Amphiregulin-Producing Pathogenic Memory T Helper 2 Cells Instruct Eosinophils to Secrete Osteopontin and Facilitate Airway Fibrosis.

Memory T cells provide long-lasting protective immunity, and distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes remain unknown. We found that interleukin-33 (IL-33) enhanced amphiregulin production by the IL-33 receptor, ST2hi memory T helper 2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of amphiregulin-producing CRTH2hiCD161hiCD45RO+CD4+ Th2 cells and osteopontin-producing eosinophils. Thus, the IL-33-amphiregulin-osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders.

S100A8 enhances IL-1ß production from nasal epithelial cells in eosinophilic chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis is classified into eosinophilic chronic rhinosinusitis (ECRS) and non-eosinophilic chronic rhinosinusitis (NECRS). ECRS is a refractory allergic disease involving a variety of immune and epithelial cells. S100A8 is a damage-associated molecular pattern that is closely related to allergic inflammation. However, the pathological implications of S100A8 in ECRS have not been clarified. METHODS: We evaluated the role of S100A8 in the pathogenesis of ECRS. Gene expression profiles of nasal polyps obtained from patients with ECRS or NECRS were evaluated using RNA sequencing. RESULTS: S100A8 was identified as a significantly upregulated gene in nasal polyps associated with ECRS. Immunohistochemistry consistently revealed intense S100A8 staining in nasal polyps from patients with ECRS. Human nasal epithelial cells expressed the receptor for advanced glycation end products and Toll-like receptor 4. Recombinant S100A8 protein induced interleukin-1ß secretion in human nasal epithelial cells. CONCLUSIONS: Our data demonstrate that S100A8 results in production of interleukin-1ß in the nasal epithelium, which may be involved in the pathogenesis of ECRS.

Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis.

BACKGROUND: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis. Clinical markers for ECRS disease activity and treatment strategies have not been sufficiently established. Although semaphorins are originally identified as neuronal guidance factors, it is becoming clear that they play key roles in immune regulation and inflammatory diseases. OBJECTIVE: We sought to investigate the pathological functions and therapeutic potential of semaphorin 4D (SEMA4D) in ECRS. METHODS: Serum soluble SEMA4D levels in patients with paranasal sinus diseases were measured by ELISA. The expression of SEMA4D in blood cells and nasal polyp tissues was assessed by flow cytometry and immunohistochemistry, respectively. Generation of soluble SEMA4D was evaluated in matrix metalloproteinase-treated eosinophils. Endothelial cells were stimulated with recombinant SEMA4D, followed by eosinophil transendothelial migration assays. Allergic chronic rhinosinusitis was induced in mice using Aspergillus protease with ovalbumin. The efficacy of treatment with anti-SEMA4D antibody was evaluated histologically and by nasal lavage fluid analysis. RESULTS: Serum soluble SEMA4D levels were elevated in patients with ECRS and positively correlated with disease severity. Tissue-infiltrated eosinophils in nasal polyps from patients with ECRS stained strongly with anti-SEMA4D antibody. Cell surface expression of SEMA4D on eosinophils from patients with ECRS was reduced, which was due to matrix metalloproteinase-9-mediated cleavage of membrane SEMA4D. Soluble SEMA4D induced eosinophil transendothelial migration. Treatment with anti-SEMA4D antibody ameliorated eosinophilic infiltration in sinus tissues and nasal lavage fluid in the ECRS animal model. CONCLUSIONS: Eosinophil-derived SEMA4D aggravates ECRS. Levels of serum SEMA4D reflect disease severity, and anti-SEMA4D antibody has therapeutic potential as a treatment for ECRS.

Multiple Biological Aspects of Eosinophils in Host Defense, Eosinophil-Associated Diseases, Immunoregulation, and Homeostasis: Is Their Role Beneficial, Detrimental, Regulator, or Bystander?

Eosinophils are innate immune leukocytes and play important roles as terminal effector cells owing to their mediators, such as tissue-destructive cationic proteins, cytokines, chemokines, and lipid mediators. Historically, they are not only considered an important player in host defense against parasitic, viral, fungal, and bacterial infections but also implicated in the pathogenesis of eosinophil-associated diseases, such as allergic rhinitis, asthma, eosinophilic chronic rhinosinusitis, esophagitis, atopic dermatitis, myopathies, and hypereosinophilic syndrome. Moreover, recent studies have shown that eosinophils have an immune regulatory and homeostatic function. Interestingly, there is emerging evidence that eosinophils are accumulated through adoptive T-helper 2 (Th2) and innate Th2 responses, mechanisms of the classical allergen-specific immunoglobulin E (IgE)-mediated response, and group 2 innate lymphoid cell-derived interleukin-5, respectively. Furthermore, in agreement with current concepts of eosinophil subtypes, it has been shown that resident and phenotypically distinct eosinophils, i.e., resident and recruited inflammatory eosinophils, exist in inflamed sites, and each has different functions. Thus, the classical and novel studies suggest that eosinophils have multiple functions, and their roles may be altered by the environment. In this article, we review multiple biological aspects of eosinophils (novel and classical roles), including their beneficial and detrimental effects, immunoregulation, and homeostatic function.

Residual exhaled nitric oxide elevation in asthmatics is associated with eosinophilic chronic rhinosinusitis.

OBJECTIVE: Eosinophilic chronic rhinosinusitis (ECRS) is as a subgroup of chronic rhinosinusitis (CRS) with nasal polyps. ECRS is a refractory disease closely related to bronchial asthma. Fractionated exhaled nitric oxide (FeNO) levels were reportedly elevated in some asthmatics with CRS after adequate treatment, suggesting that residual eosinophilic airway inflammation or ECRS might affect FeNO levels. METHODS: To investigate the association between asthma with ECRS and FeNO levels, we examined FeNO levels in 133 asthmatics (99 with ECRS and 34 without ECRS) and 13 patients with ECRS without asthma. The severity of asthma was defined by the Global Initiative for Asthma guidelines and that of sinusitis was evaluated by the sinus CT score based on the Lund-Mackay scale. RESULTS AND CONCLUSIONS: FeNO levels were elevated even in well-controlled asthmatics with ECRS, whereas asthmatics without ECRS and ECRS patients without asthma did not have high FeNO levels (>50 ppb). Although FeNO levels were not correlated with asthma severity, they were positively correlated with the sinus CT score. In asthmatics with ECRS, patients with higher FeNO levels had more severe ECRS and asthma. There is a possibility of having comorbid ECRS, particularly in asthmatics with high FeNO levels even after adequate treatment, including ICS, suggesting that asthma and ECRS may be closely associated as one airway disease with eosinophilic inflammation. Continual awareness of the coexistent ECRS is ideally recommended for asthmatics with high FeNO levels.

Blood Eosinophil Percentage and Improved Sinus CT Score as Diagnostic Tools for ECRS.

Objective: Differentiating 2 types of chronic rhinosinusitis with nasal polyps (CRSwNP) is important for the treatment. The current diagnostic methods using single indicators, including peripheral blood eosinophils and traditional sinus computed tomography (CT) scores, are not accurate. In this study, we aimed to investigate the diagnostic value of combining peripheral blood eosinophils and improved sinus CT scores for eosinophic chronic rhinosinusitis (ECRS). Study Design: Retrospective cohort. Setting: Tertiary medical center. Methods: We conducted a study involving 81 patients with CRSwNP. Peripheral blood samples were collected from the non-ECRS and ECRS groups. Improved three-dimensional volume image analysis and Lund-Mackay scoring system were performed to quantify the thickening of sinus mucosa. Multivariate binary logistic regression analysis was carried out to detect the predictive value of the scoring indicators. For significant indexes, receiver operating characteristic (ROC) curve analysis was applied. Results: The ECRS group had higher levels of blood eosinophil percentage and count, ethmoid sinus score, total sinus score, the ratio of ethmoid sinus score and maxillary sinus score, and the difference between ethmoid and maxillary score, compared to the non-ECRS group (P < 0.05). Binary logistic regression analysis demonstrated that both blood eosinophil percentage and the improved E - M score (subtraction of ethmoid and maxillary sinus scores) were significant predictors of ECRS diagnosis (P < .01). ROC curve analysis indicated that the combination of improved E - M score and blood eosinophil percentage had a higher diagnostic value compared to either factor alone (area under the curve = 0.874). Conclusion: Our study suggested the combination of improved total ethmoid sinus-maxillary score and blood eosinophil percentage is more accurate in predicting the diagnosis of ECRS.

The current findings in eosinophilic chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a persistent inflammatory disease of the nasal cavity and paranasal sinuses. Traditional classification is denoted by the presence (CRSwNP) or absence of nasal polyps (CRSsNP). Particularly, CRSwNP is distinguished by the presence of infiltrating cells and inflammatory markers in the nasal mucosa. Patients with CRSwNP in Western countries predominantly display a type 2 endotype, whereas those in Asian regions display a mixed type 2 endotype. Nevertheless, recent transcriptome analyses have revealed two types of nasal polyps - type 2 and non-type 2 polyps, suggesting that geographical differences in endotypes likely resulted from the different proportions of each endotype. Moreover, various endotypes of CRSsNP have been identified, making phenotype a crucial factor for predicting treatment efficacy. Type 2 endotypes, designated as eosinophilic CRS (ECRS) in Japan, are characterized by severe eosinophilic infiltration into the paranasal sinus tissue and are particularly refractory. In this review, we discuss the latest developments in ECRS. We also provide recent findings on the involvement of nasal epithelial cells in pathogenesis.

A Case of Pott's Puffy Tumor in a Patient With Eosinophilic Chronic Rhinosinusitis.

Eosinophilic chronic rhinosinusitis (ECRS) is a refractory type 2 inflammation-based airway allergic disease that is prone to complications such as bronchial asthma. Pott's puffy tumor (PPT) is a rare clinical entity characterized by osteomyelitis of the frontal bone accompanied by a subperiosteal abscess. A 56-year-old female with a history of cranial surgery and bronchial asthma presented to an otolaryngology clinic with nasal obstruction and loss of smell, later developing swelling and redness on her forehead. She was diagnosed and treated for ECRS and was thought to have developed PPT during her course. Nasal endoscopy reveals bilateral polyp formation originating from the middle meatus. Paranasal computed tomography (CT) indicates substantial swelling extending from the opening of the frontal sinus to the adjacent subcutaneous tissue, accompanied by a defect in the frontal bone and osteolysis at the base of the frontal skull. Her management included conservative antibiotic therapy adjusted due to a drug eruption and, subsequently, endoscopic sinus surgery (ESS). The case was complicated by the patient's medical history and the absence of detailed surgical records, which limited the use of enhanced imaging techniques. This underscores the complexity of diagnosing and managing PPT in adults, particularly those with prior surgeries, emphasizing the need for a tailored diagnostic and therapeutic approach that integrates detailed patient history with current clinical indicators to effectively guide treatment. This case contributes to the limited literature on adult PPT and underscores the critical need for careful patient monitoring and detailed surgical history.

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.

Systematic Review of Protein Biomarkers in Adult Patients With Chronic Rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous condition characterized by differing inflammatory endotypes. The identification of suitable biomarkers could enable personalized approaches to treatment selection. OBJECTIVE: This study aimed to identify and summarize clinical studies of biomarkers in adults with CRS in order to inform future research into CRS endotypes. METHODS: We conducted systematic searches of MEDLINE and Web of Science from inception to January 30, 2022 and included all clinical studies of adult CRS patients and healthy controls measuring biomarkers using enzyme-linked immunosorbent assays or Luminex immunoassays. Outcomes included the name and tissue type of identified biomarkers and expression patterns within CRS phenotypes. Study quality was assessed using the National Institutes of Health quality assessment tool for observational cohort and cross-sectional studies. A narrative synthesis was performed. RESULTS: We identified 78 relevant studies involving up to 9394 patients, predominantly with CRS with nasal polyposis. Studies identified 80 biomarkers from nasal tissue, 25 from nasal secretions, 14 from nasal lavage fluid, 24 from serum, and one from urine. The majority of biomarkers found to distinguish CRS phenotypes were identified in nasal tissue, especially in nasal polyps. Serum biomarkers were more commonly found to differentiate CRS from controls. The most frequently measured biomarker was IL-5, followed by IL-13 and IL-4. Serum IgE, IL-17, pentraxin-3 and nasal phospho-janus kinase 2, IL-5, IL-6, IL-17A, granulocyte-colony stimulating factor, and interferon gamma were identified as correlated with disease severity. CONCLUSION: We have identified numerous potential biomarkers to differentiate a range of CRS phenotypes. Future studies should focus on the prognostic role of nasal tissue biomarkers or expand on the more limited studies of nasal secretions and nasal lavage fluid.We registered this study in PROSPERO (CRD42022302787).

An Unusual Case of Eosinophilic Chronic Rhinosinusitis With Concurrent Eosinophilic Otitis Media: Limited Responsiveness to Multiple Antibody Therapies and Subsequent Cochlear Implantation.

Eosinophilic chronic rhinosinusitis (ECRS) and eosinophilic otitis media (EOM) are debilitating inflammatory conditions that affect the paranasal sinuses and middle ear, respectively, and are characterized by eosinophilic infiltration. This study describes a rare and intricate case of a 65-year-old male patient concurrently afflicted with ECRS, EOM, and bronchial asthma. Despite the systematic administration of corticosteroids and various antibody drugs, the patient's condition remained unimproved, necessitating a cochlear implant for EOM, which is seldom an aggressive intervention. The patient had a history of symptoms dating back to 2005, with notable exacerbations and treatment resistance over the years. Multiple antibody drugs, including anti-IgE, anti-IL-5, and anti-IL-4α antibodies, failed to ameliorate the patient's condition, presenting a significant clinical challenge. Pathological examination revealed marked eosinophilic infiltration and severe fibrosis, suggesting a possible mechanism underlying the poor response to antibody therapy. Cochlear implantation significantly enhanced the patient's communicative abilities. This case highlights the limitations of the current antibody drugs in managing severely intertwined cases of ECRS, EOM, and bronchial asthma, highlighting the need for novel therapeutic strategies. This case also propounds cochlear implantation as an efficacious intervention for refractory EOM with severe sensorineural hearing impairment, extending the spectrum of treatment modalities for such challenging scenarios. This singular case contributes to the growing body of evidence regarding the management of ECRS and EOM, especially against the backdrop of treatment resistance, and can aid clinicians in identifying and navigating similar complex cases in clinical practice.

An analytical framework-based pedagogical method for scholarly community coaching: A proof of concept.

Working in academia is challenging, even more so for those with limited resources and opportunities. Researchers around the world do not have equal working conditions. The paper presents the structure, operation method, and conceptual framework of the SM3D Portal's community coaching method, which is built to help Early Career Researchers (ECRs) and researchers in low-resource settings overcome the obstacle of inequality and start their career progress. The community coaching method is envisioned by three science philosophies (cost-effectiveness, transparency spirit, and proactive attitude) and established and operated based on the Serendipity-Mindsponge-3D knowledge (SM3D) management framework (i.e., mindsponge thinking and Bayesian Mindsponge Framework analytics serve as the coaching program's foundational theory and analytical tools). The coaching method also embraces Open Science's values for lowering the cost of doing science and encouraging the trainees to be transparent, which is expected to facilitate the self-correcting mechanism of science through open data, open review, and open dialogue. Throughout the training process, members are central beneficiaries by gaining research knowledge and skills, acquiring publication as the training's product, and shifting their mindsets from "I can't do it" to "I can do it," and at the same time transforming a mentee to be ready for a future mentor's role. The coaching method is thus one of the members, for the member, by the members.•The paper provides the structure, operation method, and conceptual framework of the SM3D Portal's community coaching method, which is built to help Early Career Researchers (ECRs) and researchers in low-resource settings overcome the obstacle of inequality and start their career progress.•The paper presents three major science philosophies envisioning the establishment and operation of scholarly community coaching.•The paper employs the mindsponge theory and BMF analytics to construct a conceptual framework explaining how an environment is created to help shift members' mindsets from "I can't do it" to "I can do it."

The Percentage of PNAd-Expressing Vessels is Correlated with Disease Severity in Eosinophilic Chronic Rhinosinusitis.

BACKGROUND: Eosinophilic chronic rhinosinusitis (ECRS) is a chronic inflammatory condition of the paranasal sinuses characterized by intractable nasal polyps with prominent eosinophil infiltration. These eosinophils are presumably recruited from peripheral blood via vessels expressing peripheral lymph node addressin (PNAd), a set of glycoproteins decorated with 6-sulfo sialyl Lewis x (sLex) glycans that serve as L-selectin ligands. Based on the severity classification algorithm proposed by the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) study group, ECRS is divided into mild, moderate and severe groups; however, as yet there are few reports comparing the clinicopathological differences among these groups. OBJECTIVE: Our goal was to elucidate clinicopathological differences among the three different severities of ECRS with special reference to eosinophils and PNAd-expressing vessels. METHODS: We performed quantitative immunohistochemical analysis of PNAd-expressing vessels using surgical specimens of nasal polyps from patients exhibiting varying severity of ECRS (n = 35) and from individuals with non-ECRS (n = 10). To this end, we immunostained tissue sections with anti-PNAd and anti-CD34 monoclonal antibodies, and then determined the number of vessels immunolabeled with each antibody. RESULTS: The number of eosinophils infiltrating nasal polyps was correlated with ECRS severity. We also found that the PNAd + /CD34 + vessel ratio, namely, the percentage of PNAd-expressing vessels among all vessels, was positively correlated not only with ECRS severity but also with the number of eosinophils infiltrating nasal polyps formed in ECRS. CONCLUSION: These results strongly suggest that PNAd-expressing vessels play at least a partial role in eosinophil recruitment to nasal polyps and consequent severity of ECRS.

An Endovascular Catheterization Robotic System Using Collaborative Operation with Magnetically Controlled Haptic Force Feedback.

Robot-assisted technology is often used to perform endovascular catheterization surgeries, which generally depend on the flexible operability and the accurate force feedback of a robotic system. In this paper, an endovascular catheterization robotic system (ECRS) was developed to improve collaborative operation and haptic force feedback. A couple of operating handles were designed to maximize the use of the natural operations of surgeons on the master side, which is a flexible and ergonomic device. A magnetically controlled haptic force feedback structure is proposed based on hydrogel and solid magnetorheological (MR) fluid to offer a sense of haptic feedback to operators; this has potential influence on the field of force feedback. In addition, a unique tremor-reduction structure is introduced to enhance operating safety. Tracking performance experiments and in vitro experiments were conducted to evaluate the performance of the developed ECRS. According to these experimental results, the average translation-tracking error is 0.94 mm, and the average error of rotation is 0.89 degrees. Moreover, in vitro experiments demonstrated that haptic feedback has the advantage of reducing workload and shortening surgery completion time. The developed ECRS also has the benefits of inspiring other researchers to study collaborative robots and magnetically controlled feedback.

The SWI/SNF complex in eosinophilic and non eosinophilic chronic rhinosinusitis.

INTRODUCTION: Chronic rhinosinusitis (CRS) can be classified as eosinophilic (eCRS) or non-eosinophilic (neCRS) based on infiltration type. The SWI/SNF complex may be involved in the pathophysiology of CRS. AIM: To assess the expression of the SWI/SNF complex in both CRS groups; to correlate blood eosinophil count (BEC), and histopathology eosinophil count (HPEC) with the SWI/SNF expression level in eCRS and neCRS. MATERIALS AND METHODS: The study population consisted of 96 patients (68 eCRS, 28 neCRS). Immunohistochemical staining was performed on sinonasal mucosa for assessment of SWI/SNF protein expression. Type of tissue infiltration was assessed in samples obtained from examined groups (HPEC). The diagnostic value of eCRS was 10 cells/HPF (high power field). Complete blood count was analysed in order to calculate BEC. RESULTS: BEC and HPEC correlated negatively with all the SWI/SNF subunits. HPEC and BEC correlated positively with clinical findings (L-M and SNOT-22), while SWI/SNF correlated negatively with clinical findings (L-M and SNOT-22). CONCLUSIONS: The SWI/SNF was observed in both eCRS and neCRS, with lower expression in former. The meaning of its negative correlation with BEC, HPEC and clinical findings in eCRS group remains to be understood.

Science Diplomacy for Climate Action and Sustainable Development in Latin America and the Caribbean: How Important Is the Early Career Perspective to New Governance?

Science diplomacy and science-policy interfaces are tools that science has to address the biggest challenges that the world faces today. The scientific community needs to develop the capacity to bring this scientific knowledge to society and decision-makers for the purposes of new governance of the Earth System and thus a more resilient society. Climate change is one of the most challenging issues the world is currently facing, and the Latin America and Caribbean (LAC) region is highly vulnerable to its consequences, as it is expected to exacerbate environmental, social, and economic problems in the LAC region. In this context, and as an emergency call to address the climate crisis with the latest available science in the region, this paper collects a series of examples of the progress, best practices, gaps, challenges, and solutions. We do so from the perspective of Early Careers Researchers (ECRs) and undergraduate and graduate students, highlighting what we are doing to engage scientists in society-policy-science interaction for the sustainable development agenda and climate action in Latin America and the Caribbean.

Rapid and remarkable effectiveness of benralizumab for treating severe bronchial asthma with intractable eosinophilic rhinosinusitis and eosinophilic otitis media: A case report.

Severe bronchial asthma is a challenging disorder to treat and can impair quality of life (QOL) under conventional therapeutic modalities. We report the case of a 52-year-old woman with severe asthma associated with eosinophilic chronic rhinosinusitis (ECRS) and eosinophilic otitis media (EOM). Although the patient was treated with a full dose of inhaled corticosteroid, leukotriene receptor antagonist (LTRA), theophylline, burst use of oral corticosteroids (OCS), her asthmatic condition aggravated, disrupting her daily life. ECRS and EOM symptoms were also getting worse despite treatment with topical application of corticosteroids to the nose and ears, LTRA, and occasional use of OCS. In addition to asthmatic symptom, the patient always suffered from intractable nasal obstruction and hearing disturbance, which contributed to the heavily impaired QOL. However, the administration of benralizumab showed rapid and remarkable improvement not only in her asthmatic conditions but also in the symptoms of ECRS and EOM within a month. These results suggest that the use of benralizumab for the treatment of severe asthma with intractable ECRS and EOM should be considered when the patient's QOL is severely deteriorated.