Autoimmune Theories of Chronic Spontaneous Urticaria

Abstract

Urticaria (hives) is a highly prevalent skin disorder that can occur with or without associated angioedema. Chronic spontaneous urticaria (CSU) is a condition which persists for more than 6 weeks in duration and occurs in the absence of an identifiable provoking factor. CSU results from pathogenic activation of mast cells and basophils, which gives rise to the release of proinflammatory mediators that support the generation of urticaria. Several theories have been put forth regarding the pathogenesis of CSU with much evidence pointing toward a potential autoimmune etiology in up to 50% of patients with this condition. In this review, we highlight the evidence surrounding the autoimmune pathogenesis of chronic urticaria including recent data which suggests that CSU may involve contributions from both immunoglobin G (IgG)-specific and immunoglobulin E (IgE)-specific autoantibodies against a vast array of antigens that can span beyond those found on the surface of mast cells and basophils.

Keywords: anti-FcεR1; anti-IgE; anti-TPO; autoallergy; autoimmune urticaria; chronic idiopathic urticaria; chronic spontaneous urticaria.

Figure 1

Diagnostic workup of chronic urticaria.

Figure 2

Model of the mechanisms underlying chronic urticaria. Pathologic activation of mast cells and basophils in patients with chronic spontaneous urticaria is thought to occur via two major mechanisms: intracellular signaling defects and autoimmune mechanisms. In the former, inappropriate activation of molecules such a spleen tyrosine kinase (SYK) or inhibition of negative regulators including the Src homology 2 (SH2)-containing inositol phosphatases (SHIP) promotes spontaneous degranulation of mast cells/basophils with subsequent release of histamine and other protein and lipid mediators. The more commonly accepted theory of pathogenesis in CSU includes antibody-mediated mast cell and basophil activation, which can occur via IgG- or IgE- mediated pathways. In the former, IgG molecules directed against the Fc portion of IgE or the FcεR1 promote spontaneous cellular degranulation. In patients with autoallergy, crosslinking of Fc epsilon R1 (FcεR1) via autoreactive IgE molecules directed against self-antigens such as thyroid peroxidase (TPO) promote mast cell/basophil degranulation.