Pathogenesis of the allergic reaction
Allergy is a state of altered body reactivity. Type 1 hypersensitivity reactions occur in three sequential stages:
- Immunological stage (sensitization). Upon initial entry into the body, allergens (house dust, pollen, mold, medications) are recognized by antigen-presenting cells (APCs). APCs interact with T lymphocytes via the major histocompatibility complex (MHC). This leads to the activation of B lymphocytes and the synthesis of specific antibodies—immunoglobulin E (IgE). Released interleukin-4 (IL-4) further stimulates B lymphocytes, creating a "vicious circle". At the end of this stage, IgE binds to FcεR1 receptors on mast cell membranes.
- Pathochemical stage (degranulation). Upon re-exposure, the allergen binds to fixed IgE. This triggers an intracellular cascade: cGMP synthesis is activated and the level of calcium ions increases. Mediators are released: histamine is immediately released from granules, while leukotrienes (LTC4, LTD4), prostaglandin D2 (PgD2), and platelet-activating factor (PAF) are synthesized de novo.
- Pathophysiological stage. Mediators act on tissues. Histamine binds to the H1 receptor, which is coupled to a Gq protein. Phospholipase C (PLC) is activated, hydrolyzing phosphatidylinositol into diacylglycerol (DAG) and inositol trisphosphate (IP3). This causes a sharp rise in intracellular calcium and leads to contraction of smooth muscle (e.g., the development of bronchospasm). Clinically, this may present as mild forms (urticaria, red eyes, itching) or severe life-threatening conditions (an asthma attack, anaphylactic shock).
Sites of action and mechanisms
Pharmacotherapy is prescribed when allergen elimination is impossible. Drugs are classified depending on the localization of their effect in the allergic cascade:
- Binding of free IgE (anti-IgE therapy): drugs interrupt the bond between the immunoglobulin and the mast cell receptor, preventing sensitization.
- Mast cell membrane stabilizers: block the degranulation process, preventing the release of allergy mediators into the exterior.
- Leukotriene pathway blockers: inhibit the effects of already released leukotrienes (inflammatory mediators) or block the enzymes of their synthesis.
- H1-histamine receptor blockers: competitively bind to histamine receptors, preventing the initiation of the calcium cascade and muscle contraction.
- Mixed-action drugs: uniquely combine the properties of a membrane stabilizer (inhibiting degranulation) and an H1 receptor blocker.
Classification of antiallergic drugs
According to their mechanisms of action, the following main groups of drugs are distinguished:
- H1-histamine receptor blockers (antihistamines):
- 1st generation: diphenhydramine (dimedrol), mebhydrolin (diazolin), quifenadine (phencarol), chloropyramine (suprastin), promethazine (pipolfen), clemastine (tavegil).
- 2nd generation: cetirizine (zyrtec), loratadine (claritin), desloratadine (aerius).
- Mast cell membrane stabilizers: cromoglicic acid (intal), nedocromil sodium (tilade).
- Mixed-action drugs: ketotifen.
- Leukotriene inhibitors:
- Cysteinyl receptor blockers (CysLT1): montelukast, zafirlukast.
- 5-lipoxygenase inhibitors (synthesis enzyme): zileuton.
- Monoclonal antibody drugs: omalizumab (anti-IgE antibodies).
- Other groups: glucocorticoids (GCS) and symptomatic agents (used in severe forms).
Briefly: answers to topical questions
What is the difference between first- and second-generation H1 antihistamines?
| Characteristic | First-generation drugs | Second-generation drugs |
|---|---|---|
| Sedative effect | Have a pronounced sedative effect | Do not cause a sedative effect |
| Selectivity | Low selectivity (also block M-cholinergic receptors and $\alpha$-adrenergic receptors) | High selectivity for $H_1$ receptors |
| BBB | Cross the blood-brain barrier | Practically do not cross the blood-brain barrier |
| Duration | Shorter duration of action | Characterized by a longer duration of action |
What side effects are characteristic of first-generation H1 antihistamines?
- M-anticholinergic action (action) — pronounced in first-generation drugs.
- Sedative effect (sedatio) — pronounced depressive effect on the central nervous system.
- Receptor blockade (blockade) — non-selective blockade of M-cholinergic receptors and $\alpha$-adrenergic receptors.
The pathogenesis of allergy can be remembered by the rule of three Ps: Primary contact (immunological stage and IgE synthesis), Pepeat contact (pathochemical stage and degranulation), Pathological tissue consequences (pathophysiological stage and bronchospasm).
Class and exam questions
Why do most allergens not cause an immune response on their own?
Most of them are haptens—low-molecular-weight substances. They acquire immunogenicity only after binding to the body's carrier proteins.
How does the "vicious circle" work in allergies?
During the reaction, interleukin-4 (IL-4) is released, which additionally stimulates B lymphocytes to synthesize new portions of IgE, thereby enhancing the immune response.
What is the difference between histamine and leukotrienes at the degranulation stage?
Histamine is already present in ready-made form in mast cell granules and is released immediately. Leukotrienes, on the other hand, are synthesized de novo (anew) during cell activation.
What is the role of phospholipase C in the pathophysiological stage of allergy?
When histamine binds to the H1 receptor, phospholipase C is activated. It hydrolyzes phosphatidylinositol into diacylglycerol and inositol trisphosphate, which leads to an increase in intracellular calcium and smooth muscle spasm.
What else to study on this topic
- The role of antigen-presenting cells (APCs) and the major histocompatibility complex (MHC) in sensitization.
- Intracellular signaling pathways during mast cell degranulation (the role of cGMP and calcium ions).
- The mechanism of phospholipase C activation and phosphatidylinositol hydrolysis upon H1 receptor stimulation.
- Differences between first- and second-generation antihistamines.
- The use of glucocorticoids in the treatment of severe allergic reactions (anaphylactic shock, asthma).
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