What is the pathogenesis of chronic urticaria?

Updated: Jul 31, 2018
  • Author: Marla N Diakow, MD; Chief Editor: William D James, MD  more...
  • Print

The mast cell is the primary agent in the pathogenesis of urticaria. Dermal mast cell stimulation results in the release of both preformed (histamine) and newly formed (prostaglandin) mediators, as well as cytokines (interleukin [IL]–1, tumor necrosis factor-α [TNF-α]) from cytoplasmic granules, which cause wheal formation, vasodilatation, and erythema. Mast cells also release chemoattractants for other cells (eg, neutrophils) involved in wheal formation. A complex interplay of varied proinflammarory cytokines, chemokines, and adhesion molecules that regulate vasoactivity and the dynamics of cellular infiltration ultimately evolves to form a lymphocyte- and granulocyte-mediated hypersensitivity reaction in the skin.

This response may be augmented by complement activation and production of C5a. Unlike pulmonary mast cells, cutaneous mast cells have C5a receptors. C5a not only brings about mast cell activation, but is also a neutrophil and eosinophil chemoattractant, leading to accumulation of these cells in lesional skin.

Further, on a molecular level, it has been shown that there is an increased cis-to-trans urocanic acid ratio in the epidermis of patients with chronic urticaria, which is postulated to enhance mast cell degranulation. [8]

The complex nature of the pathogenesis of urticaria beyond the release of histamine from dermal mast cells may explain why antihistamines alone are not always effective therapy. The signals that activate mast cells in urticaria are ill-defined and varied. A number of triggers can result in degranulation of mast cells and initiation of the cascade that results in urticaria formation.

An autoimmune origin is one hypothesis for mast cell activation. IgE- and IgG-dependent mechanisms include autoantibodies encompassing either IgG autoantibodies to the alpha subunit of the Fc receptor of the IgE molecule (35-40% of patients with chronic urticaria)—that is, anti-FcεR—or, less commonly, anti-IgE autoantibodies (5-10% of patients with chronic urticaria), both of which can activate mast cells or basophils to release histamine. [9] A positive functional anti-FcεR test result does not indicate which autoantibody (anti-IgE, anti-FcεRI, or anti-FcεRII) is present, but it does support an autoimmune basis. Affected patients may be categorized as having autoimmune chronic urticaria.

Mast cells may also be degranulated through an IgE- and IgG-independent mechanism in chronic urticaria. [10] Non–IgE-mediated mast cell degranulators include radiocontrast media, morphine, codeine, and vancomycin. Approximately one third of patients with chronic urticaria may develop angioedema after administration of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). [11]

About 85% of the histamine receptors in the skin are H1 receptors, with the remaining 15% being H2 receptors. The addition of an H2-receptor antagonist to an H1-receptor antagonist augments the inhibition of a histamine-induced wheal-and-flare reaction once histamine-receptor blockade has been maximized. The combination of H2-receptor antagonists with an H1-receptor antagonist provides small additional benefit. Doxepin blocks both receptor types and is a much more potent inhibitor of H1 receptors than diphenhydramine or hydroxyzine.

Did this answer your question?
Additional feedback? (Optional)
Thank you for your feedback!