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A view words on allergy and identification of the allergen(s) relevant for a given patient

In a nut shell:
Allergies are unproportional reactions of the immune system against (mostly) unoffending agents such as foodstuffs, pollens, pet hairs or insect venoms. Effects range from mildly annoying to lethal. Allergies are diagnosed either by confrontation tests or from patient´s blood by measuring the amount of allergen-specific IgE.

Using a sledgehammer to crack a nut is a bad idea. It´s not only ridiculous, it can even be dangerous. Yet this is what many people´s immune system does with perfectly innocent compounds when it kind of “decides” to regard such a compound as an allergen. Why does our immune system eventually take this unlucky turn? Much could be said about the impact of heritage, of hygiene, of psychological factors and a lot of highly complex and bewildering molecular and cellular details, but - essentially - the pivotal trigger that turns a non-threatening compound into an object of hate in the eyes of our immune system remains to be revealed. In 1906, the Viennese physician Clemens von Pirquet coined the term “allergy” and it would be now about time to fully understand this phenomenon. Until then, we have to content ourselves with identifying the elicitors of an allergy and with dampening its deleterious effects.

Sometimes, allergy is regarded as a petty indisposition not worth complaining about. The truth is otherwise. Allergies cannot only severely impair the quality of lives of affected people, they can lead to clinical grade asthma or to acute lethality. In fact, stinging insects top the table of deaths caused by beasts far ahead of dogs, bears, wolves or snakes - at least in the northern hemisphere.

Medical definition of allergy

This cannot be given without a very brief dive into molecular immunology, but this may not be so grim as “thanks” to Covid-19, the term antibody is nowadays very familiar. Antibodies are one relevant part of our bodies army to fight basically all kinds of diseases that may come along from bacterial and viral infections to parasites or malignant cells (the monsters that eventually may cause cancer). The other arm is made up of immune cells, which we will ignore for the time being irrespective of their relevance. Antibodies are also called immunoglobulins. Each immunoglobulin molecule is strictly specific for a particular antigen - a molecule that is recognized and bound by the immunoglobulin / antibody. The antigen itself is usually a protein located e.g. on the surface of a bacterium or virus. Our blood harbors innumerable millions or billions of different antibodies, all just waiting to encounter “their” antigen in order to keep us healthy and alive.
Occasionally, the antigen rather is a carbohydrate. For many decades it is known that bacteria surround themselves with  a thick polysaccharide layer. Microbes can be differentiated on the basis of the surprisingly various structures of such polysaccharides and the vaccine against Haemophilus influenzae type B administered to infants is based upon such a polysaccharide.
Recently, the carbohydrates on proteins have been recognized as  immunogenic determinants in some cases and this is basically what this homepage is all about.

Antibody classes shown in proportion of their abundance in serum. The two tips formed by light and heavy chain represent two binding sites for allergen. They are identical for one particular antibody. The five classes differ in the structure of their heavy chain.

Antibodies, also called immunoglobulins, appear in different types, so-called classes. The immunoglobulin G class, abbreviated IgG, is the one most relevant for our well-being and health. However, there is always a small number of “soldiers” of the type immunoglobulin E (= IgE) around. Usually, these rascals don´t matter. But – eventually – the number of a particular type of IgE may explode and can no longer be contained by the IgG. In this situation, encountering the very antigen that can be bound by this IgE will not go unnoticed but it will lead to one or more of the typical manifestations of an allergic reaction such as hay fever with running nose and red eyes, dermatitis, asthma, and – if all goes very wrong – an anaphylactic shock, i.e. a sudden drop of blood pressure that may eventually lead to death if not immediately counter-acted.

These unpleasant effects are achieved in cooperation with a particular type of immune cells called mast cells, which reside in our skin and mucosa. Most probably the true task of the IgE-mast cell system is to fight skin parasites. What is certainly true, upon encounter of an allergen by IgE loaded mast-cells, these cells burst (degranulate) and release, among other nasty potions, the notorious substance histamine. Histamine now effects the unpleasant symptoms of an allergic episode and it does so by addressing yet other, neighboring cells of the immune system. The door bell of these cells can be silenced by antihistamines, a drug well-known to every allergic person.

Emergence of an allergy

When we first see the light of day, IgE is not an issue and for many of us, this will not change throughout our life time. For some, however, soon after birth, during childhood or adolescence or even much later, an at first unnoticed event will change life quality. This is the so-called “sensitization”. As already mentioned, no one exactly knows, why this sensitization occurs at this time, to this allergen and this person. Fact is, sensitization results in a strong increase of the amount of IgE against this particular allergen. While this first decisive event may go unnoticed, future encounters with this allergen will agonize the allergic individual for years to come, often forever.

Different allergens tend to elicit somewhat different allergic symptoms. Pollens, pet hair or house dust mite cause symptoms akin hay fever, which may over time develop into severe asthma. Foods may cause nausea, skin itching and other rather general symptoms. Insect stings may likewise cause rather general symptoms up to circulatory problems. Insect venoms and certain foods, in particular peanuts and a few other nuts, may eventually lead to an anaphylactic shock – a possibly lethal event. Persons with such allergies are well advised to have an emergency kit at hand, which basically consists of an easily applicable syringe containing epinephrine

Much could be said about possible evasion strategies, especially for newborns and children, but this is not the place to engage in discussions over baby nutriment, hereditary factors or the hygiene hypothesis, however interesting these items may be.

What we should notice here is that for some allergens, avoidance of this particular allergen poses a rather easy remedy. This applies to many food allergens. However, it can certainly not be applied to vegetable food from cereals to beets, legumes and fruits. This seemingly trivial statement possibly has a relevant repercussion on the topic that is at the heart of this website and our small enterprise.

The nature of an allergen

We encounter allergens as more or less handy items such as cats, shrimps, apples or – a bit less handy – pollens, mould dust or mite dander. The actual players in these allergens, however, are (usually) proteins. Most often – but not always – are the major proteins of an allergen also responsible for the allergic symptoms. During the last two decades, most of these proteins – the so-called compounds – have been identified for the relevant allergens.

Many of these allergen compounds are proteins that – in addition to amino acids – contain complex chains of sugars. These “glycoproteins” – again - are at the heart of this website and our small enterprise and thus deserve a separate chapter.

Nature of the test materials: The left side depicts the extraction of the entire mixture of allergenic proteins from pollen, food or other materials. The right side show the production of single allergen components (=proteins) using recombinant DNA technology. A special - and rarer - case is the isolation of individual proteins from mixtures as generated by extraction of natural allergens.

Allergy diagnosis

Finding the culprit allergen. The most important options are provocation tests and determination of allergen specific IgE (sIgE). Options substituting conviction for evidence are listed for the sake of completeness.

The question “Do I have an allergy and what is the trigger” is all but trivial to answer. Adverse reactions to substances may have various reasons. In the following we will deal with allergies in the narrower sense – so-called type I allergies – where the bi0nding of an allergen by specific IgE leads to the effects described above. Food intolerances or nickel “allergy” – annoying as they may be – do not fall in this category. Self-observation and medical consultation (aka anamnesis) often will provide valuable information. For a further diagnostic work-up and substantiation two options are available. The one is confrontation of the patient with the allergen either by itching the allergens in the skin (Skin-prick test) or by administering suspected food under medical supervision (oral provocation test). Such tests may be very conclusive but are time-consuming and restricted to a few allergens only. This is where serum-based allergy diagnosis takes over as a very small amount of a patient´s blood can be analyzed for sensitization towards many, eventually over a hundred allergens.

Serum, blood, what? When blood comes into contact with air, e.g. in the course of an injury, it immediately starts to clot thereby closing the wound. Similarly, a blood sample will clot within due course unless a clotting inhibitor is added. Centrifugation of clotted (aka coagulated) blood yields a red pellet containing all the blood cells and yellowish liquid called serum.

The first serum-based tests operated with allergens fixed to small cellulose sponges. One allergen was considered in one test and for economic reasons an only limited number of tests could and can be prescribed for one patient. It is, however, commonly held that these tests provide high quantitative accuracy. During the last decade systems were developed that simultaneously confronted the serum sample with several allergens. This can be realized with strip tests containing up to 20 different allergens (List of diagnosis systems). The most sophisticated realization of this principle are allergen arrays where well over a hundred tiny spots are incubated with sub-milliliter amounts of serum. Such tests routinely do not only contain traditional allergen extracts but rather harbor individual allergen components. Knowing to which particular protein a patient is sensitized often gives valuable hints on the clinical relevance of this allergen. Obviously, interpretation of results turns into a science in its own right and is usually assisted by software. Likewise, obviously, these high-end array tests are also high-end regarding costs.

It shall, however, be mentioned that these tests do not provide a simple yes/no answer. It is the amount of IgE present for a particular allergen or allergen component that matters and even then, there may be a discrepancy between sensitization and true allergy against a certain allergen. One approach towards clarity is the application of test that measure the response of IgE-loaded cells. The basophil activation test (BAT) utilizes basophilic cells of the patient´s blood, which are similar to mast cells. They likewise carry IgE on their surface and they burst upon contact with an allergen. Thus, BAT mimics provocation tests as it measures the cellular response rather than mere binding of IgE to an allergen irrespective of the actual potency to elicit allergic symptoms. An advantage over usual provocation tests, in particular oral provocation tests, is that the patient´s only involvement is the 1 sec moment of blood sampling. The patient´s immune cells are nevertheless isolated from their natural environment, notably soluble IgG, and thus BAT results may not be 100 % comparable to real provocation tests. This leads to the topic “mimickers of allergy” or reasons for false-positive allergy diagnosis that will be dealt with on page “The CCD problem”.