Features of histamine secretion and metabolism
Histamine (5-$eta$-imidazolylethylamine) is rightfully considered a key mediator of allergic reactions. Its main distinctive feature is that it is stored inside mast cell granules in a pre-synthesized, fully ready-to-use form.
Upon contact with an allergen, mast cell degranulation occurs instantaneously. As a result, the mediator is immediately released into the tissues in high concentration. This very mechanism underlies the clinical picture of immediate hypersensitivity.
Histamine is degraded just as quickly as it is released. Two enzymes participate in its breakdown:
- Histamine-$N$-methyltransferase: bears the brunt of the load (about 70% of metabolism), converting the molecule into $N$-methylhistamine.
- Diamine oxidase (histaminase): accounts for the remaining 30% of the pathway, leading to the formation of imidazole acetate.
Mechanisms of action: H1 vs H2
Four types of histamine receptors are known to science, but two of them play the main role in the pathogenesis of allergy, and their effects differ fundamentally.
Activation of $H_1$ receptors (inflammation stimulation) The binding of the mediator to the $H_1$ receptor triggers an intracellular signaling cascade: phosphoinositides undergo transformations, diacylglycerol is formed, and $Ca^{2+}$ ions are mobilized.
- Vascular response: capillaries become permeable, blood vessels dilate (partially due to the local formation of prostacyclin and nitric oxide). Edema and hyperemia develop, which are characteristic of allergic rhinitis.
- Nerve endings: irritation of the receptors causes intense itching (typical for cutaneous allergy).
Activation of $H_2$ receptors (inflammation suppression) Action via $H_2$ receptors is mediated by adenylate cyclase activation and an increase in intracellular cAMP. This produces regulatory and immunosuppressive effects:
- Neutrophil chemotaxis is reduced.
- The release of lysosomal enzymes is inhibited, and the further release of histamine itself is blocked.
- Lymphocyte proliferation and cytokine secretion are suppressed.
- Receptors of this type are also responsible for systemic effects on the heart muscle and gastric secretory cells.
Lipid mediators: eicosanoids
In addition to biogenic amines, eicosanoids—humoral lipid factors—play a crucial role in the regulation of allergy. They are formed from arachidonic acid (a 20-carbon polyunsaturated fatty acid with 4 double bonds). The acid is released from membrane phospholipids of macrophages, basophils, and the endothelium either directly (via phospholipase A) or indirectly (via phospholipase C).
Metabolism proceeds via two main pathways:
- Cyclooxygenase pathway: the enzyme cyclooxygenase converts the acid into unstable endoperoxide intermediates ($G_2$ and $H_2$), from which prostaglandins and thromboxanes are synthesized.
- Lipoxygenase pathway: under the influence of 5'-lipoxygenase, via a series of intermediate forms (e.g., leukotriene $A_4$), leukotrienes are formed. If two lipoxygenases work simultaneously, lipoxins are synthesized.
Eicosanoids exert powerful effects on smooth muscle and the vascular wall, serving as chemotactic factors. They often exhibit opposite effects within their groups while being able to enhance the action of other substances, acting as synergists of anaphylatoxins ($C_3a$, $C_5a$).
Briefly: answers to topical questions
What are the specific effects of serotonin as a mediator of immediate-type allergy?
Serotonin is a vasoactive amine and a tryptophan metabolite contained in mast cell granules. As a primary mediator of immediate-type allergy, it causes:
- vasodilation;
- increased vascular permeability;
- smooth muscle spasm.
These effects participate in the development of early manifestations of immediate hypersensitivity.
To remember the histamine degradation enzymes and their proportions, use a simple rule: Main pathway (70%) — Histamine-$N$-methyltransferase, Additional (30%) — Diamine oxidase.
Class and exam questions
Why does the body's reaction occur so rapidly upon allergen exposure?
This is because histamine is not synthesized from scratch during an allergic response. It is already stored in a ready form within mast cell granules, and the degranulation process instantly creates a huge concentration of the mediator in tissues.
How do anti-allergic drugs work?
Most of these drugs aim to block $H_1$ receptors. They are precisely responsible for the classic symptoms of allergy: itching, vasodilation, hyperemia, and increased capillary permeability.
What is the difference between the effects of $H_1$ and $H_2$ receptors?
$H_1$ receptors stimulate inflammation and the allergic response. $H_2$ receptors, conversely, exert an anti-inflammatory and immunosuppressive effect by inhibiting lymphocyte activity and reducing the release of new portions of histamine.
What else to study on this topic
- Detailed mechanism of intracellular $H_1$ receptor signaling and the role of phosphoinositides
- Synergism of eicosanoids with anaphylatoxins $C_3a$ and $C_5a$
- Structural features of leukotrienes and the role of sulfur-containing side groups
- Involvement of nitric oxide and prostacyclin in shaping the vascular effects of histamine
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