Pathogenesis Of Chronic Spontaneous Urticaria Research Articles

Role of TF-Triggered Activation of the Coagulation Cascade in the Pathogenesis of Chronic Spontaneous Urticaria

To overview recent understanding of the relationship between the blood coagulation cascade and chronic spontaneous urticaria (CSU). The relationship between severities of CSU and the increase of coagulation markers, and the effectiveness of anti-coagulants, such as warfarin, suggest a causative role of the blood coagulation in the pathogenesis of CSU. However, mechanisms of the initiation of blood coagulation, and the link between blood coagulation and wheal formation in urticaria, remained unclear. In blood vessels, vascular endothelial cells and eosinophils may express tissue factor (TF), which triggers the activation of extrinsic coagulation cascade. We recently revealed that histamine and TLR agonists synergistically induce TF expression by endothelial cells and produce active forms of coagulation factors, such as Xa and IIa, which may induce plasma extravasation. The exposure of skin mast cells to the exuded plasma may then induce degranulation of the skin mast cells via various receptors, releasing a massive amount of histamine, resulting in wheal formation observed in CSU. Further elucidation of the mechanism of blood coagulation and the pathway of mast cell activation by activated coagulation factors may be a target for the development of new and more effective treatments for CSU.

New biologics in the treatment of urticaria.

Symptomatic management of chronic spontaneous urticaria (CSU) basically depends on second-generation H1 antihistamines and omalizumab. Omalizumab is a game changer in the management, but still there is a need for new targets and new biologics targeting new pathways in the treatment which will provide long-lasting remission, which will be given orally and which will be cheaper. This review will focus on new biologics that are underway of production or are already under use for different disorders but could be beneficial for the treatment of Chronic urticaria. In this review, the treatment targets are classified according to the cells which are involved in the pathogenesis of CSU. Those are mast cells/basophils, B cells, T cells and eosinophils. The treatments that are under clinical trials for CSU are anti-IgE treatments such as ligelizumab, molecules targeting intracellular signaling pathways such as spleen tyrosine kinase inhibitors, surface inhibitory molecules such as siglec-8, anti-IL-1s such as canakinumab, Bruton kinase (BTK) inhibitors such as GDC-0853 and anti-IL-5s such as benralizumab and mepolizumab. The ongoing clinical trials on new targets of treatment hold new hopes not only for a better care of the disease but also a better understanding of the pathomechanisms lying underneath.

Decreased interleukin-35 serum levels in patients with chronic spontaneous urticaria

Chronic spontaneous urticaria (CSU), a mast cell–driven disease, is defined as the spontaneous appearance of wheals, angioedema, or both for more than 6 weeks for unknown or known causes. [1] Zuberbier T Aberer W Asero R et al. The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: The 2013 revision and update. Allergy. 2014; 69: 868-887 Crossref PubMed Scopus (850) Google Scholar Mast cells, as 1 of the major effector cells in the immune response system, play important roles in the pathogenesis of CSU. Interleukin (IL)-35 is a new anti-inflammatory cytokine that belongs to the IL-12 family and is composed of 2 subunits: Epstein-Barr virus–induced gene 3 and IL-12p35. Interleukin-35 is widely recognized as a definite immune suppressor with a huge potential for suppression. Abundant evidence had indicated that IL-35 could suppress the activity of Th1 and Th17 cells and that it plays a crucial role in the pathogenesis of many types of autoimmune diseases, such as inflammatory bowel disease, [2] Fonseca-Camarillo G Furuzawa-Carballeda J Yamamoto-Furusho JK Interleukin 35 (IL-35) and IL-37: Intestinal and peripheral expression by T and B regulatory cells in patients with Inflammatory Bowel Disease. Cytokine. 2015; 75: 389-402 Crossref PubMed Scopus (62) Google Scholar rheumatoid arthritis, [3] Nakano S Morimoto S Suzuki S et al. Immunoregulatory role of IL-35 in T cells of patients with rheumatoid arthritis. Rheumatology (Oxford). 2015; 54: 1498-1506 Crossref PubMed Scopus (58) Google Scholar and systemic lupus erythematosus. [4] Ouyang H Shi YB Liu ZC et al. Decreased interleukin 35 and CD4+EBI3+ T cells in patients with active systemic lupus erythematosus. Am J Med Sci. 2014; 348: 156-161 Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar However, the effects of IL-35 in the pathogenesis of CSU has not yet been elucidated.

Gastritis Can Cause and Trigger Chronic Spontaneous Urticaria Independent of the Presence of Helicobacter pylori

Background/Aim: In chronic spontaneous urticaria (CSU), Helicobacter pylori (HP) has been discussed as a cause, but it is unknown whether the bacterium itself or concomitant inflammation is causing the urticaria. Our aim was to investigate HP and upper gastrointestinal lesions as signs of inflammation independently of each other in the pathogenesis of CSU. Methods: A total of 36 prospectively enrolled CSU patients from Moscow were investigated by gastroscopy and screened for the presence of HP and/or upper gastrointestinal lesions. Those having a positive result were treated according to the Maastricht III recommended guidelines for eradication therapy, and success was assessed by a follow-up gastroscopy. Simultaneously, the activity of CSU was measured before and after therapy of the gastrointestinal condition. Results: HP was observed in 26 of the 36 patients. Erosions or ulcers were found in 18 of the 36 patients, 14 of whom were also positively tested for HP. There was a significant difference in improvement of urticarial symptoms between those who succeeded in healing the erosions and those who did not succeed (p < 0.01) independent of the presence of HP. No significant difference in symptom relief was observed between those who had successful eradication and those in whom HP eradication failed. Conclusions: Upper gastrointestinal inflammatory disorders can cause CSU and trigger exacerbations independently of HP. This might imply that also in HP-positive patients, urticaria is not based on an immunological reaction against the germ but rather on the underlying inflammation. These findings also strengthen the importance of a gastroenterological workup of patients with CSU.

In chronic spontaneous urticaria, IgE against staphylococcal enterotoxins is common and functional.

Chronic spontaneous urticaria (CSU) is a frequent disorder with recurrent itchy wheals and/or angioedema. Despite the known effectiveness of omalizumab therapy, the relevant IgE antigens are largely unknown. Recently, increased rates of elevated levels of IgE towards Staphylococcus aureus enterotoxins (SEs) were described in CSU. To assess the prevalence and functional relevance of IgE to SEs in CSU. We investigated serum levels of IgE against SEs in 49 CSU patients and in 15 CSU patients additional specific IgE to SE components and basophil histamine release (BHR). Sera of 15 healthy controls (HCs) served as control group. Twenty-five (51%) of the CSU patients had detectable levels of SE-IgE as compared to 5 (33%) of HCs. Specific IgE to one of the SEs, Staphylococcus enterotoxin B (SEB), was present in 5 (33%) of 15 randomly selected CSU patients vs 3 (20%) of HC. Total IgE serum levels in CSU patients were significantly correlated with SE-IgE (r=.52, P<.001) and SEB-IgE (r=.54, P=.04) serum concentrations. Interestingly, SEB-IgE levels were strongly correlated with disease activity (UASday) in CSU patients (r=.657, P=.01). Furthermore, BHR in response to SEB was significantly higher in basophils loaded with the serum of CSU patients compared to HC (P<.05) and was clinically correlated with duration of disease (r>.51, P<.05). IgE against SEs may contribute to the pathogenesis of CSU in a subpopulation of patients. Its role and relevance in the pathophysiology of CSU need to be further analysed.

Overweight and obesity may play a role in the pathogenesis of chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is one of the commonest diseases in allergological and dermatological practice. It constitutes an interdisciplinary problem, and its pathogenesis is not always easily determined. It has been suggested that metabolic syndrome and hyperlipidaemia are more frequent in patients with CSU, but the influence of overweight and obesity on the development of CSU has not been thoroughly investigated. To assess the association between body parameters and the development of CSU. The study enrolled 85 patients with CSU, who were divided into three subgroups: patients whose only symptoms were weals, patients whose only symptom was angio-oedema, and patients with urticaria and accompanying angio-oedema. Mean weight, height, body mass index (BMI), body surface area, disease duration and age of disease onset were recorded RESULTS: There was a statistically significant association between CSU and heavier weight, higher BMI, greater affected body surface area and older age at disease onset. Subjects with higher BMI values had a tendency towards longer disease duration. There were no statistically significant differences between the three subgroups. Our results suggest that CSU, especially if of long duration, may be associated with overweight and obesity, while increased body mass can result in later onset of urticaria symptoms. Further analyses to confirm the presented results and possible association between obesity and CSU occurrence are needed.

Plasma lipoxin A4 levels in childhood chronic spontaneous urticaria.

Dilek F, Özçeker D, Güler EM, Özkaya E, Yazıcı M, Tamay Z, Koçyiğit A, Güler N. Plasma lipoxin A4 levels in childhood chronic spontaneous urticaria. Turk J Pediatr 2018; 60: 527-534. Chronic spontaneous urticaria (CSU) is an idiopathic inflammatory disorder. Despite great research progress, the pathogenesis of the disease is still not fully understood. Lipoxins (LXs) are autacoid lipid metabolites that are the first discovered members of a new genus named called `specialized proresolving mediators`. In this study, we aimed to investigate the possible role of LXA4 in the pathogenesis of CSU. Forty-two children with CSU and 25 healthy children were enrolled in the study. The demographic and clinical features of patients were evaluated, autologous serum skin tests (ASSTs), and routine laboratory assessments were performed. Disease activity was determined using the urticaria activity score. An enzyme-linked immunosorbent assay was used to evaluate LXA4 plasma levels. The median value of plasma LXA4 was found to be 60.8 ng/ml (interquartile range, 48.1-71.8) in CSU patients and 137.4 ng/ml (121.4-150.8) in the control group. The difference between the groups was statistically significant (p < 0.001). Additionally, the median plasma LXA4 levels in the ASST-positive patients were significantly reduced compared to the ASST-negative ones (45.8 [36.7-67.6] versus 63.8 [58.3-78.9] ng/ml, respectively, p < 0.05). Our results showed that diminished LXA4 biosynthesis may be a critical part of CSU pathogenesis in children, especially in patients with an autoimmune component.

Increased plasma IL-17, IL-31, and IL-33 levels in chronic spontaneous urticaria

Chronic spontaneous urticaria (CSU) is considered in a subset of patients to be an autoimmune disorder. Interleukin(IL)-17, IL-31, and IL-33 are involved in some immune response. The aim of this study was to quantify plasma IL-17, IL-31, and IL-33 levels in CSU patients and to examine their relationships with disease severity. Plasma IL-17, IL-31, and IL-33 concentration were measured in 51 CSU patients and 20 healthy subjects (HCs). Plasma IL-17 (P < 0.001), IL-31 (P < 0.001), and IL-33 (P < 0.001) concentrations were significantly higher in CSU patients when compared with those of HCs. Concerning UAS7, severe group of CSU patients had significantly higher IL-17 levels than the moderate and mild groups (P = 0.028 and 0.007, respectively), and significantly higher IL-33 concentrations than the mild group (P = 0.026). Regarding only pruritus, severe group of patients had significantly higher IL-31 levels than the mild group (P = 0.003). The IL-33 levels in the total IgE positive group were significantly higher than that of negative group (P = 0.010). Our results showed higher plasma levels of IL-17, IL-31, and IL-33 among CSU patients which may highlight a functional role of these cytokines in the pathogenesis of CSU.

Different expression patterns of plasma Th1-, Th2-, Th17- and Th22-related cytokines correlate with serum autoreactivity and allergen sensitivity in chronic spontaneous urticaria.

Clinical features and basophil activation levels correlate with serum autoreactivity and allergen sensitivity in patients with chronic spontaneous urticaria (CSU). To explore the relationship of the expression patterns of plasma T-helper cell (Th) 1-, Th2-, Th17- and Th22-related cytokines with the serum autoreactivity and the allergen sensitivity in CSU. Twenty related cytokines were measured and analysed in 60 patients with CSU, 15 patients with acute urticaria, 10 patients with atopic dermatitis (AD) and 15 healthy persons, respectively. Autologous serum skin testing (ASST) and skin prick testing (SPT) were performed to detect autoreactivity and allergy sensitivity, respectively. The protein-protein interaction of cytokines and the molecular pathways were analysed by Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and KyotoEncyclopedia of Genes and Genomes (KEGG database), respectively. Th1-/Th2- and Th17-related cytokines were significantly elevated and correlated with disease activity in CSU than in healthy controls. Interleukin (IL)-6, IL-10 and IL-13 were significantly higher in acute urticaria than in patients with CSU. Granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-10 and IL-17 were significantly higher in ASST+ than in ASST- CSU patients. IFN-γ, IL-2, IL-12p70 and IL-21 were significantly higher in SPT+ than in SPT- CSU patients. The plasma levels of interferon-γ, IL-2 and IL-21 varied among ASST+/SPT+, ASST+/SPT-, ASST-/SPT+ and ASST-/SPT- CSU subgroups, which appeared to involve the positive regulation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. This study indicates acute urticaria elicits a more prominent Th2 immune response than CSU. There was association between different expression patterns of plasma Th1-, Th2-, Th17- and Th22-related cytokines and serum autoreactivity or allergen sensitivity in CSU. Further studies on the JAK-STAT pathway in the pathogenesis of CSU are warranted.

Elevated Nitrosative Stress in Children with Chronic Spontaneous Urticaria

Background: Chronic spontaneous urticaria (CSU) is an idiopathic condition that seriously affects quality of life. It is well known that oxidative stress and nitrosative stress (NS) are generally involved in many chronic inflammatory diseases. This study aimed to evaluate the possible role of NS in the pathogenesis of CSU. Methods: Thirty-two children with CSU and 22 healthy control subjects were enrolled in the study. Demographic and clinical features were defined, and disease activity was quantified using the urticaria activity score (UAS). Serum NS was assessed by the plasma levels of total nitric oxide (NOx) metabolites and nitrite and nitrate measurements using a Griess method-based commercial kit. Results: Plasma NOx levels were 82.5 ± 11.3 µmol/L in the CSU group and 50.9 ± 9.4 µmol/L in the control group. The difference was statistically significant (p < 0.001). CSU patients also had higher plasma nitrite levels than controls (53.3 ± 13.8 vs. 30.2 ± 10.1 µmol/L, respectively, p < 0.001). The median values of plasma nitrate were 27.5 µmol/L (IQR 19.1-35.5) in CSU patients and 20.9 µmol/L (IQR 17.9-23.2) in the control group, and the difference was statistically significant (p = 0.009). In addition, plasma NOx and nitrite levels were positively correlated with the UAS (rho = 0.512, p = 0.03 and rho = 0.452, p = 0.011, respectively). Conclusion: Plasma NS is elevated and positively correlated with disease activity in children with CSU.

Thyrotropin receptor gene expression in the association between chronic spontaneous urticaria and Hashimoto's thyroiditis

Chronic spontaneous urticaria (CSU) may be associated with autoimmune thyroid diseases, and the Autologous Serum Skin Test (ASST) is an autoreactivity marker. The thyrotropin (TSH) and TSH receptor (TSHR) could play a role in the pathogenesis of CSU. The aim of this study was to evaluate ASST positivity and TSHR gene expression in healthy skin and ASST wheals in euthyroid women with CSU, with (14 patients) and without (15 patients) Hashimoto's thyroiditis (HT). ASST was performed and TSHR gene expression studied in wheals induced by ASST and in healthy skin. ASST presented greater positivity (86%×40%) and larger diameter (10.8×9.6mm) in the HT group (P<0.05). TSHR gene expression was higher in the ASST area and healthy skin of HT group (P<0.01). Positive correlation of antibodies levels with ASST wheal measurements and TSHR gene expression was seen. Women with CSU and HT presented greater positivity and larger measurements for ASST and higher TSHR expression in the skin, suggesting association between CSU, thyroid autoimmunity, and TSHR.

Single nucleotide polymorphisms of IL-2, but not IL-12 and IFN-γ, are associated with increased susceptibility to chronic spontaneous urticaria

BackgroundA clear picture of interaction of Th1/Th2 cytokines in pathogenesis of chronic spontaneous urticaria (CSU), remains elusive. Impaired IFN-γ production and decreased levels of IL-2 have been reported. The aim of this study was to evaluate the association of Th1 cytokines; IL-2, IL-12 and IFN-γ polymorphisms with CSU. Methods90 patients with CSU and 140 age-sex matched subjects were included in this study. DNA samples were evaluated through PCR-SSP assay in order to detect single nucleotide polymorphisms of IL-12 (A/C −1188) or (rs3212227), IFN-γ (A/T UTR5644) or (rs2069717) and IL-2 (G/T −330 and G/T +166) or (rs2069762 and rs2069763). ResultsG allele at −330 at promoter region of IL-2 gene was overrepresented in CSU. Heterozygotes (GT) at this locus and heterozygotes at +166 of IL-2 gene (GT) were more prevalent in CSU group. Additionally, the haplotype GT for loci −330 and +166 of IL-2 gene was powerfully associated with CSU (OR (95%CI)=57.29 (8.43–112.7)). ConclusionsSNP at position −330 and +166 of IL-2 gene are differently expressed in CSU. The haplotype GT of IL-2 at −330 and +166 might confer vulnerability to a number of immunological disorders in Iranian region.

Analysis of the association of chronic spontaneous urticaria with interlekin-4, -10, transforming growth factor-β1, interferon-γ, interleukin-17A and -23 by autologous serum skin test.

AimTo contribute to the understanding of the pathogenesis of chronic spontaneous urticaria (CSU) by identifying its relationship with autoimmunity and cytokines using the autologous serum skin test (ASST) and peripheral blood mononuclear cell culture (PBMC) method.Material and methodsInterleukins (IL)-4, IL-10, transforming growth factor (TGF-β1), interferon (IFN)-γ, IL-17A, and IL-23 levels in cell supernatants obtained by the PBMC method were measured using ELISA. Disease activity was assessed by determining the urticaria activity score (UAS).ResultsA total of 40 patients diagnosed with CSU participated in this study. Twenty patients had positive ASST results, and 20 had negative results. The control group included 20 healthy volunteers. We found that the IL-23 (p = 0.01), IL-10 (p = 0.04) and IL-4 (p = 0.04) levels of the patient groups were significantly lower compared with those of the control group. The IL-23 (p = 0.009), IL-10 (p = 0.009), IL-4 (p = 0.001), and IL-17 (p = 0.05) levels of the ASST(–) patient group were significantly lower compared with those of the control group. In addition, the IL-4 (p = 0.03) and IFN-γ (p = 0.05) levels of the ASST(+) patient group were significantly lower compared with those of the control group, and the ASST(+) patients had a significantly higher UAS than the ASST(–) patients (p = 0.021).ConclusionsThese results, when considered together with current reports in the literature, indicate that immune dysregulation occurs in the pathogenesis of CSU, causing cytokine imbalance.

Mediators of Inflammation and Angiogenesis in Chronic Spontaneous Urticaria: Are They Potential Biomarkers of the Disease?

In chronic spontaneous urticaria (CSU), different pathophysiological mechanisms, potentially responsible for the development of the disease, have been recently described. It is likely that the activation of skin mast cells with consequent release of histamine and other proinflammatory mediators is responsible for vasodilation in the lesional skin of CSU. However, the underlying causes of mast cell activation in the disease are largely unknown and remain to be identified. Thus, in this review, we discuss new insights in the pathogenesis of CSU, focusing on inflammation and angiogenesis. The understanding of these mechanisms will enable the identification of biomarkers useful for the diagnosis, follow-up, and management of CSU and will allow the development of novel, more specific, and patient-tailored therapies.

Autoimmune chronic spontaneous urticaria: What we know and what we do not know

Chronic spontaneous urticaria (CSU) is a mast cell-driven skin disease characterized by the recurrence of transient wheals, angioedema, or both for more than 6weeks. Autoimmunity is thought to be one of the most frequent causes of CSU. Type I and II autoimmunity (ie, IgE to autoallergens and IgG autoantibodies to IgE or its receptor, respectively) have been implicated in the etiology and pathogenesis of CSU. We analyzed the relevant literature and assessed the existing evidence in support of a role for type I and II autoimmunity in CSU with the help of Hill's criteria of causality. For each of these criteria (ie, strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy), we categorized the strength of evidence as "insufficient," "low," "moderate," or "high" and then assigned levels of causality for type I and II autoimmunity in patients with CSU from level 1 (causal relationship) to level 5 (causality not likely). Based on the evidence in support of Hill's criteria, type I autoimmunity in patients with CSU has level 3 causality (causal relationship suggested), and type II autoimmunity has level 2 causality (causal relationship likely). There are still many aspects of the pathologic mechanisms of CSU that need to be resolved, but it is becoming clear that there are at least 2 distinct pathways, type I and type II autoimmunity, that contribute to the pathogenesis of this complex disease.

English

Functionally active autoantibodies to IgE and to the high-affinity IgE receptor (FcεRI) can be detected in serum in about 40% of patients with chronic spontaneous urticaria (CSU). Recent studies showed that serum from patients with CSU can induce activation of mast cells, irrespective of whether they carry high-affinity IgE receptors. To evaluate mast cell activation induced by factors in the serum of CSU patients with a molecular weight lower than that of autoantibodies.Eight CSU patients and 5 healthy controls were evaluated. Whole serum and serum fractionated at 100, 50, and 30 kDa were used to stimulate in vitro LAD2 mast cells. The enzymatic activity of β-hexosaminidase was evaluated in supernatants and cell pellets as a measure of mast cell degranulation.Mean (SEM) release of mast cell β-hexosaminidase induced by whole serum from CSU patients was higher than that induced by serum from the healthy controls (14.4 [2.7%] vs 5.1 [2.4%]; P=.027). In addition, serum fractions below 100 kDa and below 50 kDa from CSU patients induced mast cell degranulation that was significantly higher than that induced by the corresponding fractions in sera from healthy controls (10.2% [1.4%] vs 3.8% [1.9%] [P=.024] and 10.1% [1.2%] vs 3.9% [1.7%] [P=.012], respectively). In 4 CSU patients, we evaluated serum fractions <30 kDa, which retained their capacity to activate mast cells (11.0% [0.7%]).This study shows that sera from CSU patients may contain low-molecular-weight mast cell-activating factors other than autoantibodies. These factors could be an additional mechanism contributing to the pathogenesis of CSU.

Basophil CD63 expression in chronic spontaneous urticaria: correlation with allergic sensitization, serum autoreactivity and basophil reactivity.

The underlying causes and factors contributing to the disease severity of chronic spontaneous urticaria (CSU) are unknown. Given the important role of basophils in the pathogenesis of urticaria and that CD63 serves as a useful marker for basophil activation and detecting, CD63 expression of basophils is a reliable tool for diagnosing allergy and hypersensitivity reactions to different allergens; the objective of this study was to investigate whether the level of basophil CD63 expression is correlated with allergen sensitization, serum autoreactivity and basophil reactivity in patients with CSU. Basophil-enriched leucocytes were separated from the blood of 64 patients with chronic urticaria (54 CSU patients and 10 symptomatic dermographism patients), 18 healthy control subjects and seven atopic donors without urticaria. Flow cytometry was then used to detect CD63 expression on the cell membrane of basophils from all samples. Analysis was also preformed on basophils incubated with sera from CSU patients with positive or negative autologous serum skin test (ASST). CD63 expression was significantly higher in the basophils from patients with CSU than in those from patients with symptomatic dermographism and the healthy control group. The levels of CD63 expression in CSU patients with ASST+ and/or allergen sensitization were higher than those with ASST- and/or no allergen sensitization patients. Incubation with ASST+ serum resulted in an increased expression of CD63 in the basophils of ASST+ CSU patients, whereas no such response was observed in healthy controls or ASST- CSU patients. The increased CD63 expression in basophils from CSU patients may correlate with allergen sensitization, autoreactivity of serum and basophil reactivity. Our results suggest that CD63 may contribute new insight into the pathogenesis of CSU.

Association of TG2 from mast cells and chronic spontaneous urticaria pathogenesis

BackgroundMast cells and their mediators play important roles in chronic spontaneous urticaria (CSU) pathogenesis. Transglutaminase 2 (TG2) is expressed in activated mast cells and contributes to airway inflammation in allergic asthma. ObjectiveTo investigate the role of TG2 in CSU. MethodsPatients with CSU (n = 72) and healthy controls (n = 51) were evaluated. Skin biopsy specimens were obtained from 5 patients with CSU and 2 healthy controls. Cord blood–derived human mast cells and peripheral blood–derived human mast cells were activated with IgE. TG2 activity and inflammatory mediators, such as histamine, leukotriene C4, and cytokines, were measured in serum or supernatant from cultured mast cells by enzyme-linked immunosorbent assay. Colocalization of mast cells and TG2 was determined in skin tissues by immunofluorescence. ResultsTG2 activity was significantly higher in serum samples from patients with CSU than in serum samples from healthy controls (P < .001). Colocalization of mast cell surface marker c-kit and TG2 was significantly increased in the lesional skin of patients with CSU compared with that in healthy controls. The levels of histamine, leukotriene C4, tumor necrosis factor α, transforming growth factor β, and interleukins 4, 5, and 6 were significantly higher in patients with CSU than in healthy controls (P < .001). Serum TG2 levels had positive correlations with each inflammatory mediator (P < .001). TG2 activity was increased in cord blood–derived human mast cells (CBMCs) and peripheral blood–derived human mast cells activated with IgE compared with those without activation (P < .05). ConclusionOur findings suggest that TG2 expressed in and released from mast cells plays an important role in CSU pathogenesis.

Upregulated expression of substance P in basophils of the patients with chronic spontaneous urticaria: induction of histamine release and basophil accumulation by substance P.

Human basophils have been implicated in the pathogenesis of chronic spontaneous urticaria (CSU), and substance P (SP) is a possible candidate as histamine-releasing factor in some patients with CSU. However, little is known of relationship between basophils and SP in CSU. In the present study, we investigated expression of SP and NK1R on basophils from patients with CSU, and influence of SP on basophil functions by using flow cytometry analysis, basophil challenge, and mouse sensitization model techniques. The results showed that plasma SP level and basophil numbers in CSU patients were higher than that in HC subject. The percentages of SP+ and NK1R+ basophils were markedly elevated in CSU blood in comparison with HC blood. Once added, SP induced up to 41.2% net histamine release from basophils of CSU patients, which was comparable with that provoked by anti-IgE, and fMLP. It appeared that SP induced dramatic increase in blood basophil numbers of mice following peritoneal injection. Ovalbumin (OVA)-sensitized mice had much more SP+ and NK1R+ basophils in blood than non-sensitized mice. In conclusion, the elevated plasma concentration of SP, upregulated expression of SP and NK1R on basophils, and the ability of SP in induction of basophil degranulation and accumulation indicate strongly that SP is most likely a potent proinflammatory mediator, which contributes greatly to the pathogenesis of CSU through basophils. Inhibitors of SP and blockers of NK1R are likely useful agents for treatment of CSU.

Comorbidity and pathogenic links of chronic spontaneous urticaria and systemic lupus erythematosus--a systematic review.

Chronic spontaneous urticaria (CSU) is a common mast cell-driven disease characterized by the development of wheals (hives), angioedema (AE), or both for >6weeks. It is thought that autoimmunity is a common cause of CSU, which is often associated with autoimmune thyroiditis, whereas the link to other autoimmune disorders such as systemic lupus erythematosus (SLE) has not been carefully explored. Here, we systematically reviewed the existing literature for information on the prevalence of CSU in SLE (and vice versa) and we examined the possible clinical and pathogenetic relationship between CSU and SLE. The prevalence of CSU and CSU-like rash in SLE was investigated by 42 independent studies and comorbidity in adult patients reportedly ranged from 0% to 21.9% and 0.4% to 27.5%, respectively (urticarial vasculitis: 0-20%). In children with SLE, CSU was reported in 0-1.2% and CSU-like rash in 4.5-12% (urticarial vasculitis: 0-2.2%). In contrast, little information is available on the prevalence of SLE in patients with CSU, and more studies are needed to determine the rate of comorbidity. Recent insights on IgG- and IgE-mediated autoreactivity suggest similarities in the pathogenesis of CSU and SLE linking inflammation and autoimmunity with the activation of the complement and coagulation system. Future studies of patients with either or both conditions could help to better define common pathomechanisms in CSU and SLE and to develop novel targeted treatment options for patients with CSU and SLE.