Pathogenesis and clinical picture of urticaria

Pathogenesis: from allergy to autoimmunity

The mechanisms of development of acute and chronic urticaria differ fundamentally, despite a similar final result—mast cell activation.

Acute urticaria is based on a classical immediate-type allergic reaction (type I hypersensitivity). The process begins with sensitization: in predisposed individuals, Th2 lymphocytes are activated and release interleukins (IL-4, IL-13). These cytokines prompt B lymphocytes to synthesize specific immunoglobulins E (IgE), which then bind to high-affinity mast cell receptors. Upon re-exposure, the allergen binds to these fixed IgE, provoking degranulation.

Chronic urticaria is based predominantly on autoimmune reactions. The classical IgE-dependent mechanism is unlikely here. The body produces stimulating autoantibodies of two types:

• To the $\alpha$-subunit of the IgE receptor (anti-$Fc\varepsilon RI\alpha$) — most common.
• To the IgE molecules themselves (anti-IgE antibodies) — a rarer variant.

In the chronic form, a mixed immune response is noted with the participation of Th1 and Th2 lymphocytes, which is confirmed by elevated levels of IL-4, IL-5, and interferon-$\gamma$ (IFN-$\gamma$). In addition, specific stimulation by autoantibodies to thyroid peroxidase (IgE-anti-TPO) may be detected, indicating a connection between the disease and autoimmune thyroid pathology.

Universal cascade and the role of mediators

Regardless of the trigger (exogenous allergen or own autoantibodies), a unified biochemical mechanism of degranulation is triggered inside the mast cell. $Fc\varepsilon RI$ receptors are located on the cell membrane. Their activation leads to the phosphorylation of tyrosine residues in the $\beta$- and $\gamma$-chains of the receptor. This causes the formation and activation of tyrosine kinase, which triggers exocytosis. Preformed mediators are released from the granules: histamine, heparin, and tryptase.

Mast cells are capable of more than just classical degranulation. They can secrete vasoactive molecules (TNF$\alpha$, IL-6, platelet-activating factor) without destroying the granules themselves.

Histamine acts as the key mediator of the immediate phase. It has a direct effect on blood vessels and stimulates nerve endings, which causes an additional release of neuropeptides (substance P, endorphins). Clinically, this massive release of mediators manifests as local edema, hyperemia, intense itching, and a burning sensation.

Interaction of systems and inflammation progression

The pathogenesis of urticaria is not limited to mast cells alone. Plasma cascades are actively involved in the process:

• The hemostasis system is activated. The resulting thrombin increases endothelial permeability and promotes the formation of complement component C5a.
• C5a (anaphylatoxin) performs a dual role: it acts as a chemoattractant for neutrophils and eosinophils, and additionally activates mast cells, closing the vicious circle of inflammation.

The immediate reaction turns into a complex cascade. Adhesion molecules, chemokines, and cytokines attract new immune cells to the focus. Newly arrived cells (initially CD4+ lymphocytes, eosinophils, and an hour later predominantly neutrophils) release their mediators, leading to an intensified inflammatory response.

Histologically, pronounced dermal edema, capillary dilation, and the formation of a perivascular non-necrotizing infiltrate are observed in the affected area. It is important to note that even in visually healthy skin areas, a minimal level of inflammation persists, which lowers the threshold of cell sensitivity to new triggers.

Clinical presentation

The main morphological element of urticaria is the wheal (urtica). This is a dense, skin-elevated area with a pale center, surrounded by a zone of erythema. Eruptions appear suddenly, tending to coalesce and migrate. Patients experience severe itching (pruritus) and burning.

A pathognomonic sign of urticaria is the rapid (from 1 to 24 hours) and completely scar-free resolution of the rash elements. In children with a mild course, the general condition is little affected: activity is preserved, and sleep is not disturbed.

Angioedema may accompany urticaria. Unlike a wheal, it affects deeper layers (deep dermis and subcutaneous adipose tissue), as well as mucous membranes. Subjectively, angioedema is dominated by pain rather than itching, and it resolves significantly slower—from 24 to 72 hours.

A specific form is cholinergic urticaria. It is characterized by very small urticarial elements (less than 5 mm in diameter). The trigger is an increase in body temperature (active during physical exertion or passive when taking a hot shower), and the rash appears a few minutes after exposure.

Class and exam questions

What else to study on this topic

• Detailed analysis of the biochemical cascade of tyrosine kinase activation
• The spectrum of cytokines and eicosanoids secreted by the mast cell
• Interaction of the coagulation cascade and the complement system in inflammation
• Dynamics of the cellular composition of the dermal infiltrate over time

Other topics in "Chapter 5. Allergic Diseases"

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.