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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.

Urticaria is characterized by the occurrence of wheals and flares in response to vasoactive mediators, such as histamine. Various studies have suggested the involvement of basophils in the pathogenesis of chronic spontaneous urticaria (CSU). However, histamine release from peripheral basophils in response to stimuli acting on the high affinity IgE receptor (FcϵRI) is impaired in many patients with CSU (non/low responders). We previously demonstrated that tissue factor (TF)s expressed on vascular endothelial cells in response to a combination of various stimuli, such as that of histamine and lipopolysaccharide (LPS), activates the extrinsic coagulation pathway and produces anaphylatoxin, complement 5a (C5a), which then activates basophils and mast cells via the C5a receptor (C5aR). We have revealed that histamine release was induced in response to C5a and formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP), regardless of the response to anti-IgE antibody, the reduced numbers of basophils and severity of urticaria. Moreover, we found that spontaneous release of histamine ex vivo from basophils of patients with CSU is higher than that from healthy individuals. These results suggest that basophils and the complement system, which could be activated by coagulation factors, may play a critical role in the pathogenesis of CSU, especially in cases refractory to treatment involving the IgE/FcϵRI pathway.

Urticaria is a common skin disorder characterized by the rapid appearance and disappearance of local skin edema and flares with itching. It is characterized by various macroscopic skin eruptions unique to patients and/or subtypes of urticaria with respect to shape, size, color, and/or duration of eruptions. Nevertheless, the mechanism underlying multifarious eruptions in urticaria is largely unknown. The eruptions are believed to be evoked by histamine release from mast cells in the skin. However, the majority of visible characteristics of urticaria cannot be explained by a simple injection of histamine to the skin. To explain the multifarious eruptions of urticaria, we developed a single reaction-diffusion model suggesting the self-activation and self-inhibition regulation of histamine release from mast cells. Using the model, we found that various geometrical shapes of eruptions typically observed in patients can be explained by the model parameters and randomness or strength of the initial stimuli to mast cells. Furthermore, we verified that the wheal-expanding speed of urticaria, which is shown to be much smaller than that of the intradermal injection experimental system may be explained by our model and a simple diffusion equation. Our study suggests that the simple reaction-diffusion dynamics, including the independent self-activating and -inhibitory regulation of histamine release, may account for the essential mechanism underlying the formation of multifarious eruptions in urticaria.

Label-free evaluation and monitoring of living cell conditions or functions by means of chemical and/or physical sensors in a real-time manner are increasingly desired in the field of basic research of cells and clinical diagnosis. In order to perform multi-parametric analysis of living cells on a chip, we here developed a surface plasmon resonance (SPR) imaging (SPRI)-impedance sensor that can detect both refractive index (RI) and impedance changes on a sensor chip with comb-shaped electrodes. We then investigated the potential of the sensor for label-free and real-time analysis of living cell reactions in response to stimuli. We cultured rat basophilic leukemia (RBL)-2H3 cells on the sensor chip, which was a glass slide coated with comb-shaped electrodes, and detected activation of RBL-2H3 cells, such as degranulation and morphological changes, in response to a dinitro-phenol-conjugated human serum albumin (DNP-HSA) antigen. Moreover, impedance analysis revealed that the changes of impedance derived from RBL-2H3 cell activation appeared in the range of 1 kHz–1 MHz. Furthermore, we monitored living cell-derived RI and impedance changes simultaneously on a sensor chip using the SPRI-impedance sensor. Thus, we developed a new technique to monitor both impedance and RI derived from living cells by using a comb-shaped electrode sensor chip. This technique may enable us to clarify complex living cell functions which affect the RI and impedance and apply this to medical applications, such as accurate clinical diagnosis of type I allergy.

Many anesthetics, including Propofol, have been reported to induce elevation of intracellular calcium, and we were interested to investigate the possible contribution of calcium elevation to the mechanism of the newly approved remimazolam actions. Remimazolam is an intravenous anesthetic first approved in Japan in July 2020, and is thought to exert its anesthetic actions via γ-aminobutyric acid A (GABA A ) receptors; however, the precise mechanisms of how remimazolam elevates intracellular calcium levels remains unclear. We examined the remimazolam-induced elevation of intracellular calcium using SHSY-5Y neuroblastoma cells, COS-7 cells, HEK293 cells, HeLa cells, and human umbilical vein endothelial cells (HUVECs) loaded with fluorescent dyes for live imaging. We confirmed that high concentrations of remimazolam (greater than 300 μM) elevated intracellular calcium in a dose-dependent manner in these cells tested. This phenomenon was not influenced by elimination of extracellular calcium. The calcium elevation was abolished when intracellular or intraendoplasmic reticulum (ER) calcium was depleted by BAPTA-AM or thapsigargin, respectively, suggesting that calcium was mobilized from the ER. Inhibitors of G-protein coupled receptors (GPCRs)-mediated signals, including U-73122, a phospholipase C (PLC) inhibitor and xestospongin C, an inositol 1,4,5-triphosphate receptors (IP 3 R) antagonist, significantly suppressed remimazolam-induced calcium elevation, whereas dantrolene, a ryanodine receptor antagonist, did not influence remimazolam-induced calcium elevation. Meanwhile, live imaging of ER during remimazolam stimulation using ER-tracker showed no morphological changes. These results suggest that high doses of remimazolam increased intracellular calcium concentration in a dose-dependent manner in each cell tested, which was predicted to be caused by calcium mobilization from the ER. In addition, our studies using various inhibitors revealed that this calcium elevation might be mediated by the GPCRs-IP 3 pathway. However, further studies are required to identify which type of GPCRs is involved.

Background While immune checkpoint inhibitors (ICIs) occasionally cause immune-related adverse events (irAEs) in various organs, the prevalence of irAEs and potential risk factors have not been clarified. We identified irAE predictive factors and examined the relationship between the effect of ICIs and irAEs for patients with malignancies. Methods A total of 533 cases treated with ICIs, including programmed death 1 (PD-1), PD-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), for various malignancies were included retrospectively. We recorded irAEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 5. Prevalence and predictive factors associated with immune-related liver injury and the relationship between irAE and treatment response were analyzed. Results During a median of 10 (1–103) cycles with a median follow-up after several ICI initiations of 384 (21–1715) days, irAEs with all grades and with grade ≥ 3 developed in 144 (27.0%) and 57 (10.7%) cases. Cumulative irAE development rates were 21.9, 33.5, and 43.0% in all grades and 8.8, 14.9, and 20.7% in grade ≥ 3 at 5, 10, and 20 cycles, respectively. Patients who received anti-CTLA4 therapy were more likely to develop irAEs compared to those who received anti-PD-1 or anti-PD-L1 monotherapy. Liver injury was the most common irAE. Multivariate analysis identified the combination of PD-1 and anti-CTL-4 antibodies (hazard ratio [HR], 17.04; P  < 0.0001) and baseline eosinophil count ≥130/μL (HR, 3.01 for < 130; P  = 0.012) as independent risk factors for the incidence of immune-related liver injury with grade ≥ 2. Patients who developed irAEs had a higher disease control rate ( P  < 0.0001) and an increased overall survival rate compared to those without irAEs ( P  < 0.0001). Conclusion Combination therapy with anti-PD-1 and anti-CTL-4 antibodies resulted in higher a frequency of irAEs. Baseline absolute eosinophil count was found to be a predictive factor for immune-related liver injury. Occurrence of irAEs may be associated with higher efficacy of ICI treatment and longer survival among patients who receive ICI therapy.

Systemic sclerosis (SSc) is characterized by fibrosis of the skin and various internal organs. However, there is limited knowledge concerning small-bowel lesions. We evaluated the clinical state of patients with SSc according to the capsule endoscopy (CE) findings. Sixty-five consecutive patients with SSc (61 females; mean age, 64.3 years) underwent CE at Hiroshima University Hospital between April 2012 and December 2019. SSc was subclassified into diffuse and limited cutaneous SSc. Among the 65 patients, 55 (51 females; mean age, 64.5 years; diffuse cutaneous SSc, 27 patients) were evaluated for the presence of fibrosis in the gastrointestinal tract by biopsy. Small-bowel lesions were detected in 27 (42%) patients with SSc. Type 1b angioectasia (Yano-Yamamoto classification) was more frequent in limited cutaneous SSc patients (p = 0.0071). The average capsule transit time of the esophagus was significantly longer in diffuse cutaneous SSc patients (p = 0.0418). There were more cases of Type 1a angioectasia in SSc patients without fibrosis. The average capsule transit time of the esophagus was significantly longer in SSc patients with fibrosis. Thus, this study revealed that the frequency of small-bowel angioectasia and gastrointestinal motility in patients with SSc differed depending on SSc subclassification and the presence of fibrosis.

Chronic spontaneous urticaria (CSU) is characterized by daily recurring wheal and flare with itch for more than 6 weeks. The extrinsic coagulation system has been shown to be activated in correlation with CSU severity. We have reported that tissue factor (TF), a trigger of the extrinsic coagulation cascade, is synergistically expressed on vascular endothelial cells by simultaneous stimulation with TF inducers (TFI), followed by activation of the extrinsic coagulation cascade and hyper permeability in vitro. However, vascular endothelial cells are not likely to be simultaneously stimulated by multiple TFIs under physiological conditions. Therefore, in order to know whether sequential, rather than simultaneous, stimuli with interval may induce synergistic activation of TF, we investigated the time course of the priming effects of each TFI for synergistic TF expression in vascular endothelial cells (HUVECs). We stimulated HUVECs with a TFI (first stimulation) and then stimulated cells with another TFI at indicated time points (second stimulation) and detected TF expression and activity. The TF expression induced by simultaneous stimulation diminished in a few hours. However, both synergistic enhancement of TF expression and activation level of the coagulation cascade were detected even when the second stimulation was added 18 or 22 h after the first stimulation. Thus, the priming effect of TFI for synergistic TF expression may persist for a half day or longer.

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of skin and mucosal edema. The main treatment goal is to enable a “normal life” for all patients. However, due to high costs, there are limited options for the management of HAE in most developing and low-income countries. As a result, most of the recommended first-line treatments are not available. In this review, we attempt to highlight the disparities in health-care resources for the management of patients with HAE amongst different countries. Data was collected from HAE experts in countries who provide tabulated information regarding management and availability of HAE treatments in their countries. We reviewed the two most recent international HAE guidelines. Using India, the world’s second most populous country, as a paradigm for HAE management in lower-income countries, we reviewed the evidence for second-line and non-recommended practices reported by HAE experts. Results suggest significant inequities in provision of HAE services and treatments. HAE patients in low-income countries do not have access to life-saving acute drugs or recently developed highly effective prophylactic medications. Most low-income countries do not have specialized HAE services or diagnostic facilities, resulting in consequent long delays in diagnosis. Suggestions for optimizing the use of limited resources as a basis for future discussion and reaching a global consensus are provided. There is an urgent need to improve HAE services, diagnostics and treatments currently available to lower-income countries. We recommend that all HAE stakeholders support the need for global equity and access to these essential measures.

BackgroundSweat aggravates atopic dermatitis (AD). In patients with AD, type-I hypersensitivity to sweat may be shown by histamine release from patients’ basophils in response to the semi-purified sweat antigen (QR), and the presence of specific immunoglobulin E (IgE) binding to MGL_1304, the component of QR. However, there has been no information on the immunological changes of type-I hypersensitivity to the sweat antigen in patients with well-controlled AD using topical corticosteroids (TCSs) and/or biologics as treatments.MethodHistamine-releasing tests using patients’ basophils and QR and the detection of serum IgE against MGL_1304 and mite allergen Der f 1 were performed in patients with AD who were well controlled by topical TCS with/without dupilumab for 53–96 weeks.ResultsIn total, 14 patients were enrolled. Seven patients received TCS therapy alone (TCS group), and seven patients received TCS with dupilumab therapy (dupilumab group). In all participants, the level of specific IgE against MGL_1304 decreased after treatments, but histamine release from basophils in response to QR did not show a statistically significant reduction; rather, it increased. In the dupilumab group, all changes in histamine release induced by QR (increase), the IgE level against MGL_1304 (decrease), and that against Der f 1 (decrease) were statistically significant, whereas the TCS group showed no significant change in any of them.ConclusionThe well-controlled condition for 53–96 weeks resulted in no reduction of the hyperreactivity of basophils against in patients with AD, even with the treatment with dupilumab. This study suggests persistent basophil hyperreactivity to sweat antigen over a year or longer.