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Chronic spontaneous urticaria (CSU) is a typical example of an intractable skin disease with no clear cause and significantly affects daily life of patients. Because CSU is a human-specific disease and lacks proper animal model, there are many questions regarding its pathophysiological dynamics. On the other hand, most clinical symptoms of urticaria are notable as dynamic appearance of skin eruptions called wheals. In this study, we explored dynamics of wheal by dividing it into three phases using a mathematical model: onset, development, and disappearance. Our results suggest that CSU onset is critically associated with endovascular dynamics triggered by basophils positive feedback. In contrast, the development phase is regulated by mast cell dynamics via vascular gap formation. We also suggest a disappearance mechanism of skin eruptions in CSU through an extension of the mathematical model using qualitative and quantitative comparisons of wheal expansion data of real patients with urticaria. Our results suggest that the wheal dynamics of the three phases and CSU development are hierarchically related to endovascular and extravascular pathophysiological networks., Competing Interests: Declarations Code availability Numerical code is made available online on GitHub (https://github.com/seirin-lee/urticaria-code) and all other data are available from the corresponding author (SSL) on reasonable request. Conflict of interest The authors declare no Conflict of interest., (© 2024. The Author(s).)

Chronic spontaneous urticaria (CSU) is a common skin disorder characterized by an almost daily recurrence of wheal and flare with itch for more than 6 weeks, in association with the release of stored inflammatory mediators, such as histamine, from skin mast cells and/or peripheral basophils. The involvement of the extrinsic coagulation cascade triggered by tissue factor (TF) and complement factors, such as C3a and C5a, has been implied in the pathogenesis of CSU. However, it has been unclear how the TF-triggered coagulation pathway and complement factors induce the activation of skin mast cells and peripheral basophils in patients with CSU. In this review, we focus on the role of vascular endothelial cells, leukocytes, extrinsic coagulation factors and complement components on TF-induced activation of skin mast cells and peripheral basophils followed by the edema formation clinically recognized as urticaria. These findings suggest that medications targeting activated coagulation factors and/or complement components may represent new and effective treatments for patients with severe and refractory CSU.

MGL_1304, a major allergen in human sweat for patients with atopic dermatitis and/or cholinergic urticaria, is secreted from Malassezia globosa on human skin. The amounts of MGL_1304 and IgE against MGL_1304 are evaluated by the histamine release test using basophils or mast cells sensitized with serum containing IgE against MGL_1304, and enzyme linked sorbent assay (ELISA) using MGL_1304 and anti-MGL_1304 antibodies. Here, we identified a human monoclonal IgE (ABS-IgE) that binds to the high affinity IgE receptor (FcεRI) and MGL_1304 with high affinity (KD = 1.99 nM) but does not release histamine from basophils and mast cells. An ELISA using ABS-IgE as a standard IgE revealed that the amount of IgE against MGL_1304 (1000 U/ml) in the standard sera of patients with AD, employed in our previous report, is 32 ng/ml. A sandwich ELISA using ABS-IgE as a detection antibody showed approximately 10 times lower detection limit for MGL_1304 than ELISA in which MGL_1304 is directly bound to an ELISA plate. Moreover, ABS-IgE prevented histamine release from mast cells and basophils by neutralizing MGL_1304 not only in a free form in solution, but also on FcεRI expressed on the cell surface without cell activation. ABS-IgE may be used both to quantify the amount of MGL_1304 and anti-MGL_1304 IgE, and possibly for the treatment of diseases caused/aggravated by type I allergy to MGL_1304., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The pathogenesis of chronic spontaneous urticaria (CU) has recently been conceived to be associated with thrombin generation through the extrinsic coagulation pathway. However, little is known about the components of the intrinsic coagulation pathway potentially involved. Methods: To investigate the whole process of coagulation, both classical coagulation assays and a global coagulation test, the intrinsic coagulation pathway-dependent activated partial thromboplastin time (APTT) clot waveform analysis, were performed using plasma of 36 patients with CU who had various severities. Results: Classical coagulation assays revealed that levels of fibrinogen, D-dimer, and fibrin and fibrinogen degradation products (FDP), and positive rates of soluble fibrin monomer complex (SFMC) were significantly elevated in patients with CU, whereas the elevation of prothrombin fragment 1 + 2 was not statistically significant. On the other hand, all parameters of a global coagulation test, APTT clot waveform analysis, evidently showed a hypercoagulable pattern and were significantly correlated to disease severity of CU. Conclusions: CU is characterized by elevated blood coagulation potential with involvement of the intrinsic coagulation factors, which may contribute in vivo to the generation of fibrin even by small amounts of thrombin. [ABSTRACT FROM AUTHOR]