Abstract
Increased filaggrin expression was found to be correlated with severity scores in chronic spontaneous urticaria (CSU); however, the role of filaggrin breakdown products (FBPs) in CSU has not been studied. We collected stratum corneum (SC) specimens from the volar forearms of 10 CSU patients, 10 AD patients, and 10 healthy normal controls (NCs) and measured contents of FBPs (pyrrolidone carboxylic acid [PCA] and urocanic acid [UCA]) using UPLC-MS/MS, transepidermal water loss (TEWL) and epidermal pH. Compared to NCs, cis-UCA level was increased in CSU lesions (P < 0.05) and decreased in AD lesions (P < 0.01). The cis-to-trans-UCA ratio in SC specimens from CSU patients was significantly greater than those from AD and NC subjects. AD lesions had lower FBP and PCA contents compared to NC skin (both P < 0.001), and higher TEWL and pH compared to CSU lesions. Moreover, cis-UCA, but not trans-UCA, enhanced the IgE-mediated basophil activation, as well as IgE- and calcium-mediated degranulation of LAD-2 cells, in a dose-dependent manner. These findings suggest that increased cis-to-trans UCA ratio in the epidermis is a distinct feature of CSU, which could enhance mast cell degranulation. Modulation of cis-UCA may be a potential target for skin diseases associated with IgE-mediated mast cell degranulation.
Highlights
Chronic spontaneous urticaria (CSU) is defined as the repeated occurrence of transient wheals and/or angioedema for at least 6 weeks without an eliciting cause[1]
To verify our speculation that increased filaggrin expression leads to increased filaggrin breakdown products (FBPs) production, we measured the quantities of pyrrolidone carboxylic acid (PCA) and cis- and trans-urocanic acid (UCA) in tape-stripped skin specimens from patients with chronic spontaneous urticaria (CSU) and atopic dermatitis (AD), as well as in normal controls (NCs)
Cis-to-trans-UCA ratio was significantly higher in CSU skin than in both AD and NC skin
Summary
Chronic spontaneous urticaria (CSU) is defined as the repeated occurrence of transient (less than 24 hours) wheals and/or angioedema for at least 6 weeks without an eliciting cause[1]. In addition to the 45% of patients with autoimmune features, 55% of CSU patients have unidentified specific inducers for mast cell degranulation and associated inflammation[3]. Some clinical features (e.g., itching) and histological characteristics (e.g., infiltration of T lymphocytes, eosinophils, and mast cells into skin lesions) are shared between CSU and AD10, 11; eczema is the cutaneous manifestation of AD and transient wheals and/or angioedema are specific cutaneous manifestations in CSU. The filaggrin breakdown product (FBP), cis-urocanic acid (UCA) was found to enhance mast cell degranulation in a mouse model[12]. In the present study, we sought to compare the levels of FBPs, including pyrrolidone carboxylic acid (PCA) and the two isomers of UCA (cis- and trans-UCA), in skin from patients with CSU and AD in comparison to healthy normal controls (NCs). We attempted to outline the biologic roles of FBPs in the pathogenesis of CSU
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