Pathogenesis Of Chronic Spontaneous Urticaria Research Articles

Chronic Spontaneous Urticaria: An Etiopathogenic Study.

Importance:Exact etiopathogenesis of chronic spontaneous urticaria (CSU) remains elusive. Infections, pseudoallergens, autoimmunity, and contact sensitization are various postulated factors. Few studies are available measuring cytokine levels in CSU.Objectives:The aim was to study various etiological factors of CSU and levels of IL-6 and IFN-ϒ in cases and controls, and correlation between various etiologies with the levels of the abovementioned interleukins in the cases.Design:Case-control study performed over 2 years with no follow-up of the participants.Setting:It was a referral-center-based study.Participants:Sixty patients of CSU and equal age and sex-matched healthy controls were recruited on the basis of convenience sampling.Exposures:Biochemical and hematological investigations with hepatitis serology, thyroid function tests, anti-thyroid antibodies, and levels IL-6 and IFN-ϒ were performed in all cases and controls. All cases were subjected to ASST. Cases with all above negative tests were patch-tested with Indian standard series. Urticaria activity score (UAS7) was calculated for all the cases and repeated in patients with positive etiological factor after 3 weeks (improvement after allergen or drug avoidance, treatment of infection).Outcomes:To study the various etiological factors (food, infection, autoimmunity, autoreactivity, and contact sensitization) and the levels of IL-6 and IFN- γ in patients of chronic spontaneous urticaria.Results:Etiology was ascertained in 75% of patients (autoimmunity: 50%, contact sensitization: 21.67%, food and drug allergy: 1.67% each). Mean values of the interleukins and anti-thyroid antibodies were significantly higher in cases versus controls. Levels of IFN-ϒ were significantly elevated in patients with higher UAS7 scores.Conclusion:Antithyroid antibodies, ASST, and patch testing are important tools and should be considered in patients of CSU after a thorough history and history-based workup. Elevated levels of IL-6 and IFN- ϒ in cases suggest that both Th1 and Th2 type of immune responses are implicated in pathogenesis of CSU.

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

BackgroundIncreasing 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.MethodsFecal 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.ResultsThe 16S rRNA gene sequencing results showed a significant difference in the β-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.ConclusionsThis study suggests that disturbances in the gut microbiome composition and metabolites and their crosstalk or interaction may participate in the pathogenesis of CSU.

Serum Leptin in correlation to clinical severity in patients with chronic urticaria

Abstract Background Chronic urticaria (CU) is a complex disease associated with a systemic inflammatory response. This inflammation could be related to the release of adipokines with proinflammatory properties such as leptin. In recent years, leptin has been associated with different diseases, wound healing and immune cell activation. Objective to evaluate leptin levels in patients with chronic spontaneous urticaria, to investigate the possible role of leptin in chronic spontaneous urticaria pathogenesis and to outline relationships between serum leptin and urticaria severity. Methods A case-control study was conducted at the allergy and immunology outpatient clinic at Ain Shams University hospital, and included 60 patients with chronic spontaneous urticaria and 30 healthy individuals who were group matched with cases for age and sex serving as the control group. All the patients were subjected to the following: Full history, clinical examination, calculation of body mass index (BMI), CBC, ESR, CRP, Thyroid profile, AST, ALT, Skin prick test or Specific IgE for common allergens, and measurement of serum leptin level after overnight fasting by ELISA. Results The present study showed that patients with chronic spontaneous urticaria had higher level of serum leptin in comparison to control subjects and there was a positive correlation between leptin level and urticaria severity which was assessed by urticaria activity score. Conclusion serum leptin is increased in chronic spontaneous urticaria and it is positively correlated to urticaria severity.

The Role of Coagulation and Complement Factors for Mast Cell Activation in the Pathogenesis of Chronic Spontaneous Urticaria.

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.

Variations of Thiol-Disulfide Homeostasis Parameters after Treatment with H1-Antihistamines in Patients with Chronic Spontaneous Urticaria.

Background. The pathogenesis of chronic spontaneous urticaria involves metabolic, immunological, and psychological factors. The thiol–disulfide exchange reactions could be a mechanism to counteract oxidative stress in patients with chronic spontaneous urticaria. Objective: The assessment of thiol–disulfide homeostasis parameters (TDHPs) according to disease severity and the influence of H1-antihistamine therapy in patients with chronic spontaneous urticaria. Material and method. We have included 30 patients with chronic spontaneous urticaria in the study and we have determined the levels of native thiol, total thiol, disulfides as well as the disulfide/native thiol ratio, disulfide/total thiol ratio and the native thiol/total thiol ratio, before and after therapy with H1-antihistamines. Results. The results of the study showed altered levels of TDHPs and their normalization after treatment with H1-antihistamines in patients with chronic spontaneous urticaria. We determined a statistically significant increase in the serum levels of total thiol, native thiol, and native thiol/total thiol ratio and a significant reduction in the levels of disulfides, disulfide/native thiol ratio and disulfide/total thiol ratio after treatment with H1-antihistamines. The normalization of the serum levels of TDHPs has been associated with the relief of symptoms and reduction or resolution of pruritus and urticarial plaques. Conclusion. These results suggest the involvement of thiol–disulfide homeostasis in the defense against the harmful effects of reactive oxygen species in patients with chronic spontaneous urticaria and the potential role of TDHPs in monitoring H1-antihistamine therapy. To the best of our knowledge, this is the first study investigating TDHPs in patients with chronic spontaneous urticaria before and after treatment.

Systemic and local evidence for complement involvement in chronic spontaneous urticaria.

BackgroundThe pathogenesis of chronic spontaneous urticaria (CSU), including the mechanism of action of omalizumab, remain unclear. We hypothesized complement system involvement given the often fast clinical response induced by treatment, including omalizumab. Therefore, we assessed the role of various complement factors surrounding omalizumab treatment.MethodsThirty CSU patients (median age 42 [range 21–70]; 73 % female) with a median once daily Urticaria Activity Score over 7 days (UAS7) score at baseline of 31.5 points were enrolled. Treatment consisted of six administrations of 300 mg omalizumab every 4 weeks succeeded by a follow‐up period of 12 weeks. Four punch skin biopsies were taken per patient; at baseline from lesional skin, at baseline from nonlesional skin, and after 1 and 7 days from formerly lesional skin. Complement activity, including C1q, C3, C3bc/C3, C4, C4bc/C4, C5a, and Membrane Attack Complex in peripheral blood were analyzed and complement activation in the skin was determined by the analysis of C4d deposition. Results were related to the clinical response to omalizumab.ResultsFifteen patients showed a UAS7 score of 6 or lower (median 0) at Week 24, 15 patients did not (median 16). Lesional skin biopsies at baseline revealed complement deposition (C4d) in blood vessels in the papillary dermis of 53% (16/30) of the patients, which suggests involvement of immune complexes in the pathogenesis of urticaria. Moreover, indication of increased complement activation in CSU was substantiated by increased C5a levels in peripheral blood compared to healthy controls (p = 0.010). The clinical effect of omalizumab could not be linked to the variation of complement components.ConclusionsBoth C4d deposition in lesional skin and elevated C5a levels in peripheral blood indicate the involvement of complement activation in the pathogenesis of CSU. No correlation was found between omalizumab and activation of complement indicative of independent processes in the immunopathogenesis of CSU.

Low frequency of CD4+CD25highFOXP3+ T regulatory cells in Egyptian patients with chronic spontaneous urticaria

Chronic urticaria is a prevalent disabling dermatological disease. About 90%, are considered idiopathic and referred to as chronic spontaneous urticaria (CSU), and nearly half of them are likely to have autoimmune mechanisms. Regulatory T cells play a substantial role to prevent autoimmune diseases. Subsets of Tregs expressing the CD4+CD25high and forkhead-box-P3 (FOXP3) transcription factor, crucial for their development and function, are best characterized in maintenance of self-tolerance. The objective of this study was the analysis of peripheral CD4+CD25highFOXP3+(T regs) frequency in chronic spontaneous urticaria; and its possible association with autologous serum skin test (ASST). Fifty chronic spontaneous urticaria patients (25 with positive ASST and 25 with negative ASST) and 20 healthy controls were enrolled in this study. The frequency of CD4+CD25highFOXP3+ (T regs) was analyzed by flow cytometry. A Significant decrease in peripheral blood CD4+CD25highFOXP3+ T regs% was detected in CSU patients in comparison to healthy individuals (median [IQR], 1.47% [0.71-3.12] vs 1.79% [1.15-4.00]; P = 0.05). When ASST positive patients were compared with ASST negative patients, no significant difference was found in percentage of T regs, (P=0.112). In conclusion our data provided further insights into CSU pathogenesis. Reduced frequency of CD4+CD25highFOXP3+(Tregs) in patients with urticaria, support the notion that CSU is an immune mediated disease and may help researchers to develop a novel immunotherapy strategy.

Gut Microbiome Alterations and Functional Prediction in Chronic Spontaneous Urticaria Patients.

The effects of the gut microbiome on both allergy and autoimmunity in dermatological diseases have been indicated in several recent studies. Chronic spontaneous urticaria (CSU) is a disease involving allergy and autoimmunity, and there is no report detailing the role of microbiota alterations in its development. This study was performed to identify the fecal microbial composition of CSU patients and investigate the different compositions and potential genetic functions on the fecal microbiota between CSU patients and normal controls. The gut microbiota of CSU patients and healthy individuals were obtained by 16s rRNA massive sequencing. Gut microbiota diversity and composition were compared, and bioinformatics analysis of the differences was performed. The gut microbiota composition results showed that Firmicutes, Bacteroidetes, Proteobacteria, and Verrucomicrobia were dominant microbiota in CSU patients. The differential analysis showed that relative abundance of the Proteobacteria (p = 0.03), Bacilli (p = 0.04), Enterobacterales (p = 0.03), Enterobacteriaceae (p = 0.03) was significantly increased in CSU patients. In contrast, the relative abundance of Megamonas, Megasphaera, and Dialister (all p < 0.05) in these patients significantly decreased compared with healthy controls. The different microbiological compositions impacted normal gastrointestinal functions based on function prediction, resulting in abnormal pathways, including transport and metabolism. We found CSU patients exhibited gut microbiota dysbiosis compared with healthy controls. Our results indicated CSU is associated with gut microbiota dysbiosis and pointed out that the bacterial taxa increased in CSU patients, which might be involved in the pathogenesis of CSU. These results provided clues for future microbial-based therapies on CSU.

Lower IgA Levels in Chronic Spontaneous Urticaria Are Associated With Lower IgE Levels and Autoimmunity.

BackgroundThe pathogenesis of chronic spontaneous urticaria (CSU) is still insufficiently understood. Recent findings suggest that immunoglobulins, in particular IgE but also IgA, play a role in the development of CSU.ObjectiveOur aim was to assess differences in clinical and laboratory markers between CSU patients with and without lower levels of serum IgA and IgE.MethodsWe analyzed the data of 606 patients with CSU by dividing them into four groups based on their IgA and IgE levels. The groups were compared for their spectrum of symptoms, disease activity, concomitant autoimmunity and routine laboratory markers. Autoreactivity was assessed by basophil activation test (BAT). Moreover, IgE-anti-thyroid peroxidase (TPO) was measured.ResultsOf the patients with lower IgE levels, 66.5% also had lower IgA levels (r=0.316, p<0.001). Patients with lower IgA and lower IgE levels showed a higher prevalence of recurrent angioedema (p=0.03, p=0.04) and concomitant autoimmunity (p=0.006, p<0.001). Autoreactivity was also found more frequently in patients with lower IgA and lower IgE levels (p=0.003, p<0.001). Reduced basophil counts were linked to both, lower IgA and lower IgE levels (p<0.001), whereas low eosinophil counts were primarily present in patients with lower IgE levels (p=0.04, p<0.001). Patients with elevated IgE-anti-TPO levels had lower IgA (p=0.007) and IgE levels (p=0.001).ConclusionLower IgA levels in CSU are linked to lower IgE levels and features of autoimmune urticaria. Our findings encourage to screen CSU patients for serum IgA and IgE levels and to further assess their role as disease biomarkers.

The Role of Interleukin 10 and 18 in Chronic Spontaneous Urticaria Pathogenesis in the Context of Angioedema Coexistence

Chronic spontaneous urticaria (CSU) is defined using clinical symptoms as spontaneous occurrence of itchy wheals and/or angioedema for at least 6 weeks. Angioedema is underdiagnosed in CSU patients, and its presence has significant negative impact on health-related quality of life, daily activities, health care resource utilization, and work. Various cytokines have been found to be involved in pathogenesis of CSU. To study levels of interleukin (IL)-10 and IL-18 in CSU patients and to look for the differences in CSU subgroups divided with regard to angioedema reoccurrence, we included consecutive CSU patients into the study. To assess disease activity, urticaria activity score was used. In addition, we calculated disease duration time. In all groups, Il-10 and Il-18 serum concentrations were measured. The study involved 52 patients with CSU and 47 healthy volunteers. The IL-10 level was statistically significantly higher in patients with CSU compared to the control group. There were no significant differences in level of IL-18 between those groups. Comparison of patients with CSU and angioedema with those without angioedema showed no significant differences in level of IL-10 and IL-18. We see the need for further studies of serum levels of IL-10 and IL-18 to better understand the pathogenesis of the disease and to find markers useful in predicting the symptom type in the course of CSU.

The Pathogenesis of Chronic Spontaneous Urticaria: The Role of Infiltrating Cells

Chronic spontaneous urticaria is characterized by a perivascular non-necrotizing cellular infiltrate around small venules of the skin. It consists primarily of CD4(+) lymphocytes, a prominence of the T helper (Th)2 subtype but also Th1 cells, with Th17 cell-derived cytokines elevated in plasma. There are also neutrophils, eosinophils, basophils, and monocytes. Chemokines derived from mast cells and activated endothelial cells drive the process. Although the role of the cellular infiltrate has not previously been addressed, each constituent can contribute to the overall pathogenesis. It is of interest that CSU responds to corticosteroid, yet, short-term steroids do not affect autoimmunity or degranulation of mast cells, and act on margination of cells along the endothelium and chemotaxis to enter the surrounding dermis. In this review, we address each cell's contribution to the overall inflammatory response, as it is currently understood, with a view toward development of therapeutic options that impede the function of critical cells and/or their secretory products.

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.

Biologics for the Use in Chronic Spontaneous Urticaria: When and Which

Guidelines for the treatment of chronic spontaneous urticaria (CSU) recommend the use of the IgE-targeted biologic omalizumab in patients with antihistamine-refractory disease. The rationale for this is supported by the key role of IgE and its high-affinity receptor, FcεRI, in the degranulation of skin mast cells that drives the development of the signs and symptoms of CSU, itchy wheals, and angioedema. Here, we review the current understanding of the pathogenesis of CSU and its autoimmune endotypes. We describe the mechanisms of action of omalizumab, the only biologic currently approved for CSU, its efficacy and ways to improve it, biomarkers for treatment response, and strategies for its discontinuation. We provide information on the effects of the off-label use, in CSU, of biologics licensed for the treatment of other diseases, including dupilumab, benralizumab, mepolizumab, reslizumab, and secukinumab. Finally, we discuss targets for novel biologics and where we stand with their clinical development. These include IgE/ligelizumab, IgE/GI-310, thymic stromal lymphopoietin/tezepelumab, C5a receptor/avdoralimab, sialic acid-binding Ig-like lectin 8/lirentelimab, CD200R/LY3454738, and KIT/CDX-0159. Our aim is to provide updated information and guidance on the use of biologics in the treatment of patients with CSU, now and in the near future.

Interleukin-23/ Interleukin -17 Axis in Chronic Spontaneous Urticaria: A Case- Control Study

Background: Chronic Spontaneous Urticaria (CSU) is a common health problem and its clear etiology is not established yet. Several theories have been tried to illustrate its etiology and pathogenesis. Autoantibodies and inflammatory cytokines like IL-23 and IL17 are hypothesized to take part in CSU pathogenesis and outcome. Objectives: To detect serum levels of IL-23 and IL-17A among CSU patients and to determine its correlation with disease severity and its relation to autoreactivity. Methodology: Serum levels of IL-23 and IL-17A were measured in 23 patients with CSU (CSU group) and 23 healthy controls (control group). In CSU group, Weekly Urticaria Activity Score (UAS7) was recorded to assess disease severity. Autologous Serum Skin Test (ASST) was performed to assess autoreactivity. CSU patients᾿ group was subdivided, based on ASST, into positive ASST (ASST+ ) and negative ASST (ASST- ) subgroups. Correlation of serum IL-23 &amp; IL-17A levels, with UAS7 and ASST response were analyzed. Results: CSU group had higher serum IL-17A and IL-23 levels than control group (P=0.000). ASST+ CSU had higher serum IL-17A and IL-23 levels than ASSTones (P=0.000). Additionally, UAS7 was higher in ASST+ subgroup than ASST- subgroup (32+11.7 versus 16.27+ 9.92; P =0.005). There was significant positive correlation between disease severity and serum levels of both IL-17A and IL-23 among CSU patients (r= 0.626 &amp; P= 0.001 and r=0.515 &amp; P= .012, respectively). Conclusion: Increased serum IL-17A and IL-23 levels may constitute two major determinants of CSU pathogenesis and severity.

The Emerging Role of IL-17 in the Immune-Pathogenesis of Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is considered to be an autoimmune disorder (type I and type II) in 50% of all cases. However, autoreactive T cells and their proximity with activated mast cells in the skin of CSU patients are believed to be the primary event in mast cell degranulation. The finding of anti-FcɛRIα on mast cells or IgE autoantibodies against thyroid antigens should be considered to be a consequence of the auto-reactive T cells’ recognition of the above-mentioned antigens. Our recent finding of increased Th17 and IL-17 expression in both CD4+ T cells and mast cells in the skin of severe CSU patients is supportive for the major role that T cells perform in the pathogenesis of CSU. Supporting this are numerous previous reports in which increased serum IL-17 was found to be in association with CSU disease severity. The beneficial effect of anti-IL-17A (secukinumab) in CSU patients in whom high dose anti-histamines, recurrent course of steroids and omalizumab fail to achieve a reasonable response should be investigated as a new therapeutic strategy in future studies with a large cohort of patients.

Interleukin 1 Gene Polymorphisms Presumably Participate in the Pathogenesis of Chronic Spontaneous Autoreactive Urticaria.

Recent studies underline a potential role of autoimmune and genetic disturbances in this disorder pathogenesis. Variants in genes related to inflammatory processes may possibly predispose to chronic spontaneous urticaria (CSU) occurrence. The objective of this study was to search for an association of Il1 genes polymorphisms with the pathogenesis of CSU. The examined group consisted of 153 unrelated chronic spontaneous autoreactive urticaria patients. The control group consisted of 104 unrelated healthy volunteers. In all studied subjects, IL1 rs1304037 and rs180058 polymorphisms were examined. The Urticaria Activity Score was used to assess disease intensity. The age of disease onset was also analyzed. Statistically significantly higher prevalence of Il1 rs1304037 TT genotype and T allele among CSU was proved. Similarly, the prevalence of Il1 rs1800587 GG genotype and G allele was statistically significantly higher in the CSU group. Haplotype combination rs1304037C/rs1800587G was statistically significantly more frequent in CSU, whereas rs1304037C/rs1800587A revealed statistically significantly less frequent occurrence in CSU. We did not observe any relationship between Il1 genotypes and the disease severity or age of disease onset. We are the first to suggest a significant role of IL1 gene polymorphisms in the susceptibility to CSU. This observation may lead to a better pathogenesis understanding and more effective treatment. We recommend further studies on other polymorphisms in chronic urticaria to analyze the role of the genetic mechanisms in the pathogenesis of this disorder.

The association of Th17/Treg cells expression in peripheral blood and chronic spontaneous urticaria: A protocol of systematic review and meta-analysis.

Background:The pathogenesis of chronic spontaneous urticaria (CSU) is not clear, but its occurrence is closely related to the immune state of the body, that is, the balance of T cell subsets. Previous studies have confirmed that the dynamic imbalance of Th1/Th2 cells in CD4+T cell subsets of T cell subsets is closely related to the pathogenesis of CSU, but there are few studies on the relationship between the dynamic imbalance of Th17/Treg cells in CD4+T cell subsets and the pathogenesis of CSU. The purpose of this study is to evaluate the relationship between Th17/Treg cells expression in peripheral blood and CSU, so as to provide a reference basis for the pathogenesis of CSU.Methods:PubMed, Embase, CENTRAL, Web of Science, China Biology Medicine Database, China National Knowledge Database, Wan Fang Database, and Chongqing VIP Database will be searched to collect case-control studies and cohort studies evaluating the relationship between Th17/Treg cells expression in peripheral blood and CSU. The search time limits will be from the establishment of the database to December 2020. The meta-analysis will be carried out with the RevMan V.5.3 statistical software. The quality of all included studies will be evaluated by the Newcastle-Ottawa scale.Results:The results of this study will comprehensively evaluate the Th17/Treg cells expression levels in peripheral blood of patients with CSU, and provide a reference basis for the pathogenesis of CSU.Conclusion:The findings of this study may provide new evidence for the relationship between Th17/Treg cells balance in peripheral blood and CSU.OSF registration number:DOI 10.17605/OSF.IO/S8MYW

Histamine- or vascular endothelial growth factor-induced tissue factor expression and gap formation between vascular endothelial cells are synergistically enhanced by lipopolysaccharide, tumor necrosis factor-α, interleukin (IL)-33 or IL-1β.

The pathogenesis of chronic spontaneous urticaria (CSU), also called chronic idiopathic urticaria, has been considered to be associated with the activation of the extrinsic blood coagulation cascade. However, the trigger for the extrinsic coagulation cascade in patients with CSU remains unclear. We previously reported that histamine and lipopolysaccharide (LPS) synergistically induced the expression of tissue factor (TF), a trigger for the extrinsic coagulation cascade, in human umbilical vein endothelial cells (HUVEC). Because the elevation of tumor necrosis factor (TNF)-α, interleukin (IL)-33, IL-1β and vascular endothelial growth factor (VEGF) in serum has also been observed in patients with CSU, we examined the effects of LPS, TNF-α, IL-33, IL-1β, VEGF and histamine on TF expression in HUVEC by reverse transcription polymerase chain reaction and flow cytometry, as well as examining the activity that triggers the extrinsic coagulation cascade and induces intercellular gap formation of HUVEC in the presence of plasma by Actochrome® TF activity assay and impedance sensor, respectively. The expression of TF mRNA and surface protein of TF on HUVEC in response to histamine or VEGF were synergistically enhanced by the treatment with LPS, TNF-α, IL-33 or IL-1β. Moreover, the activation of the extrinsic coagulation pathway and intercellular gap formation of HUVEC in response to histamine or VEGF were also synergistically increased in the presence of TNF-α and LPS. Thus, TF expression on vascular endothelial cells was strongly enhanced by co-stimulation with CSU-related molecules in blood. Blocking a common pathway of LPS, TNF-α, IL-33 and IL-1β, and/or that of VEGF and histamine may be an effective therapeutic measure for patients with severe and refractory CSU.

Serum transglutaminase 2 activity as a potential biomarker of disease severity and response to omalizumab in chronic spontaneous urticaria

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No.2018R1A2B6009178) and Hallym University Research Fund 2017 (HURF-2017-76). Transglutaminase 2 (TG2) is expressed in mast cells and contributes to allergic asthma. We have previously reported that TG2 was associated with the pathogenesis of chronic spontaneous urticaria (CSU). The aim of this study is to investigate the clinical implication of serum TG2 levels in CSU. Patients with CSU (n=111), acute urticaria (AU, n=31), and normal controls (NC, n=45) were enrolled. TG2 activity in serum were measured by ELISA. Serum TG2 activity was serially measured in 9 patients with CSU in accordance with omalizumab treatment. Patients were divided by disease severity (mild, moderate, severe, very severe) which is defined by the treatment level from the guidelines for treatment of CSU. Student’s T-test and Wilcoxon signed-rank test were done for statistical analyses using SPSS, ver. 21 (SPSS Inc, Chicago, Illinois). TG2 activity was significantly higher in sera of CSU patients (132.8 ± 81.6 mU/mL) than AU (86.4 ± 57.8 mU/mL) and NC (70.0 ± 42.4 mU/mL). (P < 0.05, respectively), while Serum TG2 activity in AU was not significantly different from NC (P > 0.05). Serum TG2 activity in CSU patients was significantly increased according to disease severity (mild: 87.1 ± 66.3 mU/mL, moderate: 136.1 ± 64.0 mU/mL, severe: 159.7 ± 59.0 mU/mL, very severe: 222.1 ± 68.1 mU/mL, P < 0.0001). Initial TG2 activity was significantly decreased after omalizumab treatment (P < 0.05). Serum TG2 activity represents disease severity of CSU. Serum TG2 activity could be a useful marker of disease severity and treatment response of CSU.

Dietary habits in Japanese patients with chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is defined as the spontaneously appearing weals and/or angioedema for more than 6weeks. Dietary habits can modulate the pathogenesis of CSU. However, dietary intakes of nutrients or food in CSU patients, compared with healthy controls, have not been examined in quality and quantity. We evaluated dietary habits in adult Japanese patients with chronic spontaneous urticaria using a validated, brief-type self-administered diet history questionnaire and compared the results to those of age- and sex-matched healthy controls. The severity of CSU was evaluated using the Urticaria Control Test. Japanese CSU patients showed higher body mass indices, higher intakes of eggs, vegetables other than green/yellow vegetables/mushrooms/algae, cholesterol, folic acid, dietary fibres, vitamin D, vitamin K, Cu, Fe, Pi, Ca, Mg, Na and salt, and lower intake of alcohol, compared to controls. The logistic regression analysis showed that CSU was associated with high body mass index and high intake of eggs. The intake of beverages was higher in uncontrolled CSU patients (Urticaria Control Test ≦11 points) than in controlled patients. The logistic regression analysis showed that uncontrolled CSU was associated with high intake of beverages. The intake of coffee, caffeine-rich and non-alcohol beverage, in uncontrolled CSU patients was higher than that in controlled patients. Chronic spontaneous urticaria was associated with high body mass index and high intake of eggs. Uncontrolled CSU was associated with high intake of beverages. Further studies should elucidate the relationships of these results with the development or exacerbation of CSU.