PTGS2: A potential immune regulator and therapeutic target for chronic spontaneous urticaria.

AIMS: Chronic spontaneous urticaria (CSU) is a common and debilitating skin disease that is difficult to control with existing treatments, and the pathogenesis of CSU has not been fully revealed. The aim of this study was to explore the underlying mechanisms of CSU and identify potential treatments. MATERIALS AND METHODS: Microarray datasets of CSU were obtained from Gene Expression Omnibus database. Differentially expressed genes between skin lesions of CSU and normal controls (LNS-DEGs) were identified, and the enrichment analyses of LNS-DEGs were performed. Hub genes of LNS-DEGs were selected by protein-protein interaction analysis. The co-expression and transcriptional regulatory networks of hub genes were conducted using GeneMANIA and TRRUST database, respectively. CIBERSORT was utilized for immune cell infiltration analysis. Experimental validation was performed by ß-hexosaminidase release examination and passive cutaneous anaphylaxis (PCA) mouse model. KEY FINDINGS: A total of 247 LNS-DEGs were identified, which were enriched in cell migration, cell chemotaxis, and inflammatory pathways such as TNF and interleukin (IL) -17 signaling pathway. Among LNS-DEGs, seven upregulated (PTGS2, CCL2, IL1B, CXCL1, IL6, VCAM1, ICAM1) and one downregulated hub gene (PECAM1) were selected. Immune infiltration analysis identified eight different immune cells, such as activated/resting mast cells and neutrophils. Furthermore, PTGS2, encoding cyclooxygenase 2 (COX2), was selected for further validation. COX2 inhibitor, celecoxib, significantly inhibited mast cell degranulation, and reduced vascular permeability and inflammatory cytokine expression in PCA mouse model. SIGNIFICANCE: PTGS2 may be a potential regulator of immunity and inflammation in CSU. Targeting PTGS2 is a new perspective for CSU treatment.

Fisetin alleviates chronic urticaria by inhibiting mast cell activation via MRGPRX2.

OBJECTIVES: The activation of mast cell (MC) plays an important part in the pathogenesis of chronic urticaria (CU), and the expression of MRGPRX2 (Mas-related G-protein coupled receptor X2) and the circulating levels of SP (substance P) in skin MC of CU patients increased. Fisetin is a natural flavonoid with anti-inflammatory and antiallergic pharmacological effects. This study aimed to investigate the inhibitory effect of fisetin on CU via MRGPRX2 and its possible molecular mechanisms. METHODS: OVA/SP co-stimulated and SP-stimulated CU like murine models were used to evaluate the effect of fisetin on CU. MRGPRX2/HEK293 cells and LAD2 cells were used to perform the antagonism effect of fisetin on MC via MRGPRX2. KEY FINDINGS: The results indicated that fisetin prevented urticaria-like symptoms in murine CU models, and inhibited MCs activation by suppressing calcium mobilization and degranulation of cytokines and chemokines via binding to MRGPRX2. The bioinformatics analysis showed that fisetin might have an interaction relationship with Akt in CU. The western blotting experiments showed that fisetin downregulated the phosphorylation levels of Akt, P38, NF-κB, and PLCγ in C48/80 activated LAD2 cells. CONCLUSIONS: Fisetin alleviates CU progression by inhibiting mast cell activation via MRGPRX2, which may be a novel therapeutic candidate for CU.

Paeonol attenuates Substance P-induced urticaria by inhibiting Src kinase phosphorylation in mast cells.

BACKGROUND: Treatment of chronic urticaria is challenging, the discovery of effective therapeutic drugs is urgently in demand. PURPOSE: To study the effect and mechanism of Paeonol targeting mast cells and its therapeutic effect on chronic urticaria. STUDY DESIGN: We developed a chronic urticaria model in vivo and mast cell model in vitro examined the effect of Paeonol in the treatment of chronic urticaria and its mechanism of action in mast cells. METHOD: The anti-anaphylactoid effect of Paeonol was evaluated in PCA and systemic anaphylaxis models. The treatment role of Paeonol was studied in urticaria model. The release of cytokines and chemokines was measured using enzyme immunoassay kits. Western blot analysis was conducted to investigate phosphorylation of Src, PI3K, and PLC. In vitro kinase assays were conducted to investigate the kinase activity of Lyn, PLC, PI3K and Src. RESULTS: In our study, Paeonol was able to attenuate evans blue leakage, serum histamine and chemokine release in a passive skin allergic reaction model. Simultaneously, Paeonol inhibited vasodilation and mast cell degranulation in C57BL/6 mice. Further research found that Paeonol alleviated symptoms such as erythema and rash in the Substance P-induced urticaria model, this is accompanied by inhibiting the release of related inflammatory factors. Validation experiments on mast cells in vitro found that Paeonol inhibited the activation of Src-PI3K/Lyn-PLC-NF-κB signaling pathway by crosslinking with Src kinase. Moreover, calcium influx, mast cell degranulation, cytokines generation and chemotaxis were reduced in LAD2 cells. Molecular docking experiments revealed that Paeonol is a specific antagonist targeting Src kinase in the treatment of skin diseases such as urticaria. CONCLUSION: Paeonol, a herb-derived phenolic compound, can provide drug candidate for developing new drug in treatment of skin disease such as urticaria. SIGNIFICANCE STATEMENT: In this study, we primarily examined the effect of Paeonol in the treatment of chronic urticaria and its mechanism of action in mast cells. Interestingly, Paeonol was found to regulate Src kinase activity downstream of MRGPRX2 triggered signaling cascade in mast cells. Therefore, this plant-derived phenolic compound may provide a therapeutic option for the treatment of chronic urticaria.

Characteristics of immune response profile in patients with immediate allergic and autoimmune urticarial reactions induced by SARS-CoV-2 vaccines.

Severe allergic reactions following SARS-COV-2 vaccination are generally rare, but the reactions are increasingly reported. Some patients may develop prolonged urticarial reactions following SARS-COV-2 vaccination. Herein, we investigated the risk factors and immune mechanisms for patients with SARS-COV-2 vaccines-induced immediate allergy and chronic urticaria (CU). We prospectively recruited and analyzed 129 patients with SARS-COV-2 vaccine-induced immediate allergic and urticarial reactions as well as 115 SARS-COV-2 vaccines-tolerant individuals from multiple medical centers during 2021-2022. The clinical manifestations included acute urticaria, anaphylaxis, and delayed to chronic urticaria developed after SARS-COV-2 vaccinations. The serum levels of histamine, IL-2, IL-4, IL-6, IL-8, IL-17 A, TARC, and PARC were significantly elevated in allergic patients comparing to tolerant subjects (P-values = 4.5 × 10-5-0.039). Ex vivo basophil revealed that basophils from allergic patients could be significantly activated by SARS-COV-2 vaccine excipients (polyethylene glycol 2000 and polysorbate 80) or spike protein (P-values from 3.5 × 10-4 to 0.043). Further BAT study stimulated by patients' autoserum showed positive in 81.3% of patients with CU induced by SARS-COV-2 vaccination (P = 4.2 × 10-13), and the reactions could be attenuated by anti-IgE antibody. Autoantibodies screening also identified the significantly increased of IgE-anti-IL-24, IgG-anti-FcεRI, IgG-anti-thyroid peroxidase (TPO), and IgG-anti-thyroid-related proteins in SARS-COV-2 vaccines-induced CU patients comparing to SARS-COV-2 vaccines-tolerant controls (P-values = 4.6 × 10-10-0.048). Some patients with SARS-COV-2 vaccines-induced recalcitrant CU patients could be successfully treated with anti-IgE therapy. In conclusion, our results revealed that multiple vaccine components, inflammatory cytokines, and autoreactive IgG/IgE antibodies contribute to SARS-COV-2 vaccine-induced immediate allergic and autoimmune urticarial reactions.

Abnormalities in Gut Microbiota and Metabolism in Patients With Chronic Spontaneous Urticaria.

Background: Increasing evidence suggests that the gut microbiome plays a role in the pathogenesis of allergy and autoimmunity. The association between abnormalities in the gut microbiota and chronic spontaneous urticaria (CSU) remains largely undefined. Methods: Fecal samples were obtained from 39 patients with CSU and 40 healthy controls (HCs). 16S ribosomal RNA (rRNA) gene sequencing (39 patients with CSU and 40 HCs) and untargeted metabolomics (12 patients with CSU and 12 HCs) were performed to analyze the compositional and metabolic alterations of the gut microbiome in CSU patients and HCs. Results: The 16S rRNA gene sequencing results showed a significant difference in the ß-diversity of the gut microbiota, presented as the Jaccard distance, between CSU patients and HCs. No significant differences were found in the α-diversity of the gut microbiota between patients and HCs. At the phylum level, the major bacteria in the gut microbiome of patients with CSU were Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. At the genus level, Lactobacillus, Turicibacter, and Lachnobacterium were significantly increased and Phascolarctobacterium was decreased in patients with CSU. PICRUSt and correlation analysis indicated that Lactobacillus, Turicibacter, and Phascolarctobacterium were positively related to G protein-coupled receptors. Metabolomic analysis showed that α-mangostin and glycyrrhizic acid were upregulated and that 3-indolepropionic acid, xanthine, and isobutyric acid were downregulated in patients with CSU. Correlation analysis between the intestinal microbiota and metabolites suggested that there was a positive correlation between Lachnobacterium and α-mangostin. Conclusions: This study suggests that disturbances in the gut microbiome composition and metabolites and their crosstalk or interaction may participate in the pathogenesis of CSU.

The Expression of IL-17, in Chronic Spontaneous Urticaria Is Linked to Semaphorin5A.

Background: Patients with chronic spontaneous urticaria (CSU), an autoimmune disorder, show increased skin expression of IL-17A and can benefit from treatment with the anti-IL-17A biologic secukinumab. The mechanisms that drive IL-17A expression in CSU are currently unknown, but may involve Semaphorin5A (Sema5A). Objective: To explore the expression, role, and effects of Sema5A in CSU and its link to IL-17A. Material and Methods: We investigated patients with CSU and healthy controls for skin expression of expressing peripheral T cells. Results: Sema5A was highly expressed in the skin of CSU patients as compared to healthy control skin. Both CD4+ T cells and mast cells in CSU skin expressed Sema5A, and many of them expressed both Sema5A and IL-17A. Patients with CSU had significantly higher rates of IL-17A-expressing CD4+ T cells as compared to healthy controls. Incubation with Sema5A increased the rates of IL-17A-expressing CD4+ T cells in healthy controls to CSU levels. Conclusion: Sema5A may drive the expression and effects of IL-17A in CSU. Further studies in larger cohorts are needed to confirm the role of Sema5A in the pathogenesis of CSU and to explore its potential as a therapeutic target.

The efficacy of omalizumab treatment in chronic spontaneous urticaria is associated with basophil phenotypes.

BACKGROUND: The mechanisms underlying disease pathogenesis in chronic spontaneous urticaria (CSU) and improvement with omalizumab are incompletely understood. OBJECTIVES: This study sought to examine whether the rate of clinical remission is concordant with baseline basophil features or the rate of change of IgE-dependent functions of basophils and/or plasmacytoid dendritic cells during omalizumab therapy. METHODS: Adults (n = 18) with refractory CSU were treated with omalizumab 300 mg monthly for 90 days. Subjects recorded daily urticaria activity scores, and clinical assessments with blood sampling occurred at baseline and on days 1, 3, 6, 10, 20, 30, 60, and 90 following omalizumab. At baseline, subjects were categorized by basophil functional phenotypes, determined by in vitro histamine release (HR) responses to anti-IgE antibody, as CSU-responder (CSU-R) or CSU-non-responder (CSU-NR), as well as basopenic (B) or nonbasopenic (NB). RESULTS: CSU-R/NB subjects demonstrated the most rapid and complete symptom improvement. By day 6, CSU-R/NB and CSU-NR/NB had increased anti-IgE-mediated basophil HR relative to baseline, and these shifts did not correlate with symptom improvement. In contrast, CSU-NR/B basophil HR did not change during therapy. The kinetics of the decrease in surface IgE/FcεRI was similar in all 3 phenotypic groups and independent of the timing of the clinical response. Likewise, plasmacytoid dendritic cells' surface IgE/FcεRI decline and TLR9-induced IFN-α responses did not reflect clinical change. CONCLUSIONS: Changes in basophil IgE-based HR, surface IgE, or FcεRI bear no relationship to the kinetics in the change in clinical symptoms. Baseline basophil count and basophil functional phenotype, as determined by HR, may be predictive of responsiveness to omalizumab.

SELE Downregulation Suppresses Mast Cell Accumulation to Protect against Inflammatory Response in Chronic Idiopathic Urticaria.

BACKGROUND: Chronic idiopathic urticaria (CIU) represents a common skin disorder often characterized by mast cell activation and secretion of histamine and other proinflammatory factors. E-selectin (SELE) has been implicated in the pathogenesis of common inflammatory cutaneous disorders, while the role of SELE in CIU is yet to be fully understood. Thus, we aimed to investigate the mechanism by which SELE influences CIU in connection with the involvement of mast cells. METHODS: SELE expression was measured in blood samples obtained from CIU patients and normal individuals. A CIU mouse model was subsequently established by intradermally injecting a normal saline solution with ovalbumin IgE antiserum into the mice. Loss- and gain-of-function investigations were conducted on the mouse models. The number of degranulated mast cells and the amount of histamine release in vitro were determined. The levels of SELE, tumor necrosis factor (TNF)-α, homologous restriction factor (HRF), and interleukin (IL)-6 levels were determined. RESULTS: The CIU clinical samples exhibited upregulated SELE, while the CIU mice showed increased mast cell degranulation and an increased rate of histamine directional release, as well as an elevated expression of SELE, TNF-α, HRF, and IL-6. SELE silencing was found to decrease the number of degranulated mast cells and reduce the rate of histamine directional release, along with suppressed TNF-α, HRF, and IL-6 expression, in the serum of CIU mice. Ketotifen was observed to rescue the increased expression of TNF-α, HRF, and IL-6 caused by SELE overexpression. CONCLUSIONS: This study highlights the potential of SELE downregulation to repress inflammatory factor secretion caused by the accumulation of mast cells, which ultimately inhibits the development of CIU.

Mas-related G protein-coupled receptor X2 and its activators in dermatologic allergies.

The Mas-related G protein-coupled receptor X2 (MRGPRX2) is a multiligand receptor responding to various exogenous and endogenous stimuli. Being highly expressed on skin mast cells, MRGPRX2 triggers their degranulation and release of proinflammatory mediators, and it promotes multicellular signaling cascades, such as itch induction and transmission in sensory neurons. The expression of MRGPRX2 by skin mast cells and the levels of the MRGPRX2 agonists (eg, substance P, major basic protein, eosinophil peroxidase) are upregulated in the serum and/or skin of patients with inflammatory and pruritic skin diseases, such as chronic spontaneous urticaria or atopic dermatitis. Therefore, MRGPRX2 and its agonists might be potential biomarkers for the progression of cutaneous inflammatory diseases and the response to treatment. In addition, they may represent promising targets for prevention and treatment of signs and symptoms in patients with skin diseases or drug reactions. To assess this possibility, this review explores the role and relevance of MRGPRX2 and its activators in cutaneous inflammatory disorders and chronic pruritus.

Effects of omalizumab on basophils: Potential biomarkers in asthma and chronic spontaneous urticaria.

Omalizumab is an anti-IgE humanized monoclonal antibody approved for the treatment of severe asthma and chronic spontaneous urticaria. Omalizumab binds free serum IgE and antagonizes its interaction with FcεRI, which is considered the main pharmacodynamic mechanism responsible for the clinical response to the treatment. The reduction of IgE serum concentration down-regulates the cellular expression of FcεRI on basophils. However, the biological events occurring on basophils during the therapy with omalizumab are multiple and complex. Here we review the current evidence regarding the specific biological effects of omalizumab on basophils in patients with asthma and chronic spontaneous urticaria. In addition to the modulation of IgE receptors, omalizumab may affect basophils homeostasis, intra-cellular signaling, cellular responsiveness/activation and cytokine release. These effects may be partially responsible for the clinical success of omalizumab and potentially provide useful biological markers for future assessment of the clinical response to the treatment. However, further investigation is required to better elucidate the role of basophils during the treatment with omalizumab.

25-hydroxyvitamin D levels are low but not associated with disease activity in chronic spontaneous urticaria and depression.

AIM: To evaluate vitamin D levels in patients with chronic spontaneous urticaria (CSU), depression and both of them, thus to find out whether vitamin D may be a common causative factor of CSU and depression. METHODS: Thirty patients with CSU, 30 patients with depression, 30 patients with both CSU and depression and 30 healthy volunteers as control group were involved in the study. Serum 25-hydroxyvitamin D (25(OH)D) levels of these groups were measured and compared. Correlations between 25(OH)D levels and the activity of CSU and depression were analyzed. RESULTS: Healthy controls' 25(OH)D levels (17.2±8.8 ng/mL) were higher than patients with CSU (9.1±5.1 ng/mL), depression (8.9±6.1 ng/mL) and CSU with depression (7.7±4.7 ng/mL) (p<0.001, p<0.001 and p<0.001, respectively). There were no differences in 25(OH)D levels between CSU patients with and without depression, between depression patients and CSU patients with and without depression (p=0.43, p=0.82 and p=0.92, respectively). There were no correlations between 25(OH)D levels and the activity of CSU or depression (p=0.99 and p=0.76, respectively). CONCLUSION: Lower 25(OH)D levels in CSU and/or depression may appear as a secondary phenomenon, which means being result of these diseases rather than the cause (Tab. 1, Fig. 2, Ref. 41). Text in PDFwww.elis.sk Keywords: vitamin D, vitamin D deficiency, chronic urticaria, depression.

A case report of hypocomplementemic urticarial vasculitis presenting with membranoproliferative glomerulonephritis.

BACKGROUND: Hypocomplementemic urticarial vasculitis syndrome is an infrequent condition characterized by ocular, renal, gastrointestinal and pulmonary involvement with low serum complement levels and autoantibodies. Renal manifestations vary from microscopic hematuria to nephrotic syndrome and acute kidney injury. Accordingly differing histologic patterns have been reported. CASE PRESENTATION: We present the case of a 65 years old woman with a history of chronic uveitis who presented with arthralgias, urticarial rush, nephrotic syndrome, glomerular hematuria and low serum complement. Kidney biopsy revealed an immune-complex membranoproliferative glomerulonephritis. The patient received induction therapy with steroids, cyclophosphamide and hydroxychloroquine followed by rapid clinical improvement and remission of proteinuria. Maintenance treatment consisted of rituximab pulses. CONCLUSIONS: The majority of hypocomplementemic urticarial vasculitis syndrome cases is idiopathic, although an association to drugs, infections or other autoimmune disorders has been recorded. Given the rarity and heterogeneity of the disease, no standard treatment is established.

Vitamin D suppress the production of vascular endothelial growth factor in mast cell by inhibiting PI3K/Akt/p38 MAPK/HIF-1α pathway in chronic spontaneous urticaria.

Mast cells play a significant role in urticaria pathogenesis. It's evidenced that vitamin D has positive impact in chronic spontaneous urticaria (CSU) recently, but underlying mechanisms remain unclear. In this study, isobaric tag for relative and absolute quantification-liquid chromatography-mass spectrometer/mass spectrometer was used to detect the expression of proteins in sera of CSU patients and healthy subjects. Thirty-one differentially expressed proteins were identified, in which vitamin D binding protein (VDBP) was higher in CSU patients than that in healthy subjects after verification. Our results indicated that sera of CSU patients induced the production of vascular endothelial growth factor (VEGF) in mast cells through PI3K/Akt/p38 MAPK/HIF-1α axis in an IgE-depended way, and 25(OH)D3 suppressed the expression of VEGF by inhibiting this signaling pathway axis in this process. Collectively, these results suggest VDBP to be a potential biomarker and propose a potential mechanism of benefit for vitamin D therapy in CSU.

MicroRNA-194 reduces inflammatory response and human dermal microvascular endothelial cells permeability through suppression of TGF-ß/SMAD pathway by inhibiting THBS1 in chronic idiopathic urticaria.

Chronic idiopathic urticaria (CIU) is a polyetiological dermatologic disease. Reports have stated that some microRNAs (miRNAs) have their roles to play in inflammatory response. In this present study, we aim to investigate whether miR-194 has an effect on attenuating inflammatory response and human dermal microvascular endothelial cells (HDMECs) permeability of CIU mast cells through TGF-ß/SMAD pathway by binding to thrombospondin 1 (THBS1). The Gene Expression Omnibus database was used to obtain the CIU-related microarray data, and then the analysis of differentially expressed genes was conducted and the miRNA regulated by THBS1 was predicted. After transfection of different mimic, inhibitor, or small interfering RNA, the effect of miR-194 on inflammatory reaction, mast cell degranulation, histamine release rate, HDMECs permeability, and the expression of THBS1, interferon γ (IFN-γ), TGF-ß, Smad3, and interleukin 4 (IL-4) were detected. THBS1 was verified to be the miR-194 target. After transfected with overexpressed miR-194 and si-THBS1, the degranulation rate, histamine release rate, and HDMECs permeability were significantly reduced, while the expression of IFN-γ was higher, and the expression of THBS1, TGF-ß, Smad3, IL-4 was significantly lower, accompanied with alleviated inflammatory reaction. Our study provides evidence that miR-194 negatively modulates THBS1 and inhibits the activation of TGF-ß/SMAD pathway, thereby alleviating the inflammatory response and HDMECs permeability of mast cells in CIU.

Somatic Mosaic NLRP3 Mutations and Inflammasome Activation in Late-Onset Chronic Urticaria.

Chronic urticaria is a common skin disorder with heterogeneous causes. In the absence of physical triggers, chronic urticarial rash is called idiopathic or spontaneous. The objective of this study was to identify the molecular and cellular bases of a disease condition displayed by two unrelated patients aged over 60 years who presented for two decades with a chronic urticaria resistant to standard therapy that occurred in the context of systemic inflammation not triggered by cold. In both patients, a targeted sequencing approach using a next generation technology identified somatic mosaic mutations in NLRP3, a gene encoding a key inflammasome component. The study of several of both patients' cell types showed that, despite the late onset of the disease, NLRP3 mutations were not found to be restricted to myelomonocytic cells. Rather, the data obtained strongly suggested that the mutational event occurred very early, during embryonic development. As shown by functional studies, the identified mutations-an in-frame deletion and a recurrent NLRP3 missense mutation-have a gain-of-function effect on NLRP3-inflammasome activation. Consistently, a complete remission was obtained in both patients with anti-IL-1 receptor antagonists. This study unveils that in late-onset chronic urticaria, the search for autoinflammatory markers and somatic mosaic NLRP3 mutations may have important diagnostic and therapeutic consequences.

The expression of serotonin transporter protein in the skin of patients with chronic spontaneous urticaria and its relation with depression and anxiety.

Studies have indicated a possible role for serotonin transporter protein (SERT) in the pathophysiology of inflammatory skin disorders. This study was aimed to determine the expression of SERT in the skin of patients with chronic spontaneous urticaria (CSU) and its relation to depression and anxiety. In this case-control study, 30 CSU patients and 30 healthy controls were evaluated with skin biopsies to evaluate the expression of the SERT protein based on histopathologic findings. Beck depression and anxiety inventories were used to investigate depression and anxiety in the case group. Data were analyzed by SPSS software. P values < 0.05 were considered significant. The case group showed significantly higher percentage of stained cells (P < 0.0001) and intensity of SERT expression (P < 0.0001) compared with the control group. The patients with uncontrolled CSU showed significantly higher percentage (P < 0.002) and intensity (P < 0.006) of SERT expression, compared with those with controlled CSU. The intensity of SERT expression in CSU patients had no significant correlation with the severity of depression, but was significantly correlated with the severity of anxiety (r = 0.555; P = 0.001). The percentage of stained cells was significantly correlated with the severities of depression (r = - 0.433; P = 0.017) and anxiety (r = 0.528; P = 0.003). The SERT expression in patients with CSU was higher compared with controls, which can demonstrate the role of serotonin in the pathogenesis of this disease. This higher SERT expression is correlated with the severity of the disease.

Biomarkers and clinical characteristics of autoimmune chronic spontaneous urticaria: Results of the PURIST Study.

BACKGROUND: Autoimmune chronic spontaneous urticaria (aiCSU) is an important subtype of chronic spontaneous urticaria (CSU) in which functional IgG autoantibodies to IgE or its high-affinity receptor (FcεRI) induces mast cell degranulation and subsequent symptom development. However, it has not been tightly characterized. This study aimed to better define the clinical and immunological features and to explore potential biomarkers of aiCSU. METHODS: This was a multinational, multicenter study of 182 CSU patients. The clinical features studied included: urticaria activity and impact (UAS7 and quality of life); autologous serum skin test (ASST); IgG anti-FcεRI and IgG anti-IgE; IgG-anti-thyroperoxidase (IgG anti-TPO); total serum IgE; and basophil reactivity (BASO) using the basophil activation test (BAT) and basophil histamine release assay (BHRA). RESULTS: Of the 182 patients, 107 (59%) were ASST+, 46 (25%) were BASO+, and 105 (58%) were IgG anti-FcεRI+/IgE+. Fifteen patients (8%) fulfilled all three criteria of aiCSU. aiCSU patients appeared more severe (UAS7 21 vs 9 P < 0.016) but showed no other clinical or demographic differences from non-aiCSU patients. aiCSU patients also had markedly lower total IgE levels (P < 0.0001) and higher IgG anti-TPO levels (P < 0.001). Of biomarkers, positive BAT and BHRA tests were 69% and 88% predictive of aiCSU, respectively. CONCLUSIONS: aiCSU is a relatively small but immunologically distinct subtype of CSU that cannot be identified by routine clinical parameters. Inclusion of BHRA or BAT in the diagnostic workup of CSU patients may aid identification of aiCSU patients, who may have a different prognosis and benefit from specific management.

Relevance of the Basophil High-Affinity IgE Receptor in Chronic Urticaria: Clinical Experience from a Tertiary Care Institution.

BACKGROUND: The high-affinity IgE receptor (FcεRI) expression on effector cells has been poorly characterized in patients with chronic urticaria (CU) to date. OBJECTIVES: To investigate the FcεRI expression on blood basophils in a large cohort of patients with CU and its potential relationship with relevant features of the disease. METHODS: Basophil FcεRI expression was measured by flow cytometry in 287 patients with CU (192 with chronic spontaneous urticaria and 95 with chronic inducible urticaria) at their initial evaluation in our department. A control group of healthy nonatopic individuals was included to provide reference data, and the effect of antihistamine and anti-IgE therapy on the basophil FcεRI expression was also evaluated in a cohort of patients with CU. RESULTS: The median FcεRI expression was found significantly higher in patients with CU compared with healthy controls (P < .0001). A positive correlation was found between serum IgE levels and basophil FcεRI expression (R = 0.422; P < .001). Significantly higher FcεRI levels on basophils were detected in patients with CU who presented with concomitant atopic features (P = .003), negative autologous serum skin test (P = .002), negative autologous plasma skin test (P = .009), or undetected levels of antithyroid antibodies (P = 0.01). Baseline FcεRI expression was not related to the activity and duration of the disease, and was not significantly modified during antihistamine therapy; however, it correlated with the clinical response to omalizumab (P = .003). CONCLUSIONS: Although further multicenter studies are needed to corroborate these findings, the assessment of basophil FcεRI levels might be relevant in daily clinical practice supporting an autoimmune pathogenesis and predicting response to anti-IgE treatment.