Histamine release test

Histamine (HA) was first synthesized in 1907. Shortly afterwards, Sir Henry Dale discovered the contracting effect of histamine on smooth muscle and its blood pressure-lowering properties (Aktories 2017).

In 1927, histamine was detected for the first time in liver and lung tissue, and subsequently also in kidney tissue (Aktories 2017).

The first inhibitors of the histamine effect were developed in the 1930s. These were known as "antihistamines". However, as so-called histamine H1 receptor antagonists, they only inhibit part of the histamine effect (Aktories 2017).

Sir James Black and his colleagues led to the characterization of the second histamine subtype in 1972. This made it possible to develop numerous antagonists that blocked H1 and H2 receptors (Aktories 2017).

The H3 receptor was not identified until 1999.

In 2011, a modified H1 receptor was developed in complex with the antagonist doxepin (Aktories 2017).

Histamine is a widespread natural substance that can act as a neurotransmitter. It is ubiquitous in the human body and is found in particularly high concentrations in the skin, lungs and gastrointestinal tract (Aktories 2017).

Release and storage of histamine

Mast cells play an important role in the release of histamine, as they are the main storage site for histamine and at the same time mast cells also have their own histamine receptors that can activate or block histamine (Schoebel 2019).

The different histamine receptors have different effects on organs and tissue types:

- H1 receptors:

These cause, for example, the blood vessels to dilate and the bronchi to constrict

- H2 receptors:

They cause, for example, increased production of gastric juice and can trigger cardiac tachycardia and cardiac arrhythmias (Schoebel 2019)

- H3 receptors

These are located on the nerve cells of the central and peripheral nervous system. They regulate the wake-sleep rhythm and energy levels. They are also able to curb further histamine release (Storr 2022).

- H4 receptors

This is mainly located on the cells of the immune system and the cells of the haematopoietic system (Storr 2022).

Degradation of histamine

Histamine is broken down by the enzymes diaminooxidase and histamine N-methyltransferase. If there is a genetic deficiency in these enzymes, histamine is only produced to a reduced extent or its effect is blocked by food, resulting in symptoms of excess histamine (Schoebel 2019).

Effect of histamine

Histamine is an important component of the immune system. It can increase blood flow and increase the permeability of blood vessels (Schoebel 2019).

It also plays a role in regulating the sleep-wake rhythm and a number of other physiological processes, such as nutrition, cognition, motor control, as a primary transmitter for visual input. In addition, histamine also influences pathological processes in the central nervous system, such as allergic reactions including anaphylaxis, migraine, epilepsy, Tourette's syndrome, narcolepsy, etc. (Dong 2023).

Triggers of histamine release

There are numerous triggers for histamine release. These include in particular:

- Various foods

- Various drinks, including alcohol

- Heat, cold, but also sudden changes in temperature

- Sunlight

- Mechanical irritation

- Physical stress such as pain, environmental toxins, weather changes, animal hair, pollen, etc.

- Emotional stress

- Physical exertion

- Natural and chemical odors such as perfume

- Exhaustion

- Poisons such as those of bees, wasps, snakes, biting insects, spiders, jellyfish, ants

- Viral, bacterial or fungal infections

- Medications such as NRSA, antibiotics, opioids, contrast agents, local anesthetics (Schoebel 2019)

Histamine release test

In this test, a suspension of leukocytes is added to suspected allergens in vitro and the release of histamine is then measured. The test is used in allergy diagnostics, e.g. in bronchial asthma (Herold 2022).

In the meantime, Dong et al (2023) have presented GRAB HA sensors that can measure histamine release both in vitro and in vivo. These sensors show high specificity and sensitivity. The sensors also demonstrated that certain brain regions exhibit different patterns of histamine kinetics.

Histamine is produced by decarboxylation of the semi-essential amino acid L-histidine by means of histidine decarboxylase. It is primarily stored in mast cells, but also in leukocytes and thrombocytes.

The histamine content in the blood is up to 1 ng / ml, that in the plasma is significantly lower. However, in anaphylactic shock, for example, the histamine content in plasma can increase 100-fold (Aktories 2017).

Various factors can become effective when histamine levels rise:

Type Iallergy:

In a type I allergy-induced histamine release, the IgE molecules bound to the receptors of the mast cells are bound bridge-like by the antigen. This results in an immediate reaction with the formation of wheals and itching (Aktories 2017).

All other forms of allergy, endotoxin shock, inflammation, burns:

All other forms involve mast cell activation and histamine release, particularly in the early phase. This occurs through activation of the cleavage products of the compliment and basic ingredients from decaying leukocytes (Aktories 2017).

Histamine release through histamine liberators:

Other alkaline substances can also activate the tissue mast cells and thereby release histamine. These include, for example, some bee and wasp venoms, but also various medications. The mechanism of action here differs from the IgE-mediated reaction. The basic liberators activate the G protein Gi in the mast cell membrane in an as yet unexplained way, which ultimately leads to a phospholipase and, via signal transduction, to exocytosis.

Especially after an intravenous injection, a sudden drop in blood pressure, cramp-like abdominal pain or an asthma attack can occur (Aktories 2017).

The basic histamine liberators include:

- the body's own substances: anaphylatoxins, bradykinin, substance P.

- bee and wasp venoms: mast cell degranulating peptide, mastoparan

- to the pharmaceuticals: muscle relaxants (alcuronium and suxamethonium), analgesics(codeine, morphine, pethidine), chemotherapeutics (chloroquine)

(Aktories 2017)

The metabolites of histamine are excreted via the urine. These metabolites can be increasingly detected in:

- Acute allergic diseases

- Pathological mast cell proliferation in the skin (e.g. as part of urticaria pigmentosa)

- Carcinoid syndrome

- Extensive burns of the skin

- Systemic mastocytosis (Aktories 2017).

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2. Dong H, Li M, Yan Y, Qian T, Lin Y, Ma X, Vischer H F, Liu C, Li G, Wang H, Leurs R, Li Y (2023) Genetically encoded sensors or measuring histamine release both in vitro and in vivo. Neurosource 111 (10) 1564 - 1576
3. Herold G et al. (2022) Internal medicine. Herold Verlag 364,
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5. Schoebel F C (2019) Histamine - release, function and degradation in the body. Doi: https://www.cardiopraxis.de/histamin-freisetzung-funktion-und-abbau-im-koerper/
6. Storr M (2022) Instant guide to histamine intolerance: Understand, recognize, treat - this is how it's done. Digesta Verlag Munich 22