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B cell initial activity is regulated through a balance of activation and suppression mediated by regulatory molecules expressed in B cells; however, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the function of the Fc receptor-like (Fcrl) family molecule Fcrl5, which is constitutively expressed in naive B cells, in humoral immune responses. Our study demonstrated that B cell-specific overexpression of Fcrl5 enhanced antibody (Ab) production in both T cell-independent type 1 (TI1) and T cell-dependent (TD) responses. Additionally, it promoted effector B cell formation under competitive conditions in TD responses. Mechanistically, in vitro ligation of Fcrl5 by agonistic Abs reduced cell death and enhanced proliferation in lipopolysaccharide-stimulated B cells. In the presence of anti-CD40 Abs and IL-5, the Fcrl5 ligation not only suppressed cell death but also enhanced differentiation into plasma cells. These findings reveal a novel role of Fcrl5 in promoting humoral immune responses by enhancing B cell viability and plasma cell differentiation. [ABSTRACT FROM AUTHOR]

Objectives: Chronic rhinosinusitis (CRS) endotypes have demonstrated clinical value in guiding treatment decisions. Bacterial lysates are immunomodulators that have shown beneficial effects in various respiratory inflammatory diseases. This study aimed to evaluate the effect of postoperative bacterial lysate therapy on different CRS endotypes. Methods: Patients diagnosed with CRS who underwent endoscopic sinus surgery were recruited. Bacterial lysates were administered postoperatively for 10 days per month for 3 months to the experimental group comprising patients with a history of frequent upper respiratory infections without adverse reactions. The remaining participants were allocated to the control group. The results of the postoperative 3-, 6-, and 12-month assessments, including the modified Lund-Kennedy (mLK) endoscopic and Sinonasal Outcome Test (SNOT) 22 scores, for the groups were compared. The tissue samples obtained from the participants were evaluated to detect the presence of relevant inflammatory mediators. Results: Among the 92 participants, 47 started bacterial lysate therapy 2 weeks after the surgery. The tissue cytokine profiles and clinical parameters, such as the disease severity and blood eosinophil percentage, of the bacterial lysate and control groups were comparable before treatment. The mLK endoscopic and SNOT-22 scores did not differ after 3, 6, and 12 months of follow-up. The subgroup analysis revealed that the bacterial lysate group had significantly lower mLK endoscopic scores than the control group for CRS without nasal polyps, while there was a tendency toward significance for the interleukin (IL)-5 negative group after 6 months. Conclusion: Postoperative bacterial lysate therapy has some beneficial effects on the endoscopic findings of patients with CRS without nasal polyps or those who are negative for IL-5. [ABSTRACT FROM AUTHOR]

(1) Multiple sclerosis (MS) is identified by a complex interaction between central inflammation and neurodegeneration. Genetic individual variability could play a significative role in clinical presentation. The interleukin-5 (IL-5) rs2069812 single-nucleotide polymorphism (SNP) seems to define the clinical course of Th2 autoimmune diseases, while its role in MS has never been investigated. (2) In a group of 230 patients diagnosed with relapsing–remitting MS (RR-MS) or progressive MS (P-MS) and controls (IC), rs2069812 polymorphism, cerebrospinal fluid (CSF) levels of inflammatory mediators, and clinical and demographic characteristics were determined. In RR-MS patients, No Evidence of Disease Activity (NEDA-3) at three years of follow-up was detected. (3) We identified higher levels of proinflammatory cytokines, particularly IL-2 (median [IQR], RR-MS = 0.2 [0–0.7]; P-MS = 0.1 [0–1.6]; IC = 0.1 [0.0–0.1]; p < 0.005), IL-6 (RR-MS = 0.9 [0.3–2.3]; P-MS = 0.8 [0.1–2.7]; IC = 0.1 [0.0–0.5]; p < 0.005), IL-12 (RR-MS = 0.5 [0–1.1]; P-MS = 0.5 [0–1.1]; IC = 0.0 [0.0–0.3]; p < 0.005), and GM-CSF (RR-MS = 15.6 [4.8–26.4]; P-MS = 14 [3.3–29.7]; IC = 8.9 [4.7–11.7]; p < 0.005) in MS patients compared with IC. Conversely, anti-inflammatory cytokines, specifically IL-5 (RR-MS = 0.65 [0–2.4]; P-MS = 0.1 [0–0.8]; IC = 1.7 [0.6–2.8]; p < 0.005) and IL-1ra (RR-MS = 14.7 [4.9–26.4]; P-MS = 13.1 [4.7–22.2]; IC = 27.8 [17.7–37.6]; p < 0.005) were higher in controls. According to rs2069812, in MS patients, the T-allele was associated with higher concentrations of proinflammatory mediators (IL-2, CT/TT = 0.2 [0.0–2.0]; CC = 0.1 [0.0–0.4], p = 0.015; IL-6, CT/TT = 1.2 [0.4–3.2] vs. CC = 0.7 [0.1–1.7], p = 0.007; IL-15, CT/TT = 0.1 [0.0–9.5] vs. CC = 0.0 [0.0–0.1], p = 0.019; and GM-CSF, CT/TT = 0.1 [0.0–0.6] vs. CC = 0.05 [0.0–0.1], p < 0.001), and CC was associated with anti-inflammatory mediators (IL-5, CT/TT = 0.03 [0.0–1.9] vs. CC = 1.28 [0.0–2.7], p = 0.001; IL-1ra, CT/TT = 12.1 [4.1–25.9] vs. CC = 18.1 [12.1–26.9], p = 0.006). We found the same differences in RR-MS patients (IL-2, T-allele median [IQR] = 0.3 [0.0–2.0] vs. C-allele, median [IQR] = 0.04 [0.0–0.3]; p = 0.005; IL-6, T-allele, median [IQR] = 1.3 [0.4–3.3] vs. C-allele, median [IQR] = 0.6 [0.03–1.5]; p = 0.001; IL-15, T-allele, median [IQR] = 0.1 [0.0–9.5] vs. C-allele, median [IQR] = 0.0 [0.0–0.1]; p = 0.008; GM-CSF, T-allele, median [IQR] = 0.1 [0.0–97.9] vs. C-allele, median [IQR] = 0.0 [0.0–0.001]; p < 0.001; IL-5, T-allele, median [IQR] = 0.02 [0.0–2.2] vs. C-allele, median [IQR] = 1.5 [0.0–2.9]; p = 0.016; and IL-1ra, T-allele, median [IQR] = 12.1 [4.3–26.4] vs. C-allele, median [IQR] = 18.5 [12.7–28.3]; p = 0.006) but not in P-MS, except for IL-5 (T-allele, median [IQR] = 0.1 [0–0.23] vs. C-allele, median [IQR] = 0.6 [0.0–2.5]; p = 0.022). Finally, we identified an association between CC in RR-MS patients and NEDA-3 after three years of follow-up (p = 0.007). (4) We describe, for the first time, the role of an SNP of the IL-5 gene in regulating central neuroinflammation and influencing clinical course in MS patients. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting in decreased quality of life. Histamine and specifically the H4 receptor play a key role in the inflammatory process in AD and serve as targets for novel therapeutic approaches. Objective: In the present study we aimed to elucidate the immunopathological mechanisms with which the H4 receptor impacts TH2 cells and contributes to AD pathophysiology. Methods: Total CD4+ T cells obtained from healthy or AD individuals and in vitro differentiated TH2 cells were cultured under different conditions and the mRNA expression or protein production of target molecules were determined using quantitative real‐time PCR and ELISA. Results: H4 receptor mRNA expression was upregulated concentration dependent upon IL‐4 stimulation in in vitro differentiated TH2 cells progressively during the differentiation. Transcriptomic analysis of in vitro differentiated TH2 versus TH1 cells revealed that the H4 receptor among other genes represents one of the highly upregulated genes in TH2 cells. Most importantly, increased amounts of IL‐5 and IL‐13 mRNA expression were detected in in vitro differentiated TH2 cells as well as protein secretion in the presence of histamine or of the H4 receptor‐selective‐agonist when compared to the untreated control. Conclusion: We show for the first time an H4 receptor dependent upregulation of the pro‐inflammatory cytokines IL‐5 and IL‐13 in human TH2 cells by histamine. This suggests that the blockade of the H4 receptor may lead to downregulation of these cytokines and amelioration of AD symptoms as reported in first clinical studies. [ABSTRACT FROM AUTHOR]

While several studies have examined the role of T cells and related cytokines in the development of chronic spontaneous urticaria (CSU), there is a limited amount of research focusing on the changes in cytokine levels during omalizumab treatment. The primary objective of this study was to investigate the inflammatory cytokine profile (including IL-4, IL-5, IL-10, IL-13, IL-17, IL-31, IL-33, and TNFα) among CSU patients undergoing to omalizumab treatment. Plasma levels of cytokines were measured using ELISA. Measurements were taken before CSU treatment, at the 3rd and 6th months of omalizumab treatment, and once in the control group. The severity of the patients’ disease was assessed using the weekly Urticaria Activity Score(UAS7), and disease control was evaluated using the Urticaria Control Test(UCT). Thirty-one CSU patients and 56 age- and gender-matched healthy controls were included. Plasma levels of IL-4 and IL-33 were significantly lower in patients with CSU compared to healthy controls (p = 0.001; p = 0.038, respectively). During omalizumab treatment, IL-4 levels showed a significant increase in the 3rd month compared to baseline (p = 0.01), and IL-5 levels significantly decreased in the 6th month compared to both the 3rd month and baseline (6th month vs. baseline; p = 0.006, 6th month vs. 3rd month; p = 0.001). One potential mechanism of action for omalizumab may involve its regulatory effects on type 2 inflammatory cytokines in CSU patients. This finding partially explains the efficacy of anti-IL-4/13 treatments in chronic spontaneous urticaria. Further investigations on drugs targeting type 2 inflammatory cytokines in CSU are warranted. [ABSTRACT FROM AUTHOR]

Soil-transmitted helminth (STH) among children aged 24-59 months is one cause of chronic infection that could lead to stunting. The association of 25(OH)D and immune responses during chronic infection in stunted populations has not yet been well established. an association study of case--control data was conducted in Bandung district from October 2019 to January 2023. sociodemographic factors, stool samples, and serum levels of 25(OH)D, interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13) were assessed. statistical analysis was performed to evaluate the prevalence and association of 25(Oh) D, IL-4, IL-5, and IL-13 with the burden of sth infection in stunted children. in total, 401 stunted children were recruited. a higher burden of sth infection was found for lower levels of IL-5 (r = -0.477; p = 0.004) and IL-13 (r = -0.433; p = 0.028). Thus, 25(OH)D, IL-4, IL-5, and IL-13 play a role in the burden of sth infection. [ABSTRACT FROM AUTHOR]

Objective: Although sporadic case reports have demonstrated successful management of eosinophilic granulomatosis with polyangiitis (EGPA) by anti-IL-5 therapy, larger-scale monocentric studies for the efficacy of mepolizumab (MEP), an IL-5 monoclonal antibody, are still lacking in Taiwan. Methods: Hospitalized EGPA patients aged at least 18 years were enrolled from November 1998 to October 2023, and analyzed for demographic, clinical, laboratory, medication and outcome data, focusing on the efficacy and safety of biologics use, particularly induction therapy with MEP. Results: Twenty-seven EGPA patients aged 10–70 years (43 ± 15) at disease diagnosis were recruited with 21 under combined corticosteroids/cyclophosphamide induction therapy. Seventeen patients received biologics with 13 under MEP therapy. Ten patients aged 19–71 years (48 ± 15) completed 12-month induction therapy with a 100 mg quadri-weekly subcutaneous injection regimen indicated for active or relapse disease. There were reduced BVAS with complete remission in 6 and partial remission in 4 patients, lower CRP levels, decreased eosinophil counts with an inhibition of 92∼96 %, and tapered prednisolone dosages from 5 to 25 (13.0 ± 6.3) to 0–10 (3.3 ± 3.1) mg/day. Only one patient had an adverse event of injection site reactions. Nine patients received the same regimen for annual maintenance therapy. All had a persistent clinical remission. In these patients, 13–56 injections (41 ± 15) were prescribed with a follow-up period of 12∼52 months (38 ± 14). Conclusion: In this retrospective study, induction therapy with a 12-month 100 mg MEP quadri-weekly subcutaneous injection regimen demonstrates the efficacy and safety for active and relapsing EGPA patients.

AbstractIntroductionCase StudyResultsConclusionNear-fatal asthma (NFA) is a severe condition that can lead to respiratory arrest or high carbon dioxide levels, often requiring mechanical ventilation. Biologics have revolutionized the management of severe asthma, significantly improving symptom severity, reducing the number of exacerbations and hospitalizations, and decreasing the need for oral corticosteroids. However, their effectiveness in acute settings, particularly for ICU patients experiencing severe respiratory failure, is not well-studied. More research is needed to determine if biologics can improve recovery during severe asthma exacerbations.We report a case of NFA in a patient with severe allergic eosinophilic asthma, who experienced global respiratory failure necessitating hospitalization, intubation, and veno-venous extracorporeal membrane oxygenation (VV-ECMO). Given the severity of the clinical condition, compassionate administration of Benralizumab, which targets the IL-5 receptor, was attempted.Five days from anti-IL5 receptor treatment start, the patient was extubated and the ECMO stopped. After the stepdown to the respiratory intensive care unit (RICU), the patient was weaned from oxygen therapy and subsequently discharged from hospital.Benralizumab demonstrated rapid effectiveness in improving respiratory failure leading to successful weaning from VV-ECMO and subsequent extubation. [ABSTRACT FROM AUTHOR]

Although sporadic case reports have demonstrated successful management of eosinophilic granulomatosis with polyangiitis (EGPA) by anti-IL-5 therapy, larger-scale monocentric studies for the efficacy of mepolizumab (MEP), an IL-5 monoclonal antibody, are still lacking in Taiwan. Hospitalized EGPA patients aged at least 18 years were enrolled from November 1998 to October 2023, and analyzed for demographic, clinical, laboratory, medication and outcome data, focusing on the efficacy and safety of biologics use, particularly induction therapy with MEP. Twenty-seven EGPA patients aged 10–70 years (43 ± 15) at disease diagnosis were recruited with 21 under combined corticosteroids/cyclophosphamide induction therapy. Seventeen patients received biologics with 13 under MEP therapy. Ten patients aged 19–71 years (48 ± 15) completed 12-month induction therapy with a 100 mg quadri-weekly subcutaneous injection regimen indicated for active or relapse disease. There were reduced BVAS with complete remission in 6 and partial remission in 4 patients, lower CRP levels, decreased eosinophil counts with an inhibition of 92∼96 %, and tapered prednisolone dosages from 5 to 25 (13.0 ± 6.3) to 0–10 (3.3 ± 3.1) mg/day. Only one patient had an adverse event of injection site reactions. Nine patients received the same regimen for annual maintenance therapy. All had a persistent clinical remission. In these patients, 13–56 injections (41 ± 15) were prescribed with a follow-up period of 12∼52 months (38 ± 14). In this retrospective study, induction therapy with a 12-month 100 mg MEP quadri-weekly subcutaneous injection regimen demonstrates the efficacy and safety for active and relapsing EGPA patients. [ABSTRACT FROM AUTHOR]

Background: The introduction of biological drugs in the management of chronic rhinosinusitis with nasal polyps (CRSwNP) is allowing new and increasingly promising therapeutic options. This manuscript aims to provide a multicenter trial in a real-life setting on Mepolizumab treatment for severe uncontrolled CRSwNP with or without comorbid asthma. Methods: A retrospective data analysis was jointly conducted at the Otolaryngology–Head and Neck Surgery departments of La Sapienza University and San Camillo Forlanini Hospital in Rome. Both institutions participated by sharing clinical information on patients with CRSwNP treated with Mepolizumab. Patients were evaluated before starting Mepolizumab, at six months and at twelve months from the first drug administration. During follow–up visits, patients underwent endoscopic evaluation, quality of life assessment, nasal symptoms assessment, and blood tests to monitor mainly neutrophils, basophils, eosinophils, and IgG, IgA, and IgE assay. Results: Twenty patients affected by CRSwNP and treated with Mepolizumab were enrolled (12 females and 8 males with a mean age of 63.7 years). Sixteen patients (80%) had concomitant asthma. During follow-up, a gradual improvement in nasal polyp score, quality of life and nasal symptoms, assessed by SNOT-22 and VAS and loss of smell measured by olfactory VAS, was found. Regarding blood tests, eosinophils decreased gradually, while other blood parameters showed no statistically significant changes. Conclusions: Mepolizumab has been shown to be effective in the therapeutic management of patients with CRSwNP. Further studies are needed to support our findings and better understand the underlying immune pathways to predict patients' response to biological treatment in CRSwNP. [ABSTRACT FROM AUTHOR]

Background: The effectiveness of immunotherapy in atopic dermatitis (AD) has been debated for many years. Immunotherapy suppresses Th2 cytokines, such as IL-5, which play a crucial role in the pathogenesis of AD. This study assessed the effect of immunotherapy on severity and IL-5 expression in AD mice. Methods: Male BALB/c mice were separated into three groups. The mice were sensitized with Dermatophagoides pteronyssinus allergen for seven days, except the mice in control group. The house dust mite (HDM) immunotherapy was injected subcutaneously every 3 days for 1.5 months with increasing doses (0.1, 1, 10, 100 µg in 100 µL PBS) every 4 injections. The mice in AD model and control group received placebo injections. Following immunotherapy, the mice were exposed to HDM allergen patch two times with 2 weeks interval in between. The mice were evaluated for severity score as the clinical marker and IL-5 expression with semiquantitative method as the histological marker. Results: The evaluation of severity score from two independent researchers showed a substantial agreement (Cohen's kappa 0.613, p <0.001). The severity score of the immunotherapy group was significantly lower than the AD model group, while both immunotherapy and AD model group had significantly higher score than control group. IL-5 expression in the immunotherapy group was lower than the AD model group and slightly higher than control group. The mean difference between groups was not significant. Conclusion: The severity of skin lesion and IL-5 expression in AD mice receiving immunotherapy were lower than AD model group. [ABSTRACT FROM AUTHOR]

AbstractSoil-transmitted helminth (STH) among children aged 24–59 months is one cause of chronic infection that could lead to stunting. The association of 25(OH)D and immune responses during chronic infection in stunted populations has not yet been well established. An association study of case–control data was conducted in Bandung district from October 2019 to January 2023. Sociodemographic factors, stool samples, and serum levels of 25(OH)D, interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13) were assessed. Statistical analysis was performed to evaluate the prevalence and association of 25(OH)D, IL-4, IL-5, and IL-13 with the burden of STH infection in stunted children. In total, 401 stunted children were recruited. A higher burden of STH infection was found for lower levels of IL-5 (r = −0.477; p = 0.004) and IL-13 (r = −0.433; p = 0.028). Thus, 25(OH)D, IL-4, IL-5, and IL-13 play a role in the burden of STH infection.

Background and purpose: The Bushenyiqi decoction (BYD), a contemporary prescription of traditional Chinese medicine (TCM), has been observed to significantly ameliorate asthma symptoms in patients based on clinical observations. Although multi-component and multi-target characteristics are important attributes of BYD treatment, its pharmacological effect on asthma and the underlying mechanism of action remain unclear. Method: Network pharmacology: the asthma-related genes were retrieved from the GeneCards and OMIM database. The active constituents of BYD and their corresponding target genes were collected from the TCMSP database. The underlying pathways associated with overlapping targets between BYD and asthma were identified through GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis. Experimental validation: pulmonary function tests, enzyme-linked immunosorbent assay (ELISA), Hematoxylin and eosin (HE), periodic acid-Schiff (PAS), and Masson's trichrome stainings were conducted to validate the efficacy of BYD in ameliorating airway inflammation in allergic asthma mice. Western blot (WB) and molecular docking were performed to confirm the involvement of the underlying pathway in BYD treatment of asthma. Results: The results of animal experiments demonstrated that BYD may improve airway responsiveness and suppress airway inflammation in allergic asthma mice. The network pharmacological analysis revealed the involvement of 11 potentially key active components, 9 potential key targets, and the phosphatidylinositol3 kinase-RAC-α serine/threonine-protein kinase (PI3K/AKT) signaling pathway in the mechanism of action of BYD for asthma treatment. Our findings have confirmed that BYD effectively alleviated airway inflammation by targeting interleukin 6 (IL-6), epidermal growth factor receptor (EGFR), and hypoxia inducible factor 1 alpha (HIF1A), with quercetin, kaempferol, and luteolin performing as the pivotal active constituents. BYD may potentially reduce inflammatory cell infiltration in lung tissues by regulating the PI3K/AKT signaling pathway. Conclusion: In conclusion, the integration of network pharmacology and biological experiments has demonstrated that key constituents of BYD, such as quercetin, kaempferol, and luteolin, exhibit targeted effects on IL-6, EGFR, and HIF1A in combating asthma-related inflammation through inhibition of the PI3K/AKT signaling pathway. The findings of this investigation provide evidence supporting the effectiveness of TCM's "bushenyiqi" therapy in asthma management, as corroborated by contemporary medical technology. [ABSTRACT FROM AUTHOR]

Cumulative data suggest that neuroinflammation plays a prominent role in amyotrophic lateral sclerosis (ALS) pathogenesis. The purpose of this work was to assess if patients with ALS present a specific peripheral cytokine profile and if it correlates with neurological disability assessed by ALSFRS-R, the rate of disease progression, and the pattern of disease progression (horizontal spreading [HSP] versus vertical spreading [VSP]). We determined the levels of 15 cytokines in the blood of 59 patients with ALS and 40 controls. We identified a positive correlation between levels of pro-inflammatory cytokines (interleukin [IL]-17F, IL-33, IL-31) and the age of ALS patients, as well as a positive correlation between IL-12p/70 and survival from ALS onset and ALS diagnosis. Additionally, there was a positive correlation between the ALSFRS-R score in the upper limb and respiratory domain and IL-5 levels. In our ALS cohort, the spreading pattern was 42% horizontal and 58% vertical, with patients with VSP showing a faster rate of ALS progression. Furthermore, we identified a negative correlation between IL-5 levels and the rate of disease progression, as well as a positive correlation between IL-5 and HSP of ALS. To the best of our knowledge, this is the first study reporting a "protective" role of IL-5 in ALS. [ABSTRACT FROM AUTHOR]

We developed pulmonary emphysema and a type 2 airway inflammation overlap mouse model. The bronchoalveolar lavage (BAL) interleukin 13 (IL‐13), IL‐4, and IL‐5 levels in the overlap model were higher than in the pulmonary emphysema model and lower than in the type 2 airway inflammation model, but IL‐33 level in the lung was higher than in other models. IL‐33 and interferon‐γ (IFNγ) in lungs may control the severity of a type 2 airway inflammation in lung. [ABSTRACT FROM AUTHOR]

Background: The immune response to hepatitis B vaccine may be influenced by numerous factors, and patients with non/low response re-exposed to hepatitis B virus remain susceptible. Thus, a better understanding of the underlying mechanisms of non/low immune response in infants born to Hepatitis B surface antigen (HBsAg)-positive mothers is essential. Methods: 100 infants born to HBsAg-positive mothers from 2015 to 2020 were enrolled in the study, further divided into the non/low response group (n=13) and the moderate strong response group (n=87) based on the quantification of hepatitis B surface antibody at 12 months of age. The differential expression of 48 immunerelated cytokines in the two groups was compared and analyzed in detail. The key cytokines were further identified and clinically predictive models were developed. Results: We found that 13 cytokines were lowly expressed and one cytokine was highly expressed in the non/low response group, compared with the moderate strong response group at birth. In addition, 9 cytokines were lowly expressed and one cytokine was highly expressed in the non/low response group at 12 months of age. Furthermore, we found that IL-5 and HGF were promising predictors for predicting the immunization response to hepatitis B vaccine in infants, and the combination of the two cytokines showed the best predictive efficiency, with an area under the curve (AUC) value of 0.844. Conclusion: The present study provides a theoretical basis on cytokines for developing and implementing effective immunotherapies against non/low immune response in infants born to HBsAg-positive mothers. [ABSTRACT FROM AUTHOR]

Vernal keratoconjunctivitis (VKC) is a complex and multifactorial disease process that employs Th2 cell-mediated immunologic processes, which involves the overexpression of interleukin 4 (IL-4), IL-5, IL-9, IL-13, and IL-31, and the activation of mast cells that release IL-5 and CCL-11, recruiting eosinophils to the site of inflammation. The disease primarily affects young males and is more common in regions with warm climates. VKC is characterized by persistent and recurrent conjunctival inflammation that can adversely affect the patient's quality of life, and, when inadequately treated, may lead to a host of ocular complications, such as corneal shield ulcers and scarring. The major distinct forms of VKC include limbal or palpebral, which may occur in combination. The clinicopathological features of VKC include the presence of pseudogerontoxon, limbal gelatinous hyperplasia, and perilimbal hyperpigmentation. Topical immunomodulators are effective anti-steroidal options for controlling severe and chronic cases of VKC. This review will provide a brief overview of topical immunomodulators, including cyclosporin and tacrolimus, and will highlight the clinical manifestations, pathological mechanisms, and fibroproliferative changes in the conjunctiva that can result from recurrent disease. [ABSTRACT FROM AUTHOR]

Allergic conjunctivitis is one of the common immune hypersensitivity disorders that affect the ocular system. The clinical manifestations of this condition exhibit variability contingent upon environmental factors, seasonal dynamics, and genetic predisposition. While our comprehension of the pathophysiological engagement of immune and nonimmune cells in the conjunctiva has progressed, the same cannot be asserted for the cytokines mediating this inflammatory cascade. In this review, we proffer a comprehensive description of interleukins 4 (IL-4), IL-5, IL-6, IL-9, IL-13, IL-25, IL-31, and IL-33, as well as thymic stromal lymphopoietin (TSLP), elucidating their pathophysiological roles in mediating the allergic immune responses on the ocular surface. Delving into the nuanced functions of these cytokines holds promise for the exploration of innovative therapeutic modalities aimed at managing allergic conjunctivitis. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis with nasal polyps (CRSwNP) causes nasal obstruction and olfactory dysfunction. Aspirin-exacerbated respiratory disease (AERD) is the triad of CRSwNP, asthma, and respiratory reactions to COX-1 inhibitors. Patients with AERD have elevated nasal IL-5 levels and high numbers of antibody-secreting cells (ASCs), including plasma cells and plasmablasts, in their polyp tissue; in addition, their nasal polyp (NP) IgE levels are correlated with disease severity and recurrence of nasal polyposis. We sought to explore differences in the transcriptomic profile, activation markers, and IL-5Rα expression and function of NP ASCs from patients with AERD and CRSwNP. NP tissue was collected from patients with AERD and CRSwNP and digested into single-cell suspensions. NP cells were analyzed for protein expression by mass cytometry. For IL-5Rα functional studies, plasma cells were purified and cultured in vitro with or without IL-5 and analyzed by bulk RNA sequencing. Compared with polyp tissue from patients with CRSwNP, polyp tissue from patients with AERD contained significantly more ASCs and had increased ASC expression of IL-5Rα. ASCs from patients with AERD expressed higher protein levels of B-cell activation and regulatory markers (CD40, CD19, CD32, and CD38) and the proliferation marker Ki-67. ASCs from patients with AERD also expressed more IL5RA , IGHE , and cell cycle– and proliferation-related transcripts (CCND2 , MKI67 , CDC25A, and CDC25B) than did ASCs from patients with CRSwNP. Stimulation of plasma cells from patients with AERD with IL-5 induced key cell cycle genes (CCND2 and PTP4A3), whereas IL-5 stimulation of ASCs from patients with CRSwNP induced few transcriptomic changes. NP tissue ASCs from patients with AERD express higher levels of functional IL-5Rα and markers associated with cell cycling and proliferation than do ASCs from patients with aspirin-tolerant CRSwNP. [ABSTRACT FROM AUTHOR]

Long-term persistence of inflammation is the main factor of pathogenesis in chronic polypous rhinosinusitis (CRSwNP). Prospectives of current clinical otorhinolaryngology include modification of drugs containing topical glucocorticosteroids in order to increase local bioavailability, reduce the concentration of glucocorticosteroids, and alleviate the local inflammatory response. The aim of our work was to evaluate the effect of urea, magnesium sulfate, and mannitol on the concentrations of mometasone furoate and IL-5 in the polypous tissue of patients with CRSwNP. The study included 146 patients with CRSwNP aged 18 to 62 years. Biopsies of polypous tissue were taken during polypotomy. In the fluid samples obtained by microdialysis of polypous tissues, mometasone concentrations were determined by high-performance liquid chromatography. Concentrations of IL-3, IL-4, IL-5 and IL-10 cytokines in blood serum, and IL-5 in microdialysates of polypous tissue were measured by ELISA technique. The average age of patients with CRSwNP was 42.9±7.2 years, with prevalence of male patients (n = 93, 63.7%) over females (n = 53, 36.3%). Severity parameters of the disease by the SNOT-22 scale were significantly higher in CRSwNP patients than in control group (p ≤ 0.05). The results of biochemical analysis of microdialysates from polypous tissue showed increased content of Na+ ions in the resistant clinical cases of CRSwNP compared with the sensitive and dependent clinical forms (p < 0.05). Curves with the level of mometasone furoate were obtained in all the studied samples. It was found that the addition of magnesium sulfate solution to mometasone increases the Cmax of mometasone to 154 ng/mL in biological fluids after microdialysis. When urea solution is added to mometasone, Cmax increases to 198 ng/mL. In the native nasal polypous tissue dialysate, IL-5 levels were 89±2.01 pg/mL. Two hours after the addition of mometasone furoate, IL-5 concentrations decreased to 61±3.5 pg/mL, upon addition of urea, it changed to to 69±2.98 pg/mL (p ≤ 0.01, compared with the control without the addition of drugs). Analysis of serum cytokine levels showed that IL-5 concentrations in the patients with CRSwNP significantly exceeded (> 3-fold) those in the control group (p ≤ 0.05). There was a trend for increase of IL-3 and IL-4 (2-fold) and to decreased IL-10 levels in blood sera (> 1.5-fold) in patients with CRSwNP compared with controls. These results may be helpful for development of novel clinical approaches, in order to increase bioavailability of topically administered glucocorticosteroids, thus allowing to promote the effectiveness of basic therapy of CRSwNP and to develop therapy for the prevention of resistant forms of polyposis.

(1) Multiple sclerosis (MS) is identified by a complex interaction between central inflammation and neurodegeneration. Genetic individual variability could play a significative role in clinical presentation. The interleukin-5 (IL-5) rs2069812 single-nucleotide polymorphism (SNP) seems to define the clinical course of Th2 autoimmune diseases, while its role in MS has never been investigated. (2) In a group of 230 patients diagnosed with relapsing–remitting MS (RR-MS) or progressive MS (P-MS) and controls (IC), rs2069812 polymorphism, cerebrospinal fluid (CSF) levels of inflammatory mediators, and clinical and demographic characteristics were determined. In RR-MS patients, No Evidence of Disease Activity (NEDA-3) at three years of follow-up was detected. (3) We identified higher levels of proinflammatory cytokines, particularly IL-2 (median [IQR], RR-MS = 0.2 [0–0.7]; P-MS = 0.1 [0–1.6]; IC = 0.1 [0.0–0.1]; p < 0.005), IL-6 (RR-MS = 0.9 [0.3–2.3]; P-MS = 0.8 [0.1–2.7]; IC = 0.1 [0.0–0.5]; p < 0.005), IL-12 (RR-MS = 0.5 [0–1.1]; P-MS = 0.5 [0–1.1]; IC = 0.0 [0.0–0.3]; p < 0.005), and GM-CSF (RR-MS = 15.6 [4.8–26.4]; P-MS = 14 [3.3–29.7]; IC = 8.9 [4.7–11.7]; p < 0.005) in MS patients compared with IC. Conversely, anti-inflammatory cytokines, specifically IL-5 (RR-MS = 0.65 [0–2.4]; P-MS = 0.1 [0–0.8]; IC = 1.7 [0.6–2.8]; p < 0.005) and IL-1ra (RR-MS = 14.7 [4.9–26.4]; P-MS = 13.1 [4.7–22.2]; IC = 27.8 [17.7–37.6]; p < 0.005) were higher in controls. According to rs2069812, in MS patients, the T-allele was associated with higher concentrations of proinflammatory mediators (IL-2, CT/TT = 0.2 [0.0–2.0]; CC = 0.1 [0.0–0.4], p = 0.015; IL-6, CT/TT = 1.2 [0.4–3.2] vs. CC = 0.7 [0.1–1.7], p = 0.007; IL-15, CT/TT = 0.1 [0.0–9.5] vs. CC = 0.0 [0.0–0.1], p = 0.019; and GM-CSF, CT/TT = 0.1 [0.0–0.6] vs. CC = 0.05 [0.0–0.1], p < 0.001), and CC was associated with anti-inflammatory mediators (IL-5, CT/TT = 0.03 [0.0–1.9] vs. CC = 1.28 [0.0–2.7], p = 0.001; IL-1ra, CT/TT = 12.1 [4.1–25.9] vs. CC = 18.1 [12.1–26.9], p = 0.006). We found the same differences in RR-MS patients (IL-2, T-allele median [IQR] = 0.3 [0.0–2.0] vs. C-allele, median [IQR] = 0.04 [0.0–0.3]; p = 0.005; IL-6, T-allele, median [IQR] = 1.3 [0.4–3.3] vs. C-allele, median [IQR] = 0.6 [0.03–1.5]; p = 0.001; IL-15, T-allele, median [IQR] = 0.1 [0.0–9.5] vs. C-allele, median [IQR] = 0.0 [0.0–0.1]; p = 0.008; GM-CSF, T-allele, median [IQR] = 0.1 [0.0–97.9] vs. C-allele, median [IQR] = 0.0 [0.0–0.001]; p < 0.001; IL-5, T-allele, median [IQR] = 0.02 [0.0–2.2] vs. C-allele, median [IQR] = 1.5 [0.0–2.9]; p = 0.016; and IL-1ra, T-allele, median [IQR] = 12.1 [4.3–26.4] vs. C-allele, median [IQR] = 18.5 [12.7–28.3]; p = 0.006) but not in P-MS, except for IL-5 (T-allele, median [IQR] = 0.1 [0–0.23] vs. C-allele, median [IQR] = 0.6 [0.0–2.5]; p = 0.022). Finally, we identified an association between CC in RR-MS patients and NEDA-3 after three years of follow-up (p = 0.007). (4) We describe, for the first time, the role of an SNP of the IL-5 gene in regulating central neuroinflammation and influencing clinical course in MS patients.

Human interleukin‐5 (IL‐5) functions as an important pro‐inflammatory factor by binding to its specific receptor, IL‐5Rα, which has been implicated in the pathogenesis of asthma. Previously, a disulfide‐bonded cyclic peptide AF17121 obtained from random library screening and sequence variation was found to competitively disrupt the cognate IL‐5Rα/IL‐5 interaction with moderate potency. In this study, the crystal complex of IL‐5Rα with AF17121 was investigated at structural and energetic levels. It is revealed that the side‐chain indole moiety of the AF17121 Trp5 residue is a potential site for a stem putative halogen bond (X‐bond) with IL‐5Rα, which is just located within the key 3EXXR6 motif region recognized specifically by IL‐5Rα. We systematically examined four halogen substitution types at five positions of the indole moiety; QM/MM calculations theoretically unraveled that only halogenations at 5 and 6 positions can form effective X‐bonds with the side‐chain hydroxyl oxygen of the IL‐5Rα Thr21 residue and the backbone carbonyl oxygen of Ala66 residue, respectively. Binding assays observed that I‐substitution at the 5 position and Br‐substitution at the 6 position can result in two potent halogenated peptides, [5I]AF17121 and [6Br]AF17121, which are improved by 1.6‐fold and 3.5‐fold relative to the native AF17121, respectively. 5I/6Br‐double substitution, resulting in [5I/6Br]AF17121, can further enhance the peptide affinity by 7.5‐fold. Structural analysis revealed that the X‐bond stemming from 6Br‐substitution is also involved in an orthogonal interaction system with a H‐bond; they share a common backbone carbonyl oxygen acceptor of IL‐5Rα Ala66 residue and exhibit a significant synergistic effect between them. [ABSTRACT FROM AUTHOR]

Objective: To evaluate eosinophil peroxidase (EPX) as a biomarker for tissue levels of eosinophilia, cytokines, and chemokines within chronic rhinosinusitis (CRS). Methods: Twenty‐eight subjects undergoing sinonasal surgery were prospectively enrolled. Ethmoid tissue was analyzed with an in‐house EPX immunoassay and a 48‐plex cytokine‐chemokine array. Clinical severity was assessed using SNOT‐22 and Lund‐Mackay scores. Subjects were grouped as follows: controls, polyp status (CRS with [CRSwNP] and without nasal polyps [CRSsNP]), tissue eosinophilia (eosinophilic CRS [eCRS], non‐eosinophilic CRS [neCRS]), or combinations thereof (eCRSwNP, eCRSsNP, neCRSsNP). eCRS was defined as >10 eosinophils per high power field (HPF). Subjects without CRS or asthma were enrolled as controls. Results: EPX was elevated in CRSwNP compared to control (p = 0.007), in eCRS compared to neCRS (p = 0.002), and in eCRSwNP along with eCRSsNP compared to neCRSsNP (p = 0.023, p = 0.015, respectively). eCRS displayed elevated IL‐5 compared to neCRS (p = 0.005). No significant differences in EPX or IL‐5 were observed between eCRSwNP and eCRSsNP. IL‐5 was elevated in eCRSwNP (p = 0.019) compared neCRSsNP. Area under the receiver operator characteristic curve was 0.938 (95% CI, 0.835–1.00) for EPX and tissue eosinophilia, with an optimal cut‐point of 470 ng/mL being 100% specific and 81.25% sensitive for tissue eosinophilia. Linear regression revealed a strong correlation between EPX and IL‐5 (R2 = 0.64, p < 0.001). Comparing EPX and IL‐5, only EPX displayed significant correlation with SNOT‐22 (p = 0.04) and Lund‐Mackay score (p = 0.004). Conclusion: EPX is associated with tissue eosinophilia in CRS patients regardless of polyp status. EPX correlates with IL‐5 and could be potentially considered a biomarker for anti‐IL‐5 therapies. Level of Evidence: 3 Laryngoscope, 134:69–78, 2024 [ABSTRACT FROM AUTHOR]

The current study was conducted to measure some immunoglobulin IgE, IgG, IgM, some interleukins interleukin 4 (IL-4), interleukin 5 (IL-5) and a complete blood count (CBC) in patients suffering from hypersensitivity type 1 (drug allergy, and asthma). The study began from 1/9/2022 to 1/3/2023 and included 59 people of all ages. The current results showed that people with drug allergy and asthma had an increase in the concentration of IL-4 (407.8 ±27.0), (837.6 ± 29.4), IL-5 (323.1 ±39.7) (568.4 ± 32.1) respectively. The level of IgE, IgG and IgM was elevated in patients suffering from drug allergies (11.2±2.6) (18.1±2.8) (and 47.9±5.3) respectively and asthma was (30.3±3.4), (26.1 ± 4.6) and (50.2 ± 8.6) respectively. The results of the complete blood count showed a significant increase in the white blood cells, Eosinphile. In addition to many differences in blood parameters compared to normal proportions. It was also found that the IgE concentration decreased with age, while the IgG antibody concentration increased compared to the standard sample and with the increase in age groups. [ABSTRACT FROM AUTHOR]

Background: Eosinophils have been divided into different subpopulations with distinct phenotypes based on CD62L expression. No data are available regarding the correlation between eosinophils subphenotypes and clinical severity of asthma, as well as the effect of anti‐IL‐5 therapy on these cells. The study investigates the correlation between blood CD62Llow inflammatory eosinophils (iEos) and clinical severity of severe eosinophilic asthma (SEA) and evaluates the impact of mepolizumab on iEos. Methods: 112 patients were screened and were divided in two groups: biological‐naive (n = 51) and biological‐treated patients (n = 61). The Biological‐naive patients were analyzed before treatment (Group A) and 19 out of 51 patients, were longitudinally analyzed before and after treatment with mepolizumab 100 mg s.c/4 weeks (Group B); 32 patients were excluded because they were being treated with other biological therapies. Blood eosinophils were analyzed by FACS and correlated with clinical scores. In vitro effect of IL‐5 and mepolizumab on CD62L expression was assessed. Results: A significant correlation between blood CD62Llow cells and clinical scores of asthma and nasal polyps, as well as the number of asthma exacerbations in the last year was shown in untreated patients. In longitudinally studied patients we observed a marked reduction of CD62Llow cells paralleled by an increase in the proportion of CD62Lbright cells, associated with clinical improvement of asthma control. In vitro, CD62L expression on eosinophils is modulated by IL‐5 and anti‐IL‐5. Conclusion: A positive correlation between CD62Llow iEos and the baseline clinical features of SEA with CRSwNP was shown. Furthermore mepolizumab restores the healthy balance among eosinophils sub‐phenotypes in SEA patients. [ABSTRACT FROM AUTHOR]

Trichinellosis is a cosmopolitan zoonosis that is caused mainly by Trichinella spiralis infection. The human disease ranges from mild to severe and fatality may occur. The treatment of trichinellosis still presents a challenge for physicians. Anti-inflammatory drugs are usually added to antiparasitic agents to alleviate untoward immuno-inflammatory responses and possible tissue damage but they are not without adverse effects. Thus, there is a need for the discovery of safe and effective compounds with anti-inflammatory properties. This study aimed to evaluate the activity of β-glucan during enteral and muscular phases of experimental T. spiralis infection as well as its therapeutic potential as an adjuvant to albendazole in treating trichinellosis. For this aim, mice were infected with T. spiralis and divided into the following groups: early and late β-glucan treatment, albendazole treatment, and combined treatment groups. Infected mice were subjected to assessment of parasite burden, immunological markers, and histopathological changes in the small intestines and muscles. Immunohistochemical evaluation of NF-κB expression in small intestinal and muscle tissues was carried out in order to investigate the mechanism of action of β-glucan. Interestingly, β-glucan potentiated the efficacy of albendazole as noted by the significant reduction of counts of muscle larvae. The inflammatory responses in the small intestine and skeletal muscles were mitigated with some characteristic qualitative changes. β-glucan also increased the expression of NF-κB in tissues which may account for some of its effects. In conclusion, β-glucan showed a multifaceted beneficial impact on the therapeutic outcome of Trichinella infection and can be regarded as a promising adjuvant in the treatment of trichinellosis. [ABSTRACT FROM AUTHOR]

Interleukin-7 (IL-7) is a cytokine critical for the development and maintenance of group 2 innate lymphoid cells (ILC2s). ILC2s are resident in peripheral tissues such as the intestine and lung. However, whether IL-7 produced in the lung plays a role in the maintenance and function of lung ILC2s during airway inflammation remains unknown. IL-7 was expressed in bronchoalveolar epithelial cells and lymphatic endothelial cells (LECs). To investigate the role of local IL-7 in lung ILC2s, we generated two types of IL-7 conditional knockout (IL-7cKO) mice: Sftpc-Cre (SPC-Cre) IL-7cKO mice specific for bronchial epithelial cells and type 2 alveolar epithelial cells and Lyve1-Cre IL-7cKO mice specific for LECs. In steady state, ILC2s were located near airway epithelia, although lung ILC2s were unchanged in the two lines of IL-7cKO mice. In papain-induced airway inflammation dependent on innate immunity, lung ILC2s localized near bronchia via CCR4 expression, and eosinophil infiltration and type 2 cytokine production were reduced in SPC-Cre IL-7cKO mice. In contrast, in house dust mite (HDM)-induced airway inflammation dependent on adaptive immunity, lung ILC2s localized near lymphatic vessels via their CCR2 expression 2 weeks after the last challenge. Furthermore, lung ILC2s were decreased in Lyve1-Cre IL-7cKO mice in the HDM-induced inflammation because of decreased cell survival and proliferation. Finally, administration of anti-IL-7 antibody attenuated papain-induced inflammation by suppressing the activation of ILC2s. Thus, this study demonstrates that IL-7 produced by bronchoalveolar epithelial cells and LECs differentially controls the activation and maintenance of lung ILC2s, where they are localized in airway inflammation. [ABSTRACT FROM AUTHOR]

Background: House dust mite extract–based allergen immunotherapy (AIT) to treat house dust mite allergy is substantially effective but still presents some safety and efficacy concerns that warrant improvement. Several major allergen-based approaches to increase safety and efficacy of AIT have been proposed. One of them is the use of the group 2 allergen, Der p 2. Objective: We sought to investigate the immunomodulatory effects of sialic acid–modified major allergen recombinant Der p 2 (sia-rDer p 2) on PBMCs from healthy volunteers. Methods: We activated PBMCs with anti-CD3/CD28 antibodies and incubated them at 37°C for 6 days in the presence or absence of either native rDer p 2 or α2-3 sialic acid–modified rDer p 2 (sia-rDer p 2). We assessed the changes in CD4+ T-cell activation and proliferation by flow cytometry and changes in T-lymphocyte cytokine production in cell culture supernatant by ELISA. Results: We observed that PBMCs treated with sia-rDer p 2 presented with a markedly decreased expression of CD69 and an increased abundance of LAG-3+ lymphocytes compared with cells treated with rDer p 2. Moreover, PBMCs treated with sia-rDer p 2 showed a reduced production of IL-4, IL-13, and IL-5 and displayed a higher IL-10/IL-5 ratio compared with rDer p 2–treated PBMCs. Conclusions: We demonstrate that sia-rDer p 2 might be a safer option than native rDer p 2 for Der p 2–specific AIT. This is most relevant in the early phase of AIT that is often characterized by heightened TH2 responses, because sia-rDer p 2 does not enhance the production of TH2 cytokines.

Abstract Background There are many studies on the relationship between vitamin D and coronavirus disease 2019 (COVID-19), while the results are matters of debate and the mechanisms remain unknown. The present study was performed to assess the impact of serum 25-hydroxyvitamin D [25(OH)D] levels on the severity of disease in hospitalized COVID-19 patients and identify potential mechanisms of 25(OH)D alterations. Methods A total of 399 hospitalized COVID-19 patients were recruited from three centers between December 19, 2022, and February 1, 2023. Medical history, laboratory examination, and radiologic data were retrospectively collected. The patients were divided into four groups based on disease severity. Serum 25(OH)D levels in the patients were determined by the electrochemiluminescence method and cytokines were detected by flow cytometry. The relationship between serum 25(OH)D status and the severity of COVID-19, and the correlation between 25(OH)D levels and cytokines in COVID-19 patients were assessed. Results Levels of 25(OH)D were significantly lower in the deceased group than in the other three groups (P 0.05). The levels of 25(OH)D (odds ratio = 0.986, 95% confidence interval: 0.973–0.998, P = 0.024) and IL-5 (odds ratio = 1.239, 95% confidence interval: 1.104–1.391, P = 0.04) were independent risk factors for the severity of COVID-19 disease upon admission. Serum 25(OH)D levels were able to predict the mortality of patients with COVID-19, and the predictive value was even higher when combined with IL-5 levels and eosinophil (Eos) count. Circulating 25(OH)D status correlated negatively with the expression of IL-5 (r=-0.262, P

Abstract Background The role of cytokines such as interleukin-5 (IL-5) in the pathogenesis of malaria remains unclear. This systematic review sought to synthesize variations in IL-5 levels between severe and uncomplicated malaria, as well as between malaria and controls not afflicted with the disease. Methods This systematic review was registered at the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022368773). Searches for studies that reported IL-5 levels in patients with malaria (any severity) and/or uninfected individuals were performed in Web of Science, PubMed, EMBASE, Scopus, CENTRAL, and MEDLINE, between 1st and 10th October, 2022. The risk of bias among all included studies was minimized using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting observational studies. The differences in IL-5 levels between malaria and uninfected controls, and between severe and uncomplicated malaria were synthesized by narrative synthesis. Results Among 1177 articles identified in the databases, 23 matched the eligibility criteria and were included in this systematic review. Qualitative syntheses showed the heterogeneity of IL-5 levels between different severities of clinical malaria and uninfected controls. The majority of the included studies (12/15 studies, 80%) found no change in IL-5 levels between malaria cases and uninfected controls. Similarly, most studies found no difference in IL-5 levels between severe (regardless of complications) and uncomplicated malaria (4/8 studies, 50%). The qualitative syntheses revealed that most studies found no difference in IL-5 levels between severe and non-severe malaria. Conclusions The comprehensive review suggests that IL-5 levels are unchanged in patients with different levels of clinical severity of malaria and uninfected controls. Given the limited number of published studies on IL-5 levels in malaria, there is a need for additional research to determine the function of this cytokine in the pathogenesis of malaria.

Introduction: Benralizumab, mepolizumab, and reslizumab are novel monoclonal antibodies approved for asthma, targeting eosinophilic inflammation. Benralizumab is directed against IL-5 receptor (IL-5R), while mepolizumab and reslizumab are directed against IL-5. The three drugs cause a reduction in eosinophils, but benralizumab also causes a cytotoxic effect on eosinophils and basophils. Recently, it has been reported that suboptimal responders to benralizumab presented exacerbations associated with concomitant infections and sputum neutrophilia and the incidence of infections was greater in patients receiving benralizumab compared to mepolizumab and reslizumab. For this reason, we wanted to explore potential differences in terms of infectious adverse events between the three different anti-IL-5 antibodies. Methods: We performed a rapid systematic review on PubMed up to April 28, 2022. We included randomized controlled trials (RCTs) evaluating benralizumab, mepolizumab, or reslizumab in patients with asthma. Included outcomes were the reporting of any respiratory tract infection and any emergency department (ED) or hospital admission for infection or asthma exacerbation. A Mantel-Haenszel meta-analysis was performed with Cochrane RevMan 5.4 to estimate pooled odds ratios (OR) with 95 % confidence intervals (CI). A subgroup analysis for the different active treatments was performed. Results: From 163 references we included 21 studies reporting the results of 23 different RCTs for a total population of 9156 patients. All studies compared anti-IL-5 antibodies against placebo. Anti-IL-5 treatment resulted in non-significant differences compared to placebo in the odds for nasopharyngitis (OR = 0.90; 95 % CI from 0.76 to 1.07), pharyngitis (OR = 1.45; 95 % CI from 0.92 to 2.28), upper respiratory tract infection (URTI) (OR = 0.97; 95 % CI from 0.82 to 1.15), rhinitis (OR = 1.01; 95 % CI from 0.71 to 1.44), pneumonia (OR = 0.56; 95 % CI from 0.10 to 2.01), and influenza (OR = 0.84; 95 % CI from 0.65 to 1.09). We observed significant reductions in the reporting of sinusitis (OR = 0.75; 95 % CI from 0.53 to 1.06), bronchitis (OR = 0.71; 95 % CI from 0.59 to 0.86), and ED or hospital admission due to asthma exacerbation for overall anti-IL-5 antibodies compared to placebo (OR = 0.59; 95 % CI from 0.40 to 0.88). We were not able to discriminate whether exacerbations were associated with infections or to increased sputum eosinophilia. From the subgroup analysis, we observed differences in directions and magnitudes of the effect size in the reporting of some events. Benralizumab was associated with increased odds of pharyngitis (OR = 1.56; 95 % CI from 0.97 to 2.52) and a similar trend was observed for mepolizumab in the reporting of rhinitis (OR = 1.85; 95 % CI from 0.72 to 4.78), both non-statistically significant. In terms of effect size, benralizumab also showed higher odds for bronchitis and pneumonia in comparison to mepolizumab and reslizumab (OR = 0.76, OR = 0.69, and OR = 0.60 for bronchitis and OR = 0.80, OR = 0.20, and OR = 0.45, respectively, all non-significant). Conclusion: Anti-IL-5 treatments might have different effects on the reporting of some infection events in patients with asthma. However, the evidence is limited by sample size and far than conclusive and suggest the need of future studies to evaluate the risk of infections in patients with asthma receiving anti-IL-5 treatments.

Eosinophilia is a common finding in drug hypersensitivity reactions (DHR). Its cause is unclear, as neither antigen/allergen‐driven inflammation nor clonal expansion is involved. Most delayed‐DHRs are due to p‐i (pharmacologic interaction of drugs with immune receptors). These are off‐target activities of drugs with immune receptors that result in various types of T‐cell stimulation, some of which involve excessive IL‐5 production. Functional and phenotypic studies of T‐cell clones and their TCR‐transfected hybridoma cell lines revealed that some p‐i‐induced drug stimulations occur without CD4/ CD8 co‐receptor engagement. The CD4/CD8 co‐receptors link Lck (lymphocyte‐specific protein tyrosine kinase) and LAT (linker for activation of T cells) to the TCR. Alteration of Lck or LAT can result in a TCR signalosome with enhanced IL‐5 production. Thus, if a more affine TCR‐[drug/peptide/HLA] interaction allows bypassing the CD4 co‐receptor, a modified Lck/LAT activation may lead to a TCR signalosome with elevated IL‐5 production. This "IL‐5‐TCR‐signalosome" hypothesis could also explain eosinophilia in superantigen or allo‐stimulation (graft‐versus‐host disease), in which evasion of CD4/CD8 co‐receptors has also been described. It may open new therapeutic possibilities in certain eosinophilic diseases by directly targeting the IL‐5‐TCR signalosome. [ABSTRACT FROM AUTHOR]

Background: it has been suggested that chronic low-grade inflammation plays an important role in the pathogenesis of polycystic ovary syndrome (PCOS). According to previous studies, it remains unclear which cytokines influence the development of this syndrome and whether their increase is associated with the presence of excess weight/obesity or is an independent factor. The aim of our research was to determine the parameters of chronic inflammation in women with PCOS in comparison with healthy women in the normal weight and the overweight subgroups. Methods: This case-control study included 44 patients with PCOS (19 women with a body mass index (BMI) < 25 kg/m² and 25 women with a BMI ≥ 25 kg/m²) and 45 women without symptoms of PCOS (22 women with a BMI < 25 kg/m² and 23 women with a BMI ≥ 25 kg/m²). Thirty-two cytokines were analyzed in the plasma of the participants using Immunology multiplex assay HCYTA-60K-PX48 (Merck Life Science, LLC, Germany). Results: Cytokines: interleukin-1 receptor antagonist (IL-1 RA), IL-2, IL-6, IL-17 E, IL-17 A, IL-18, and macrophage inflammatory protein-1 alpha (MIP-1 α) were increased in women with PCOS compared to controls, both in lean and overweight/obese subgroups (p < 0.05). Moreover, only lean women with PCOS had higher levels of IL-1 alpha, IL-4, IL-9, IL-12, IL-13, IL-15, tumor necrosis factor (TNF- α) alpha and beta, soluble CD40 and its ligand (SCD40L), fractalkine (FKN), monocyte-chemotactic protein 3 (MCP-3), and MIP-1 β compared to the control group (p < 0.05). IL-22 was increased in the combined group of women with PCOS (lean and overweight/obese) compared to the control group (p = 0.012). Conclusion: Chronic low-grade inflammation is an independent factor affecting the occurrence of PCOS and does not depend on the presence of excess weight/obesity. For the first time, we obtained data on the increase in such inflammatory parameters as IL-9, MCP-3, and MIP-1α in women with PCOS. [ABSTRACT FROM AUTHOR]

Background: There are many studies on the relationship between vitamin D and coronavirus disease 2019 (COVID-19), while the results are matters of debate and the mechanisms remain unknown. The present study was performed to assess the impact of serum 25-hydroxyvitamin D [25(OH)D] levels on the severity of disease in hospitalized COVID-19 patients and identify potential mechanisms of 25(OH)D alterations. Methods: A total of 399 hospitalized COVID-19 patients were recruited from three centers between December 19, 2022, and February 1, 2023. Medical history, laboratory examination, and radiologic data were retrospectively collected. The patients were divided into four groups based on disease severity. Serum 25(OH)D levels in the patients were determined by the electrochemiluminescence method and cytokines were detected by flow cytometry. The relationship between serum 25(OH)D status and the severity of COVID-19, and the correlation between 25(OH)D levels and cytokines in COVID-19 patients were assessed. Results: Levels of 25(OH)D were significantly lower in the deceased group than in the other three groups (P < 0.05), and lower in the critical group than in the general group (P < 0.05). There were no significant differences in the 25(OH)D levels between the general and severe groups (P > 0.05). The levels of 25(OH)D (odds ratio = 0.986, 95% confidence interval: 0.973–0.998, P = 0.024) and IL-5 (odds ratio = 1.239, 95% confidence interval: 1.104–1.391, P = 0.04) were independent risk factors for the severity of COVID-19 disease upon admission. Serum 25(OH)D levels were able to predict the mortality of patients with COVID-19, and the predictive value was even higher when combined with IL-5 levels and eosinophil (Eos) count. Circulating 25(OH)D status correlated negatively with the expression of IL-5 (r=-0.262, P < 0.001) and was positively linked with CD8+ T cell counts (r=-0.121, P < 0.05) in patients with COVID-19. Conclusions: This study found that the serum 25(OH)D status combined with IL-5 levels and Eos counts could be identified as a predictive factor for recognizing the risk of COVID-19 mortality. The serum 25(OH)D status in COVID-19 patients correlated negatively with the expression of IL-5. The potential mechanism for this relationship is worth further exploration. [ABSTRACT FROM AUTHOR]

Objective To observe the expression of peripheral blood IL-1β，IL-2，IL-4，IL-5，IL-6 levels in patients with gestational hypertension and explore the importance of peripheral blood cytokines in HDCP and their relations to the severity of the disease. Methods Multiple microsphere flow immunofluorescence assay was used to measure the levels of IL-1β，IL-2，IL-4，IL-5，IL-6 (27 patients with gestational hypertension, 18 patients with preeclampsia, 15 patients with severe preeclampsia)and 20 normal pregnant women were measured in 60 HDCP patients . Results　The serum levels of IL-1β, IL-2, IL-4, IL-5 and IL-6 in HDCP group were (12.53±1.32) pg/mL, (10.69±1.40) pg/mL， (1.02± 6.77) pg/mL， (4.41±1.29) pg/mL， (23.32±4.58) pg/mL，respectively. Normal pregnant women were ( 10.25±1.42) pg/mL, ( 4.41±1.32) pg/mL, ( 6.86±4.62) pg/mL， (5.31±1.31) pg/mL，and (6.82±1.02) pg/mL，respectively，The difference in IL-2、IL-4、IL-6 was statistically significant ( P < 0.05)，while the difference in IL-1β and IL-5 was not statistically significant (P >0.05). The levels of IL-2 and IL-6 were significantly different in the classificationof HDCP（P < 0.05). However, there was no significant difference in serum levels of IL-4（ P > 0.05). Conclusion Patients with gestational hypertension have significantly increased levels of IL-2 and IL-6 in their peripheral blood, which increase with the severity of the condition. IL-4 levels are significantly reduced but not related to the severity of the disease. Abnormal expression levels of IL-2，IL-6，and IL-4 in peripheral blood may induce the endothelial cell damage, abnormal immune activation，and promote the occurrence and development of pregnancy-induced hypertension. [ABSTRACT FROM AUTHOR]

The efficacy mepolizumab in severe asthmatic patients is proven in the literature. Primarily to study the effect of mepolizumab on exacerbations, steroid dependence, and the continuation of efficacy in the long term. Secondarily to evaluate the effect of the drug on nasal polyps. Analyzing data from SANI (Severe Asthma Network Italy) clinics, we observed severe asthmatic patients treated with mepolizumab 100 mg/4 weeks, for a period of 3 years. 157 patients were observed. Exacerbations were reduced from the first year (−84.6%) and progressively to 90 and 95% in the second and third ones. Steroid-dependent patients decreased from 54% to 21% and subsequently to 11% in the second year and 6% in the third year. Patients with concomitant nasal polyps, assessed by SNOT-22, showed a 49% reduction in value from baseline to the third year. The study demonstrated the long-term efficacy of mepolizumab in a real-life setting. [ABSTRACT FROM AUTHOR]

Background: The role of cytokines such as interleukin-5 (IL-5) in the pathogenesis of malaria remains unclear. This systematic review sought to synthesize variations in IL-5 levels between severe and uncomplicated malaria, as well as between malaria and controls not afflicted with the disease. Methods: This systematic review was registered at the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022368773). Searches for studies that reported IL-5 levels in patients with malaria (any severity) and/or uninfected individuals were performed in Web of Science, PubMed, EMBASE, Scopus, CENTRAL, and MEDLINE, between 1st and 10th October, 2022. The risk of bias among all included studies was minimized using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting observational studies. The differences in IL-5 levels between malaria and uninfected controls, and between severe and uncomplicated malaria were synthesized by narrative synthesis. Results: Among 1177 articles identified in the databases, 23 matched the eligibility criteria and were included in this systematic review. Qualitative syntheses showed the heterogeneity of IL-5 levels between different severities of clinical malaria and uninfected controls. The majority of the included studies (12/15 studies, 80%) found no change in IL-5 levels between malaria cases and uninfected controls. Similarly, most studies found no difference in IL-5 levels between severe (regardless of complications) and uncomplicated malaria (4/8 studies, 50%). The qualitative syntheses revealed that most studies found no difference in IL-5 levels between severe and non-severe malaria. Conclusions: The comprehensive review suggests that IL-5 levels are unchanged in patients with different levels of clinical severity of malaria and uninfected controls. Given the limited number of published studies on IL-5 levels in malaria, there is a need for additional research to determine the function of this cytokine in the pathogenesis of malaria. [ABSTRACT FROM AUTHOR]

The development of pollinosis in children and adolescents is determined by the influence of genetic and environmental factors. The pathogenetic basis of pollinosis in children and adolescents is the differentiation of Th0 to Th2, activation of Th2cells and increasing of the production of IL-4, IL-5, IL-13, sIgE, activation of mast cells, basophils, eosinophils, with following development of IgE-mediated allergic reaction after exposure to pollen allergens and the manifestation of clinical symptoms of pollinosis (allergic rhinitis, allergic conjunctivitis, bronchial asthma). Children and adolescents with pollinosis often develop cross-allergic reactions to plant-based foods. Pathogenetic pharmacotherapy (antihistamines of the second generation, topical corticosteroids, antileukotrienes, decongestants) allows to achieve control over the symptoms of pollinosis. Subcutaneous and sublingual ASIT are high effective, they reduce the severity of symptoms of pollinosis, decrease the risk of developing bronchial asthma and severe clinical forms of pollinosis. The sublingual ASIT is more safe than subcutaneous ASIT.

Cumulative data suggest that neuroinflammation plays a prominent role in amyotrophic lateral sclerosis (ALS) pathogenesis. The purpose of this work was to assess if patients with ALS present a specific peripheral cytokine profile and if it correlates with neurological disability assessed by ALSFRS-R, the rate of disease progression, and the pattern of disease progression (horizontal spreading [HSP] versus vertical spreading [VSP]). We determined the levels of 15 cytokines in the blood of 59 patients with ALS and 40 controls. We identified a positive correlation between levels of pro-inflammatory cytokines (interleukin [IL]-17F, IL-33, IL-31) and the age of ALS patients, as well as a positive correlation between IL-12p/70 and survival from ALS onset and ALS diagnosis. Additionally, there was a positive correlation between the ALSFRS-R score in the upper limb and respiratory domain and IL-5 levels. In our ALS cohort, the spreading pattern was 42% horizontal and 58% vertical, with patients with VSP showing a faster rate of ALS progression. Furthermore, we identified a negative correlation between IL-5 levels and the rate of disease progression, as well as a positive correlation between IL-5 and HSP of ALS. To the best of our knowledge, this is the first study reporting a “protective” role of IL-5 in ALS.

Allergic conjunctivitis is one of the common immune hypersensitivity disorders that affect the ocular system. The clinical manifestations of this condition exhibit variability contingent upon environmental factors, seasonal dynamics, and genetic predisposition. While our comprehension of the pathophysiological engagement of immune and nonimmune cells in the conjunctiva has progressed, the same cannot be asserted for the cytokines mediating this inflammatory cascade. In this review, we proffer a comprehensive description of interleukins 4 (IL-4), IL-5, IL-6, IL-9, IL-13, IL-25, IL-31, and IL-33, as well as thymic stromal lymphopoietin (TSLP), elucidating their pathophysiological roles in mediating the allergic immune responses on the ocular surface. Delving into the nuanced functions of these cytokines holds promise for the exploration of innovative therapeutic modalities aimed at managing allergic conjunctivitis.

Vernal keratoconjunctivitis (VKC) is a complex and multifactorial disease process that employs Th2 cell-mediated immunologic processes, which involves the overexpression of interleukin 4 (IL-4), IL-5, IL-9, IL-13, and IL-31, and the activation of mast cells that release IL-5 and CCL-11, recruiting eosinophils to the site of inflammation. The disease primarily affects young males and is more common in regions with warm climates. VKC is characterized by persistent and recurrent conjunctival inflammation that can adversely affect the patient’s quality of life, and, when inadequately treated, may lead to a host of ocular complications, such as corneal shield ulcers and scarring. The major distinct forms of VKC include limbal or palpebral, which may occur in combination. The clinicopathological features of VKC include the presence of pseudogerontoxon, limbal gelatinous hyperplasia, and perilimbal hyperpigmentation. Topical immunomodulators are effective anti-steroidal options for controlling severe and chronic cases of VKC. This review will provide a brief overview of topical immunomodulators, including cyclosporin and tacrolimus, and will highlight the clinical manifestations, pathological mechanisms, and fibroproliferative changes in the conjunctiva that can result from recurrent disease.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare vasculitis characterized by asthma, systemic manifestations, and blood and tissue eosinophilia. Objective: To assess the effectiveness and safety of mepolizumab (anti-IL-5) and benralizumab (anti-IL-5Ra) in EGPA for 24 months. Methods: We conducted a multicenter observational study, including patients with EGPA treated with anti-IL-5/Ra biologics in 9 Italian specialized facilities. Systemic disease activity, remission and relapse rate were evaluated from 3 to 24 months after treatment initiation. Respiratory outcomes, hematological parameters, corticosteroid (OCS) and immunosuppressants consumption were also assessed. Results: 49 patients with relapsing-refractory EGPA were included [26 (53.1%) benralizumab 30mg, 20 (40.8%) mepolizumab 100mg, 3 (6.1%) mepolizumab 300mg]. Overall, 38.8% and 57.1% achieved remission after 12 and 24 months, respectively (69.2% benralizumab and 43.5% mepolizumab). LowerOCS intake and higher blood eosinophil count at baseline were associated with remission at 24 months. Both biologics exerted beneficial effects on severe asthma outcomes. Indeed, 61.2% (61.5% benralizumab and 60.8% mepolizumab) remained exacerbation-free during treatment. Lung function parameters showed improvements in the overall cohort (all p<0.05), but began to decline from month 12, especially with mepolizumab. Marked reduction in blood eosinophils was registered with mepolizumab (p<0.0001), while benralizumab depleted both eosinophils (p<0.0001) and basophils (p<0.0001). In general, 69.6% (76% benralizumab and 61.9% mepolizumab) of OCS-dependent patients lowered their daily dose by 75%, while 28.3% discontinued these drugs. Immunosuppressants were suspended in88.2%of cases. Adverse eventswere reportedin8.2%ofpatients. Conclusions: These real-world data suggest that anti-IL-5/Ra biologics are effective and safe in the long-term as add-on treatments for patients with EGPA. [ABSTRACT FROM AUTHOR]

Keywords: COVID-19; Eosinophils; CD8; CD4; T cells; T2 cytokines; IL-13; IL-5; GATA-3 EN COVID-19 Eosinophils CD8 CD4 T cells T2 cytokines IL-13 IL-5 GATA-3 1 4 4 07/06/23 20230704 NES 230704 Xiaotian Ju and Kiho Son contributed equally to this work. The findings of a positive correlation between IL-5/IL-13 SP + sp CD8 SP + sp T cells and IL-5 levels (P = 0.01, R = 0.66) in ETA is suggestive that CD8 + T cells are a source of IL-5 in the airways. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Th cells play an important role in pathogenesis of type 1 diabetes (T1D). Peripheral blood mononuclear cells were isolated from peripheral blood samples from newly diagnosed (ND), 1-year (1YD), and 5-year T1D (5YD) patients (n:8 of each group), 8 healthy controls (HC), and cultured for 24 h under unstimulated (US) and stimulated conditions. Cell ratios of Th1, Th2, Th17, Treg, and intracellular levels of IFN-γ, TNF-α, IL-10, TGF-β, IL-5, IL-13, IL-17, and IL-21 cytokines were evaluated using the flow cytometry. mRNA expressions of transcription factors T-bet, GATA3, ROR-γt, and FOXP3 of these cells were determined by real-time PCR. Reduced CD4+CD25high cell ratios were detected in ND. CD4+CD25high cells were found to be reduced in ND and 1YD compared to HC under IL-2-stimulated conditions. Intracellular IFN-γ and TNF-α levels were low in all patients under US and IL-12-stimulated conditions. IL-17A and IL-21 were found to be high in patients with IL-6-stimulated conditions. Expressions of IL-10 and TGF-β have been observed to be reduced in patients. Th1/Th2, Th17/Treg, and Th1/Treg ratios were higher in patient groups. FOXP3 and GATA3 mRNA expressions were found to be low in patients, while RORγt and T-bet mRNA levels were higher than HC. Th1, Th17, and Treg cells and their cytokines have been shown to be associated with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Asthma is a chronic complex pulmonary disease characterized by airway inflammation, remodeling, and hyperresponsiveness. Vascular endothelial growth factor (VEGF) and eosinophil-derived neurotoxin (EDN) are two significant mediators involved in the pathophysiology of asthma. In asthma, VEGF and EDN levels are elevated and correlate with disease severity and airway hyperresponsiveness. Diversity in VEGF polymorphisms results in the variability of responses to glucocorticosteroids and leukotriene antagonist treatment. Targeting VEGF and eosinophils is a promising therapeutic approach for asthma. We identified lichochalcone A, bevacizumab, azithromycin (AZT), vitamin D, diosmetin, epigallocatechin gallate, IGFBP-3, Neovastat (AE-941), endostatin, PEDF, and melatonin as putative add-on drugs in asthma with anti-VEGF properties. Further studies and clinical trials are needed to evaluate the efficacy of those drugs. AZT reduces the exacerbation rate and may be considered in adults with persistent symptomatic asthma. However, the long-term effects of AZT on community microbial resistance require further investigation. Vitamin D supplementation may enhance corticosteroid responsiveness. Herein, anti-eosinophil drugs are reviewed. Among them are, e.g., anti-IL-5 (mepolizumab, reslizumab, and benralizumab), anti-IL-13 (lebrikizumab and tralokinumab), anti-IL-4 and anti-IL-13 (dupilumab), and anti-IgE (omalizumab) drugs. EDN over peripheral blood eosinophil count is recommended to monitor the asthma control status and to assess the efficacy of anti-IL-5 therapy in asthma. [ABSTRACT FROM AUTHOR]

Abstract Background Eosinophilic asthma is a common subtype of severe asthma with high morbidity and mortality. The cytokine IL-5 has been shown to be a key driver of the development and progression of disease. Although approved monoclonal antibodies (mAbs) targeting IL-5/IL-5R have shown good safety and efficacy, some patients have inadequate responses and frequent dosing results in medication nonadherence. Results We constructed a novel trivalent bispecific nanobody (Nb) consisting of 3 VHHs that bind to 2 different epitopes of IL-5 and 1 epitope of albumin derived from immunized phage display libraries. This trivalent IL-5-HSA Nb exhibited similar IL-5/IL-5R blocking activities to mepolizumab (Nucala), an approved targeting IL-5 mAb. Surprisingly, this trivalent Nb was 58 times more active than mepolizumab in inhibiting TF-1-cell proliferation. In primate studies, the trivalent IL-5-HSA Nb showed excellent pharmacokinetic properties, and peripheral blood eosinophil levels remained significantly suppressed for two months after a single dose. In addition, the trivalent IL-5-HSA Nb could be produced on a large scale in a P. pastoris X-33 yeast system with high purity and good thermal stability. Conclusions These findings suggest that the trivalent bispecific IL-5-HSA Nb has the potential to be a next-generation therapeutic agent targeting IL-5 for the treatment of severe eosinophilic asthma. Graphical Abstract

OBJECTIVE: Rabies is a lethal zoonotic infection caused by the rabies virus. Interferon- (INF) and interleukins (ILs) are a cytokine that is primarily produced by cells of the immune system. Vitamin C is an essential micronutrient in various biological processes, especially immune responses, and plays an essential part. Vaccination can successfully activate immune responses to virus infection protection. This study aimed to investigate the effect of vitamin C administration on immune responses to an inactivated rabies vaccine. MATERIALS AND METHODS: Thirty male Balb/c mice weighing between 25-30 gm (8 weeks old) were used in the current experimental study and randomly equally divided into three groups. Group I: untreated healthy control group was inoculated with PBS as a negative control. Group II: vaccinated intradermally with rabies vaccine alone using a dose of 4 ml/animal at 0, 7, 21 days. Group III: In addition to the dose of vaccine, mice were injected single intraperitoneally with 10 mg of vitamin C with each dose of vaccine on days 0, 7, 21. At experimental end, serum levels of IFN-1, IL-4, and IL-5 were measured. RESULTS: The results revealed that vitamin C supplementation significantly elevated IFN-1, IL-4, and IL-5 levels in vaccinated mice and treated with vitamin C (group III) compared to vaccinated group II and healthy control group I. Similarly, vitamin C supplementation exhibited strong positive correlations between IFN-1 and both IL-4 and IL-5 level in all experimental group. Taken together, these results showed that vitamin C is an important stimulator of interferon, interleukin-4 and -5 during inactivated rabies vaccine vaccination in mice. CONCLUSIONS: Our results supported the hypothesis that indicated the immunological improvement of vitamin C to the effectiveness of the inactivated rabies virus vaccination. High dose of vitamin C increases the levels of interferon and interleukin-4 and interleukin-5. [ABSTRACT FROM AUTHOR]