CXCR5+TIM-3-PD-1+ stem-like cytotoxic CD8+ T cells: elevated in chronic rhinosinusitis and associated with disease severity.

Background: Chronic rhinosinusitis (CRS) is a chronic inflammatory disease with an autoimmune background. Altered expression levels of T cell immunoglobulin and mucin-domain containing-3 (TIM-3), C-X-C chemokine receptor type 5 (CXCR5), and programmed cell death protein 1 (PD-1) are implicated in the progression of inflammatory and autoimmune diseases. Moreover, CXCR5+TIM-3-PD-1+ stem-like cytotoxic T cells function as memory stem cells during chronic disease processes and retain cytotoxicity-related gene networks. Objectives: To explore the expressions of CXCR5, TIM-3, and PD-1 on T cells and their correlation with clinical parameters in CRS. Methods: Flow cytometry was used to assess the expressions and co-expressions of CXCR5, TIM-3, and PD-1 on T cells in the tissues of the paranasal sinus and peripheral blood of patients with CRS as well as healthy controls. Immunofluorescence was used to assess the co-localization of TIM-3, CXCR5, and PD-1 with T cells. The disease severity of our patients with CRS was evaluated using the Lund-Mackay score. A complete blood count was also performed for the patients with CRS. Results: Expression levels of CXCR5 and PD-1 on T cells were significantly increased in the nasal tissues of patients with CRS. Compared with those in healthy controls, patients with CRS had high percentages of CXCR5+TIM-3-PD-1+ CD8+ and CD4+ T cells in nasal tissues, while no significant difference was observed in peripheral blood levels. Patients with CRS had a higher density of nasal CXCR5+TIM-3-PD-1+ T cells than that in healthy controls. CXCR5+TIM-3-PD-1+ CD8+ T cell levels in the nasal polyps of patients with CRS were negatively correlated with the patients' Lund-Mackay scores. The levels of CXCR5+TIM-3-PD-1+ T cells in nasal tissues were also negatively associated with disease duration and positively associated with the chronic inflammatory state of CRS. Conclusions: The level of CXCR5+TIM-3-PD-1+ stem cell-like T cells, especially CXCR5+TIM-3-PD-1+ CD8+ T cells, is increased in CRS. Therefore, inducing CXCR5+TIM-3-PD-1+ T cell exhaustion may be an effective immunotherapy for CRS.

Assessment of serum soluble CD40 ligand levels in patients with chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a disease highly associated with abnormal regulation of T and B cells. The underlying pathophysiology of inflammatory pathways has critical implications for the diagnosis and management of CRS. Soluble CD40-ligand (sCD40L) is a cleaved form of CD40L present in plasma which functions the same way as CD40L, which has been observed as an inflammatory biomarker in many diseases. CD40L-positive cells control B-cell maturation, proliferation, apoptosis, and antibody production by binding to its receptor CD40 on B-cells. And our results show for the first time that patients with CRS have lower serum sCD40L levels compared to healthy subjects and that decreased sCD40L levels in patients correlate with increased CD40L-positive cell counts in the sinonasal mucosa. In addition, eosinophilic chronic rhinosinusitis (eCRS) patients tend to exhibit more CD40L-positive cells in the sinonasal mucosa compared to non-eCRS patients. This supports the notion that local blockade of CD40/CD40L may suppress pathogenic T/B cell responses and reduce tissue inflammation. Significantly, sCD40L and CD40L may be involved in the development and progression of CRS by impairing peripheral blood B-cell function and enhancing the local inflammatory response in the sinonasal mucosa.

Mapping the intellectual structure of the research of omalizumab in chronic spontaneous urticaria: A bibliometric analysis.

Background: The guidelines for treating chronic spontaneous urticaria (CSU) recommend using the IgE-targeted biologic omalizumab in patients with antihistamine-refractory disease. Objective: Our aim was to present a bibliometric review of publications related to omalizumab and CSU over the past 2 decades. Methods: Relevant publications from 2003 to 2022 were extracted from the Science Citation Index-Expanded (SCI-EXPANDED) database in the Web of Science Core Collection database as of January 8, 2023. We utilized CiteSpace (version 6.1.R3), VOSviewer (version 1.6.18), and the R package (version 4.2.1) to analyze and visualize the data. The R package bibliometrix (version 4.2.1) was also used. Results: Between 2003 and 2022, a total of 566 articles on omalizumab and CSU were published. Since 2014, there has been a rapid increase in publication output. According to the collaboration network, the most influential country, institute, and scholar were the United States, Charité Universitätsmedizin Berlin, and Marcus Maurer, respectively. The study identified the Journal of Allergy and Clinical Immunology: In Practice as the most productive journal and the Journal of Allergy and Clinical Immunology as the most cocited journal. The analysis of key words revealed the presence of high-frequency terms such as angioedema, IgE, treatment, anti-IgE, asthma, and atopic dermatitis. Moreover, recent studies in this area have concentrated mainly on biomarkers, dupilumab, and coronavirus 2019 (COVID-19). Conclusion: There has been a growing interest in the use of omalizumab in CSU in recent years. The current trending topics in this research are the identification of biomarkers and the development of new mAbs for the treatment of CSU.

Visual and bibliometric analysis of chronic rhinosinusitis and nasal polyps.

Background: Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by persistent sinonasal inflammation and sinus microbiome dysbiosis. Nasal polyps (NPs) are one of the main manifestations that cause diverse clinical symptoms of CRS. Objective: We sought to conduct a bibliometric and visual analysis of articles on CRS and NPs published between 2003 and 2022 to provide researchers with the current state of research and potential directions. Methods: We searched relevant articles from 2003 to 2022 in the Web of Science database. VOSviewer and the Bibliometrix R package were used to perform the bibliometric analysis. Results: A total of 3907 publications were retrieved. The United States made the highest contributions to global research, followed by China. Northwestern University had the most publications. The most published author was C. Bachert, followed by R. P. Schleimer and R. J. Schlosser. The authors with the most co-citations were C. Bachert, W. J. Fokkens, and P. Gevaert. Moreover, the journal with the most publications was the International Forum of Allergy & Rhinology, and the Journal of Allergy and Clinical Immunology was the most cited. "Covid-19," "biologics," and "type 2 inflammation" were the top current research hotspots. Conclusions: The United States and Northwestern University were the leading country and institution in researching CRS and NPs. C. Bachert was the most influential expert. The International Forum of Allergy & Rhinology and the Journal of Allergy and Clinical Immunology were leading journals. "Covid-19," "biologics," and "type 2 inflammation" were the trending topics.

[Advances in next-generation sequencing technology to analyze the microbiome of patients with chronic sinusitis].

Chronic rhinosinusitis （CRS） is a chronic inflammatory disease of the sinus mucosa, and the pathogenesis of CRS has not been fully elucidated, and the impact of dysbiosis of the microbiome in the nasal cavity and even in the gut on the pathogenesis of CRS remains controversial. Next-generation sequencing technology, a culture-independent high-throughput sequencing method, contributes to a comprehensive understanding of the CRS microbiome. This article reviews the progress of research on the relevance of bacteria and other microorganisms to CRS and the microbial characteristics of the sinus and intestinal tract of patients with CRS, introduces next-generation sequencing technologies for the study of the CRS microbiome, and discusses the therapeutic prospects of CRS and the possibility of probiotic therapy.

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Stem cell-like memory T (TSCM) cell is a memory T cell subset with characteristics of long life span, consistent self-renewing, and the multipotent capacity to reconstitute the memory and effector T cell subsets. TSCM cell is the least differentiated cell in the memory T lymphocyte system, endowed with the stem cell-like ability, and it is essential for maintaining functional immunity. In addition, owing to its robust potential for immune reconstitution, it is central player in many physiological and pathological human processes. TSCM cell plays an important role in the occurrence and development of various autoimmune diseases. The specific role of TSCM cell in autoimmune diseases may make it a potential target for the treatment of multiple autoimmune diseases, driving effective immune reconstitution in therapy.

Involvement of CD40-CD40L and ICOS-ICOSL in the development of chronic rhinosinusitis by targeting eosinophils.

Background: Chronic rhinosinusitis (CRS), whose prevalence and pathogenesis are age-related, is characterized by nasal tissue eosinophil infiltration. CD40-CD40 ligand (CD40L) pathway involves in the eosinophil-mediated inflammation, and inducible co-stimulator (ICOS)-ICOS ligand (ICOSL) signal can strengthen CD40-CD40L interaction. Whether CD40-CD40L and ICOS-ICOSL have a role in the development of CRS remains unknown. Objectives: The aim of this study is to investigate the association of CD40-CD40L and ICOS-ICOSL expression with CRS and underlying mechanisms. Methods: Immunohistology detected the expression of CD40, CD40L, ICOS, and ICOSL. Immunofluorescence was performed to evaluate the co-localizations of CD40 or ICOSL with eosinophils. Correlations between CD40-CD40L and ICOS-ICOSL as well as clinical parameters were analyzed. Flow cytometry was used to explore the activation of eosinophils by CD69 expression and the CD40 and ICOSL expression on eosinophils. Results: Compared with the non-eCRS subset, ECRS (eosinophilic CRS) subset showed significantly increased CD40, ICOS, and ICOSL expression. The CD40, CD40L, ICOS, and ICOSL expressions were all positively correlated with eosinophil infiltration in nasal tissues. CD40 and ICOSL were mainly expressed on eosinophils. ICOS expression was significantly correlated with the expression of CD40-CD40L, whereas ICOSL expression was correlated with CD40 expression. ICOS-ICOSL expression positively correlated with blood eosinophils count and disease severity. rhCD40L and rhICOS significantly enhanced the activation of eosinophils from patients with ECRS. Tumor necrosis factor-α (TNF-α) and interleukin-5 (IL-5) obviously upregulated CD40 expression on eosinophils, which was significantly inhibited by the p38 mitogen-activated protein kinase (MAPK) inhibitor. Conclusions: Increased CD40-CD40L and ICOS-ICOSL expressions in nasal tissues are linked to eosinophils infiltration and disease severity of CRS. CD40-CD40L and ICOS-ICOSL signals enhance eosinophils activation of ECRS. TNF-α and IL-5 regulate eosinophils function by increasing CD40 expression partly via p38 MAPK activation in patients with CRS.

[Correlation between chronic sinusitis subtypes and basophil levels in peripheral blood].

Objective:To explore the clinical correlation between peripheral blood basophil levels and chronic sinusitis （CRS） subtypes. Methods:One hundred and twenty-six patients with CRS and 103 healthy cases from physical examination admitted to the First Affiliated Hospital of Soochow University from January 2021 to October 2022 were retrospectively analyzed. According to the histopathological classification, CRS patients were divided into eosinophilic chronic sinusitis （eCRS） group （47 cases） and non eosinophilic chronic sinusitis （non-eCRS） group （79 cases）. The differences among the three groups in peripheral blood inflammation cell counts, eosinophils-to-basophils ratio（bEBR）, basophils-to-neutrophils ratio（BNR）, basophils-to-lymphocytes ratio（BLR）, basophils-to-monocytes ratio（BMR） were compared, and study the correlation between each index and Lund-Mackay score, and the correlation between basophils in peripheral blood and other inflammatory cells. Results:The counts of basophils in the peripheral blood of the healthy control group, eCRS group and non-eCRS group were 0.03±0.01, 0.04±0.02, 0.03±0.02, respectively, the eosinophils-to-basophils ratio（bEBR） were 5.64±4.22, 8.38±5.95, 4.55±3.90, the basophils-to-neutrophils ratio（BNR） were 0.01±0, 0.01±0.01, 0.01±0.01, and the basophils-to-lymphocytes ratio（BLR） were 0.01±0.01, 0.02±0.01, and 0.02±0.01, respectively, the basophils-to-monocytes ratio（BMR） were 0.08±0.04, 0.11±0.06, and 0.08 ±0.04 respectively. There was a statistically significant difference between eCRS group and healthy control group, non-eCRS group（P<0.01）, while there was no statistically significant difference between non-eCRS group and healthy control group（P>0.05）. Basophil counts （r=0.185 5, P<0.05）, BLR（r=0.226 9, P<0.05）, BMR（r=0.228 1, P<0.01） in patients with CRS were positively correlated with Lund Makey score. In addition, basophils were also positively correlated with eosinophils（r=0.479 2, P<0.01）, lymphocytes（r=0.259 4, P<0.01）, and monocytes（r=0.256 4, P<0.01） in patients with CRS. Conclusion:The peripheral blood basophil count, BLR and BMR were significantly increased in eCRS, and were significantly positively correlated with Lund -Makey score. It has the potential to develop into disease biomarkers and new therapeutic targets of eCRS.

Galectin-9 contributes to the pathogenesis of atopic dermatitis via T cell immunoglobulin mucin-3.

Background: Atopic dermatitis (AD), a common type 2 inflammatory disease, is driven by T helper (TH) 2/TH22polarization and cytokines.Galectin-9 (Gal-9), via its receptor T cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3), can promote TH2/TH22 immunity. The relevance of this in AD is largely unclear. Objectives: To characterize the role of TIM-3 and Gal-9 in the pathogenesis of AD and underlying mechanisms. Methods: We assessed the expression of Gal-9 and TIM-3 in 30 AD patients, to compare them with those of 30 healthy controls (HC) and to explore possible links with disease features including AD activity (SCORAD), IgE levels, and circulating eosinophils and B cells. We also determined the effects of Gal-9 on T cells from the AD patients. Results: Our AD patients had markedly higher levels of serum Gal-9 and circulating TIM-3-expressing TH1 and TH17 cells than HC. Gal-9 and TIM-3 were linked to high disease activity, IgE levels, and circulating eosinophils and/or B cells. The rates of circulating TIM-3-positive CD4+ cells were positively correlated with rates of TH2/TH22 cells and negatively correlated with rates of TH1/TH17 cells. Gal-9 inhibited the proliferation and induced the apoptosis of T cells in patients with AD, especially in those with severe AD. Conclusion: Our findings suggest thatGal-9, via TIM-3, contributes to the pathogenesis of AD by augmenting TH2/TH22 polarization through the downregulation of TH1/TH17immunity. This makes Gal-9 and TIM-3 interesting to explore further, as possible drivers of disease and targets of novel AD treatment.

The Number of MRGPRX2-Expressing Cells Is Increased in Skin Lesions of Patients With Indolent Systemic Mastocytosis, But Is Not Linked to Symptom Severity.

Background: Recently, the expression of the mast cell (MC) receptor Mas-related G protein-coupled receptor X2 (MRGPRX2) has been detected in lesional skin of adult patients with cutaneous mastocytosis. As of yet, little is known about the clinical relevance of MRGPRX2 and its agonists in patients with mastocytosis, including indolent systemic mastocytosis (ISM). Methods: MRGPRX2 and MRGPRX2 agonists, cortistatin (CST), and major basic protein (MBP) were analyzed in lesional and non-lesional skin of patients with ISM and skin of healthy controls by immunohistochemistry. Co-localization of MRGPRX2 and MRGPRX2-mRNA with the MC marker tryptase was assessed by immunofluorescence microscopy and in situ hybridization, respectively. We assessed clinical, demographic, and laboratory data, including mastocytosis activity score (MAS), serum tryptase, and KIT D816V allele burden. Results: The number of MRGPRX2-expressing (MRGPRX2+) cells, MRGPRX2-mRNA+ MCs, and CST-expressing (CST+) and MBP-expressing (MBP+) cells was significantly higher in lesional skin as compared to non-lesional skin and/or skin of healthy controls (all p < 0.05). Increased numbers of MRGPRX2+ cells, MRGPRX2-mRNA+ MCs, and CST+ and MBP+ cells were not associated with clinical and laboratory features of ISM, including disease burden, symptom severity, evidence of anaphylaxis, and tryptase levels. Conclusions: Skin lesions of patients with ISM showed high numbers of MRGPRX2+ cells, although they were not linked to symptom severity. Clinical relevance of the MRGPRX2-mediated pathway of MC activation in ISM remains unclear and should be investigated in further studies.

Folic acid-targeted pluronic F127 micelles improve oxidative stress and inhibit fibrosis for increasing AKI efficacy.

The oxidative stress and activation of the fibrosis pathway are essential pathological mechanisms of acute kidney injury (AKI). In this article, we designed a drug delivery system that could effectively improve oxidative stress and relieve fibrosis by the combination of precise targeting, solubilization, and reducing the toxicity of nano-transport system to strengthen the efficacy of AKI. Folic acid (FA) was used as the targeting molecule, and curcumin (Cur) and resveratrol (Res), which are Chinese medicine monomers with anti-inflammatory and antioxidant effects, were used as model drugs. Here, the targeting nanosystem (Cur/Res@FA-F127/TPGS) co-loaded with Cur and Res was successfully synthesized. Finally, the comprehensive therapeutic effect of the nanosystem was evaluated through the targeted and pharmacodynamic researches on the AKI models induced by cisplatin (CDDP) in vitro and in vivo. The studies in vitro proved that the nanosystem could not only specifically target HK-2 cells and promote the effective accumulation of Cur and Res in the kidney, but also effectively improve oxidative stress by eliminating reactive oxygen species (ROS), stabilizing mitochondrial membrane potential (MMP), and reducing the expression of apoptosis-related proteins. The studies in vivo showed that the nanosystem could effectively play the role of anti-oxidation, anti-inflammatory and alleviate fibrosis to reduce the apoptosis and necrosis of renal tubular cells. The nanosystem could coordinately repair damaged HK-2 cells by improving oxidative stress, inhibiting inflammation and tissue fibrosis, which provided a new idea for the treatment of AKI.

Co-delivery of celastrol and lutein with pH sensitive nano micelles for treating acute kidney injury.

To treat acute kidney injury with high efficiency and low toxicity, a novel nanoplatform was developed to remove excess reactive oxygen species (ROS). Lutein (LU) and celastrol (Cel) were loaded into low molecular weight chitosan (CS) to prepare Cel@LU-CA-CS nanomicelles. Renal tubular epithelial (HK-2) cell uptake experiments showed that the drugs could be internalized in renal tubular via the megalin receptor. In this study, the amide bond formed by the reaction of citraconic anhydride (CA) with an amino group of CS could be destroyed under acidic conditions. Therefore, the drugs were released in HK-2 cells due to the acidic environment of the lysosome. In vitro studies showed that the nanomicelles could reduce toxicity in non-target organs and enhance therapeutic efficacy in acute kidney injury (AKI). In addition, Cel@LU-CA-CS micelles had alleviated kidney oxidative stress disorder and stabilized the mitochondrial membrane potential quickly. Next, in vivo studies proved that Cel@LU-CA-CS micelles could inhibit the activation of the NF-κB p65 and p38 MAPK inflammatory signaling pathways. Therefore, the micelles further reduced the overexpression of related inflammatory factors. In conclusion, Cel@LU-CA-CS nanomicelles could treat AKI with high efficiency and low toxicity, and inhibit renal fibrosis.

Nanozyme-natural enzymes cascade catalyze cholesterol consumption and reverse cancer multidrug resistance.

Multidrug resistance is still a major obstacle to cancer treatment. The most studies are to inhibit the activity of the drug transporter P-glycoprotein (P-gp), but the effect is not ideal. Herein, a nanosystem was built based on cascade catalytic consumption of cholesterol. Cholesterol oxidase (natural enzyme, COD) was immobilized on the carrier (NH2-MIL-88B, MOF) through amide reaction, COD catalyzed the consumption of cholesterol, the reaction product H2O2 was further produced by the MOF with its peroxidase-like activity to produce hydroxyl radicals (•OH) with killing effect. Due to the high expression of CD44 receptor on the surface of tumor cells, we encapsulated chondroitin sulfate gel shell (CS-shell) with CD44 targeting and apoptosis promoting effect on the surface of DOX@MOF-COD nanoparticles, which can accurately and efficiently deliver the drugs to the tumor site and improve the effect of reversing drug resistance. Taking drug-resistant cell membrane as "breakthrough", this paper will provide a new idea for reversing multidrug resistance of tumor.

Mast cells, cortistatin, and its receptor, MRGPRX2, are linked to the pathogenesis of chronic prurigo.

BACKGROUND: Chronic prurigo (CPG) is characterized by intensive itch and interactions among nerves, neuropeptides, and mast cells (MCs). The role of some neuropeptides such as cortistatin (CST) and its receptor, Mas-related G protein-coupled receptor X2 (MRGPRX2), in CPG remains poorly investigated. OBJECTIVES: We evaluated first whether CST activates human skin MCs, and second whether CST and MRGPRX2 are expressed in the skin of CPG patients, and by which cells. METHODS: Skin prick tests and microdialysis with CST were performed in 6 and 1 healthy volunteers, respectively. Degranulation of human skin MCs was assessed using ß-hexosaminidase and histamine release assays. Skin samples from 10 patients with CPG and 10 control subjects were stained for CST, MCs, and MRGPRX2 (protein and mRNA) using immunohistochemistry, immunofluorescence, and/or in situ hybridization. Flow cytometry was used to assess CST in human skin MCs. MRGPRX2 levels were measured in serum by ELISA. RESULTS: CST induced concentration-dependent degranulation of human skin MCs in vivo and ex vivo. Skin lesions of CPG patients exhibited markedly higher numbers of CST-expressing cells, CST-expressing MCs, MRGPRX2-expressing cells, and MRGPRX2 mRNA-expressing cells than nonlesional skin. MCs were the main MRGPRX2 mRNA-expressing cells in the lesions of most CPG patients (70%). Stimulation of human skin MCs with anti-IgE led to a release of CST. The number of MRGPRX2-expressing cells correlated with disease severity (r = 0.649, P = .04). MRGPRX2 serum levels in CPG patients correlated with disease severity (r = 0.704, P = .023) and quality-of-life impairment (r = 0.687, P = .028). CONCLUSIONS: CST and MRGPRX2 may contribute to the pathogenesis of CPG and should be evaluated in further studies as potential biomarkers and novel therapeutic targets.

Glutamine Metabolism-Regulated Nanoparticles to Enhance Chemoimmunotherapy by Increasing Antigen Presentation Efficiency.

Although the strategies to induce dendritic cells (DCs) maturation and promote their antigen presentation can stimulate the tumor immune response, the endogenous deficiency and immunosuppression of DCs reduce antigen utilization, which limits antigen presentation efficiency and reduces immunotherapy effectiveness. Here, we report an endogenous stimulus-responsive nanodelivery system (DOX@HFn-MSO@PGZL). On the one hand, doxorubicin (DOX) promoted antigen presentation by DCs after the immunogenic death of tumor cells. On the other hand, l-methionine sulfoximine (MSO) regulated the glutamine metabolism of tumor-associated macrophages (TAMs) to induce a shift toward the M1-type. M1-TAMs synergistically presented antigens with mature DCs and were more frequently produced to destroy the tumor suppressive immune microenvironment, resulting in the alleviation of DCs functional inhibition. Ultimately, the antigen presentation efficiency was improved, completely activating tumor immunity and exhibiting powerful antitumor effects.

The Diagnostic Workup in Chronic Spontaneous Urticaria-What to Test and Why.

BACKGROUND: In chronic spontaneous urticaria (CSU), the guidelines recommend very limited diagnostic procedures during the routine workup, although additional investigations might be indicated in some patients with CSU. For physicians treating patients with CSU, it is often difficult to decide which diagnostic tests are useful. OBJECTIVE: To provide recommendations on what diagnostic tests should be performed on which patients with CSU. METHODS: We performed an extensive literature search on the respective topics and identified relevant questions that should prompt diagnostic procedures based on the published evidence and expert consensus among all authors. RESULTS: We provide questions, diagnostic testing, where appropriate, and recommendation that should be included when assessing the history of a patient with CSU, to explore and rule out differential diagnoses, to assess patients for underlying causes and modifying conditions, to explore patients for comorbid diseases and consequences of having CSU, and to assess patients for CSU components that can help to predict their disease course and response to treatment. CONCLUSIONS: Here, we provide physicians treating patients with CSU with information about which clues should lead to which tests and why.

Total IgE as a Marker for Chronic Spontaneous Urticaria.

OBJECTIVE: Immunoglobulin E (IgE) and its receptor, FcɛRI, importantly contribute to the pathophysiology of chronic spontaneous urticaria (CSU). Recent findings point to a possible role of total IgE as a marker of CSU disease activity, endotypes, and responses to treatment. The evidence in support of total IgE included in the diagnostic workup of patients with CSU has not yet been reviewed. METHODS: Publications were searched via PubMed. The search terms used were "chronic urticaria" and "total IgE." Studies were screened by titles and abstracts, and 141 were used in the review. RESULTS: CSU patients frequently had elevated total IgE serum levels (up to 50%), but normal or very low total IgE levels also occurred. High total IgE may represent high disease activity, longer disease duration, high chance of responding to omalizumab treatment, quick relapse after stopping omalizumab, and lower chance of responding to cyclosporine. Low IgE, in contrast, may suggest Type IIb autoimmune CSU, poor response to treatment with omalizumab and a better chance to benefits from cyclosporine treatment. Furthermore, IgE in different CSU cohorts may have different physicochemical properties that could explain differences in treatment responses to IgE-directed therapies. CONCLUSION: The results of our review suggest that total IgE is a valuable marker for CSU, and we recommend its assessment in the routine diagnostic workup of CSU patients.

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.

Bioinformatic analysis reveals hub genes and pathways that promote melanoma metastasis.

BACKGROUND: Melanoma has the highest mortality rate of all skin tumors, and metastases are the major cause of death from it. The molecular mechanism leading to melanoma metastasis is currently unclear. METHODS: With the goal of revealing the underlying mechanism, three data sets with accession numbers GSE8401, GSE46517 and GSE7956 were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the differentially expressed gene (DEG) of primary melanoma and metastatic melanoma, three kinds of analyses were performed, namely functional annotation, protein-protein interaction (PPI) network and module construction, and co-expression and drug-gene interaction prediction analysis. RESULTS: A total of 41 up-regulated genes and 79 down-regulated genes was selected for subsequent analyses. Results of pathway enrichment analysis showed that extracellular matrix organization and proteoglycans in cancer are closely related to melanoma metastasis. In addition, seven pivotal genes were identified from PPI network, including CXCL8, THBS1, COL3A1, TIMP3, KIT, DCN, and IGFBP5, which have all been verified in the TCGA database and clinical specimens, but only CXCL8, THBS1 and KIT had significant differences in expression. CONCLUSIONS: To conclude, CXCL8, THBS1 and KIT may be the hub genes in the metastasis of melanoma and thus may be regarded as therapeutic targets in the future.

The role of eosinophils in chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is considered to be primarily a mast cell-driven disease. However, recent evidence suggests that eosinophils may also have an axial role in symptomology. Histologic studies have demonstrated the presence of both eosinophils and eosinophil granules, indicative of activation, in CSU lesions. Although many allergic and inflammatory conditions are associated with a peripheral blood eosinophilia, the converse appears to be the case in CSU, with a peripheral blood eosinopenia being observed in many patients. Possible mechanisms include the depletion of blood eosinophils by recruitment into the skin during active disease and immunologic destruction in the blood. We also address in some detail the interactions between eosinophils and mast cells, particularly the cytokine cross-talk of these cells and mediator release possibly leading to clinical symptoms. Also, activation by eosinophil proteins of the coagulation pathway leads to the generation of thrombin and increased mast cell degranulation. Finally, treatments aimed at reducing eosinophil accumulation and activation, such as the anti-IL-5 antibodies mepolizumab, reslizumab, and benralizumab, have been reported to reduce CSU symptoms. Clearly, a new picture of an important role of eosinophils in the pathogenesis of CSU is emerging.