symptoms or even completely eradicating the disease. Allergen immunotherapy involves injecting increasing amounts of an allergen to a patient over several months. Immunotherapy has been shown to prevent the development of new allergies and, in children, it can prevent the progression of the allergic disease from allergic rhinitis to asthma. Allergen immunotherapy can lead to the long-lasting relief of allergy symptoms after treatment is stopped. However, SIT has only proven effective in a limited number of patients and for a small number of allergens. Amongst others, this can be due to a lack of standardization of the extracts used for desensitization or a poly-sensitized patient not being treated for the major allergens causing his symptoms. Above all, scientists have found out that patients can gain novel allergies in the course of immunotherapy.

A possible alternative to SIT is pharmacological treatment, e.g. using anti-histamines to alleviate the symptoms of hay-fever. The gold-standard in the treatment of asthma are glucocorticoids (e.g. cortisone), mostly directly applied to the lungs using sprays.

Why is it important to pinpoint the allergy eliciting molecules ?

In order to design effective strategies for allergen avoidance and risk management in food allergy it is important to exactly identify the disease eliciting molecule. Particular allergens in certain foods (e.g. peanuts) have been shown to cause severe and life-threatening symptoms while others only lead to mild and localized reactions. The information provided by ISAC permits the sub-classification of allergens into groups of major and minor risk, hence facilitating the design of an individualized avoidance and risk management strategy for each patient. This is particularly relevant for children with food allergies.

Most importantly, tracing allergy at the molecular level improves the design of an optimal allergen cocktail for treatment with specific immunotherapy (SIT) (e.g. in pollen allergies). First, ISAC permits the identification of minor and major allergens present in different biological sources. Major allergens are molecules that have been shown to bind specific antibodies in a majority of affected patients (e.g. Bet v 1 in birch pollen), therefore posing a major risk in epidemiological terms. Therefore, allergen mixtures produced for the purpose of specific immunotherapy (-> see below) are typically standardized for these allergens with respect to relative concentration. However, patients who are exclusively reacting against a minor allergen risk being treated with an allergen cocktail not adequately representing their sensitization profile. Knowing the exact disease elicitors on a molecular level greatly facilitates the design of adequate treatments, either based on allergen avoidance or custom fabrication of desensitization cocktails for individual patients.

Furthermore, the component-resolved diagnosis (CRD) provided by ISAC facilitates the identification of possible cross-sensitizations to allergens in unrelated biological sources. Clinically, this type of reactivity to a number of structurally related proteins is caused by the promiscuous binding of IgE antibodies and is difficult to diagnose when using state-of-the-art extract-based test systems.

Example 1: Patients sensitized towards birch pollen frequently present with allergies against certain fruits or vegetables (e.g. apple, celery, or peach), based on the presence of particular cross-reactive allergen in birch pollen called Bet v 1 (see ISAC list of allergens for details).

Example 2: Patients allergic to dust mites frequently display cross-reactivities to seafood, snails or other insects, a reaction based on the binding of IgE antibodies to an allergen called Tropomyosin (see ISAC allergen list for details).

Novel trends in allergy diagnosis

Type-I allergies are being triggered by proteins, a class of bio-molecules constituting a critical building block of living cells, tissues and entire organs. Typically, at least several thousand proteins are contained in a particular biological source but only a few are capable of eliciting an allergic response in the immune system of a patient.
For example: In Europe the majority of birch pollen allergic patients (more than 95%) is sensitized against a single major allergen (Bet v 1) and a similar pattern has been observed in other environmental allergens such as grass pollens or cat hair.

Conventional allergy diagnosis, including skin and laboratory tests, employs crude allergen extracts for the determination of IgE antibodies. Frequently, these crude extracts are merely complex mixtures of bio-molecules produced by homogenization of the corresponding source material, possibly followed by a simple purification step. Consequently, these biological mixtures contain a large number of non-allergenic components. Typically, this leads to problems in the manufacturing of diagnostic assays, including the lack of standardization or the possible degradation of allergen molecules in the course of extract preparation.

Each manufacturer of allergy diagnostic tests (skin and laboratory) relies on different source materials and extraction procedures, therefore producing assays that differ in allergen composition and quality. For example, scientists have found that commercial extracts for skin testing may lack one or more of the major allergens contained in the particular biological source, possibly leading to false-negative test results. Also, allergen extracts can be contaminated with allergens from unrelated sources (e.g. animal dander contaminated with mites), possibly producing false-positive results in diagnostic assays. Eventually, an erroneous diagnosis may lead to the choice of a non-efficacious therapy or, even worse, generate side-effects resulting from the treatment!

Over the last 20 years, the disease-eliciting proteins in the most relevant allergy sources have been characterized on a molecular level. In sum, more than 1000 individual allergen molecules have described in detail. This development has been largely facilitated by the introduction of recombinant DNA technologies and improved high-throughput biocompatible purification methodologies and it has significantly boosted the creation of better diagnostic tests. For the first time, comprehensive panels of standardized allergen molecules can be used in novel diagnostic test formats, permitting the comprehensive profiling of disease-specific antibody patterns.

A major benefit of understanding the structural peculiarities of allergen molecules is their classification into families of structurally related and possibly cross-reactive proteins. Using purified allergen molecules instead of crude extracts for diagnostic testing paves the way for a paradigm shift in allergy diagnosis and treatment: Allergies can be classified on the basis of the reaction towards a particular class of allergen molecule, in Ultimately, many of these molecules will be used to develop novel therapies for allergic patients that improve the efficacy of the treatment while avoiding possible side-effects at the same time. Today, results of clinical studies indicate that these molecules lead to a better long-term reduction of symptoms, amongst others. The effective translation of allergen-molecule based immunotherapies into the clinical practice will benefit strongly from component-based testing offered by ISAC already today.

Unlike ISAC, conventional test systems don’t permit the analysis of several hundred individual disease-eliciting molecules in a single reaction. What’s more, the costs for determining a large number of disease-eliciting antibodies are significantly lower with ISAC than when using state-of-the-art assays. Therefore, ISAC will change the way allergies are being diagnosed in the near future significantly. Please, get more information about the ISAC TEST on our website!