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Background: Non-small cell lung cancer (NSCLC) is a disease related to inflammation. Proinflammatory cytokines such as interleukin 17 (IL-17) can induce cancer cell proliferation, metastasis and immune escape. Although NSCLC immune escape is partly due to the interaction between PD-1 and PD-L1 and PD-L1 expression can be upregulated in cancer cells upon stimulation with IL-17, the underlying mechanism of IL-17-triggered PD-L1 gene transcription in NSCLC cells remains elusive. Methods: RT‒PCR, real-time PCR, and IB were used to assess the levels of PD-L1, MEF2C, and TRIM31 in NSCLC tissues as well as in IL-17–stimulated H1299 or PC9 cells. Bioinformatics analysis, luciferase assays, and ChIP were utilized to investigate the transcriptional mechanism of the PD-L1 gene. Co-IP/IB was used to examine the interaction between MEF2C and PD-L1, including MEF2C ubiquitination. IHC staining was carried out to analyse the expression of IL-17RA, MEF2C, TRIM31, and PD-L1 in NSCLC tissue arrays. The corresponding plasmids were constructed and identified. An isograft model was used to verify the findings in vitro. Results: PD-L1, MEF2C and TRIM31 expression levels were increased in NSCLC tissues and NSCLC cells exposed to IL-17. Mechanistically, MEF2C could bind to the − 778 to -475 nt and − 336 to -97 nt regions of the PD-L1 promoter. TRIM31 could mediate MEF2C K63-linked polyubiquitination at Lys 25, increasing MEF2C recruitment to the PD-L1 promoter and PD-L1 gene transcription. MEF2C, TRIM31 or PD-L1 gene silencing effectively suppressed MEF2C K63-linked polyubiquitination, PD-L1 induction and NSCLC growth in mice inoculated with Lewis lung cancer (LLC) cells transfected with the corresponding shRNA and treated with IL-17. Conclusion: IL-17 induces PD-L1 gene transcription in NSCLC cells through TRIM31-dependent MEF2C K63-linked polyubiquitination. [ABSTRACT FROM AUTHOR]

IL-17 and IL-23 inhibitors have shown successful results in improving skin lesions in the treatment of moderate-to-severe plaque psoriasis. However, psoriasis is a chronic inflammatory disease characterized by systemic inflammation including joints in addition to skin lesions. Therefore, in this retrospective and observational cohort study, we aimed to evaluate the effect of IL-17 inhibitors (secukinumab and ixekizumab) and IL-23 inhibitors (risankizumab and guselkumab) on systemic inflammation in psoriasis. We included 214 treatment courses with IL-17 inhibitors (n = 116, 54.2%) and IL-23 inhibitors (n = 98, 45.8%) and compared the neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (d-NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-monocyte ratio (PMR), systemic immune inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) at baseline and Week 16 of treatment. In patients receiving IL-17 inhibitor, NLR, d-NLR, PLR, SII, SIRI, and AISI were significantly decreased at Week 16 (p = 0.003, p = 0.001, p = 0.024, p = 0.001, p = 0.008, and p = 0.002, respectively). There was no significant reduction in systemic inflammatory markers in the anti-IL-23 group. At week 16, the anti-IL-17 group showed a significantly higher mean decrease from the baseline values of NLR, d-NLR, SII, SIRI, and AISI than the anti-IL-23 group (p = 0.021, p = 0.009, p = 0.012, p = 0.028, and p = 0.021, respectively). The PASI75/90/100 scores didn't significantly differ between the IL-17 and IL-23 groups. Achieving PASI90 response at Week 16 in the IL-17 group was associated with the change in AISI (p = 0.037). The PASI75 response at Week 16 in the IL-23 group was associated with the change in NLR, d-NLR, and SII (p = 0.044, p = 0.037, and p = 0.031, respectively). NLR (rho = 0.173, p = 0.014), d-NLR (rho = 0.189, p = 0.007), SII (rho = 0.158, p = 0.024), SIRI (rho = 0.156, p = 0.026), and MLR (rho = 0.165, p = 0.019) showed positive correlations with the baseline PASI, but no correlation was found with the change in systemic inflammatory markers and the change in PASI score. In the treatment of moderate-to-severe psoriasis, IL-17 inhibitors appear to have a greater decreasing effect on systemic inflammatory markers than IL-23 inhibitors. However, more evidence-based data are needed to conclude that IL-17 inhibitors are superior to IL-23 inhibitors in suppressing systemic inflammation in psoriatic disease. [ABSTRACT FROM AUTHOR]

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by pustules that rapidly progress into ulcers that commonly affect the lower limbs. Recently, successful treatment of PG has been reported with anti-IL 17 treatments. However, there have also been several reports of "paradoxical" induction of new PG lesions after use of IL-17 inhibitors. In this narrative review, we present the currently published English literature on cases in which PG has been successfully treated with IL-17 inhibitors and cases of possible newly induced PG after the use of IL-17 inhibitors. After use of the Naranjo Adverse Drug Reaction Probability Scale, it is difficult to conclude an adverse reaction of PG from anti-IL 17 biological agents. Our review also concludes that IL-23 and IL-36 inhibitors can be considered an alternative treatment for PG. [ABSTRACT FROM AUTHOR]

Asthma is a chronic airway inflammatory disease that affects millions globally. Although glucocorticoids are a mainstay of asthma treatment, a subset of patients show resistance to these therapies, resulting in poor disease control and increased morbidity. The complex mechanisms underlying steroid-resistant asthma (SRA) involve Th1 and Th17 lymphocyte activity, neutrophil recruitment, and NLRP3 inflammasome activation. Recent studies provided evidence that innate lymphoid cells type 3 (ILC3s) might be potential therapeutic targets for non-eosinophilic asthma (NEA) and SRA. Like Th17 cells, ILC3s play crucial roles in immune responses, inflammation, and tissue homeostasis, contributing to disease severity and corticosteroid resistance in NEA. Biologics targeting ILC3-related pathways have shown promise in managing Th2-low asthma, suggesting new avenues for SRA treatment. This review aims to explore the risk factors for SRA, discuss the challenges and mechanisms underlying SRA, consolidate current findings on innate lymphoid cells, and elucidate their role in respiratory conditions. We present the latest findings on the involvement of ILC3s in human diseases and explore their potential mechanisms in SRA development. Furthermore, we review emerging therapeutic biologics targeting ILC3-related pathways in managing NEA and SRA. This review highlights current challenges, and emerging therapeutic strategies, and addresses a significant gap in asthma research, with implications for improving the management of steroid-resistant asthma. [ABSTRACT FROM AUTHOR]

Objective: This study aims to develop and validate a nomogram model for predicting the risk of obstructive coronary artery disease (CAD) in patients with rheumatoid arthritis (RA), incorporating low-density lipoprotein cholesterol (LDL-C), Th17 cells, and interleukin (IL)-17 levels. The proposed model seeks to enable personalized cardiovascular risk assessment for RA patients, thereby optimizing clinical management strategies. Methods: A total of 120 patients with rheumatoid arthritis (RA) who were treated at the Second Hospital of Shanxi Medical University between January 2019 and September 2023 were enrolled in this study. Based on coronary angiography results, patients were categorized into the RA-obstructive CAD group and the RA-non-obstructive CAD group. Additionally, 53 healthy controls (HC group) were included. Clinical characteristics, laboratory parameters, peripheral blood lymphocyte subsets, and cytokine levels were collected for analysis. Univariate logistic regression was used to identify risk factors associated with RA-obstructive CAD. These variables were further refined using a random forest model for optimal selection. Finally, multivariate logistic regression analysis was performed with the selected variables to develop a nomogram model, which was subsequently validated to assess its performance. Results: Compared with the RA-non-obstructive CAD group, the RA-obstructive CAD group demonstrated significantly elevated levels of immune cell subsets, such as Th17 cells, and cytokines, including IL-17, IL-2, and IL-4, along with a reduction in Treg cells. (2) In the training cohort, univariate and multivariate logistic regression analyses identified LDL-C (OR = 0.04, P < 0.001), Th17 cells (OR = 0.76, P = 0.005), and IL-17 (OR = 0.75, P = 0.001) as independent risk factors for obstructive CAD in RA patients. Subsequently, a predictive nomogram model for RA-obstructive CAD risk was developed based on these indicators, incorporating LDL-C, Th17 cells, and IL-17. Conclusion: This study developed a predictive nomogram for RA-obstructive CAD by combining traditional risk factors, such as LDL-C, with immune biomarkers Th17 and IL-17. The model demonstrated robust predictive accuracy, enabling more precise risk assessment of CAD in RA patients. It offers clinicians a valuable tool for advancing cardiovascular risk management in RA, underscoring its significant potential for clinical application. [ABSTRACT FROM AUTHOR]

Objective: To investigate serum TL1A levels and their correlation with Th17 cells, IL-17, and IL-21 in children with Graves' disease (GD). Methods: Thirty-seven children (12 males and 25 females) aged 9-14 years with newly diagnosed and untreated GD were enrolled in this study. Serum TL1A, IL-17, and IL-21 levels were measured using enzyme-linked immunosorbent assay (ELISA). The percentage of Th17 cells in peripheral blood was determined by flow cytometry. The correlation between serum TL1A levels and Th17 cells, IL-17, and IL-21 was analyzed using Pearson's correlation coefficient. Results: Serum TL1A levels and the percentage of Th17 cells were significantly higher in children with GD compared to healthy controls (P<0.05). Serum IL-17 and IL-21 levels were also significantly elevated in GD patients (P<0.05). Serum TL1A levels positively correlated with the percentage of Th17 cells (r=0.625, P<0.05), IL-17 (r=0.573, P<0.05), and IL-21 (r=0.542, P<0.05) in children with GD. Conclusion: Serum TL1A levels are increased in children with GD and positively correlate with Th17 cells, IL-17, and IL-21, suggesting that TL1A may play a role in the pathogenesis of GD by regulating Th17 cell differentiation and the production of IL-17 and IL-21. [ABSTRACT FROM AUTHOR]

Introduction: Fungi, including Candida , may be a trigger or exacerbate psoriasis, especially in difficult to treat (DTT) areas, through the activation of IL-17/23 axis. Methods: In this study, seventy patients with DDT psoriasis were enrolled to evaluate Candida species and/or other opportunistic fungi colonization rate at baseline (T0) and the impact of apremilast on fungal load, clinical outcome, serum cytokine levels and biochemical serum profile of patients after 16, 24 and 52 weeks of treatment. Results: In our population, 33 (47%) patients were colonized by Candida spp. at baseline. In 24 (34%) individuals Candida was detected in the oral cavity while in the remaining 9 (13%) individuals the fungus was isolated from stool samples. Twenty subjects were colonized by only the species C. albicans , whereas in the remaining 13 a combination of two or more species (C. albicans plus non- albicans strains) was found in the oral cavity. Moreover, 27 (39%) patients were affected by onychomycosis. At 52 weeks, apremilast treatment induced a full recovery from Candida colonization in 83% of patients colonized with a single species of Candida (C. albicans); while in those co-infected by two or more Candida spp. induced a significant reduction (colony counts >10 CFU/mL) in fungal load was observed in comparison to baseline. Among patients with onychomycosis, 78% (21/27) of them presented a complete clinical resolution of nail psoriasis and concomitant nail infections. Finally, improvements in clinical scores i.e., PASI, NAPSI, DLQI, itch VAS, PAIN VAS, scPGA and sPGA-G and biochemical serum profile, as well as a significant decrease in serum IL-17A, TGF-β 1 and IL-10 levels (from 8.51 to 4.16 pg/mL; from 66.10 to 48.70 ng/mL and from 20.05 to 14 pg/mL, respectively) were observed in all patients. Conclusions: Fungi may play a role in the psoriasis pathogenesis. Apremilast has been shown to ameliorate psoriasis signs and symptoms and counteract fungal overgrowth, probably by dampening inflammation, triggered by the fungal infections themselves. Thus, apremilast may represent an effective therapeutic approach in the treatment of DTT psoriasis and modulate the fungal colonization. [ABSTRACT FROM AUTHOR]

Cytokines, which are important to the tumor microenvironment (TME), play critical roles in tumor development, metastasis, and immune responses. Interleukin-17(IL-17) has emerged as a key biomarker in many malignancies; however, its precise involvement in gastric cancer is less fully understood. Elevated levels of IL-17 have been observed in stomach diseases such as Helicobacter pylori infection and autoimmune gastritis, indicating that a sustained Th17 response may precede the development of gastric cancer. While IL-17 is related to inflammatory processes that may lead to cancer, its specific influence on gastric cancer development and therapy needs to be completely understood. Specifically, the release of IL-17A by diverse immune cells has been associated with both tumor development and inhibition in gastric cancer. It may impact tumor development through mechanisms such as boosting cell proliferation, inducing angiogenesis, and enabling immune cell recruitment or, conversely, suppressing tumor growth via the activation of anti-tumor immune responses. The dual role of IL-17 in cancer, along with its various effects depending on the TME and immune cell composition, highlights the complexity of its activity. Current research reveals that although IL-17 might serve as a target for immunotherapy, its therapeutic potential is hindered by its various activities. Some studies have shown that anti-IL-17 drugs may be helpful, especially when paired with immune checkpoint inhibitors, whereas others point to concerns about the validity of IL-17 in gastric cancer therapy. The lack of clinical trials and the heterogeneity of human tumors underscore the necessity for individualized treatment approaches. Further studies are needed to identify the specific mechanisms of IL-17 in gastric cancer and to design targeted therapeutics appropriately. [ABSTRACT FROM AUTHOR]

Background: Gonadotropin-releasing hormone (GnRH) is commonly used in animal reproduction and production, but it was previously reported that GnRH decreases the embryo implantation rate during artificial insemination or embryo transfer in sheep. In addition to the finding that GnRH can target S100A4 to inhibit endometrial epithelial cells proliferation, it was also found that endometrial cells were in poor condition and experienced cell death in S100A4 knockout mice, but the mechanism is unclear. Methods: The protein PPP1CA, which interacts with S100A4, was detected by immunoprecipitation-mass spectrometry of overexpression and knockdown of S100A4 and PPP1CA. The effect of S100A4 and PPP1CA on cell senescence was detected by Galactosidase staining. To further reveal the mechanism effect of S100A4 and PPP1CA on cell senescence, transcriptome sequencing was conducted. Additionally, in vivo experiments were performed to assess PPP1CA protein expression in the endometrial tissue of S100A4 knockout mice. Results: S100A4 inhibited cell senescence by activating PPP1CA, while PPP1CA overexpression suppressed the activation of the IL-17 signaling pathway. Inhibition of the IL-17 signaling pathway inhibited the senescence of endometrial cells. Conclusion: S100A4 can target the PPP1CA/IL-17 signaling pathway and inhibit endometrial epithelial cell senescence. [ABSTRACT FROM AUTHOR]

In recurrent pregnancy loss (RPL), peripheral and local immune cells are activated, decreasing the leukocyte tolerogenic response in the uterus and decidua. The aim was to examine the role of IL-17 in RPL critically. The study included genetic polymorphism, the analysis of the number of circulating IL-17 lymphocyte populations, before and after cell priming, serum cytokine quantification, and the assessment of T-reg cells in a group of 50 RPL and 50 normal women from the admixed Venezuelan population. The study found no differences in the genetic polymorphisms rs2275913 and rs763780. However, when IL-17+ cell populations of controls and RPL patients were compared, a significant increase was observed in the cell populations CD3+ and CD4+ (p < 0.001), while the contrary was recorded in CD8+ and CD56+ cells. Upon cell priming, all IL-17+ populations were significantly decreased (p < 0.001) in RPL patients compared to controls. The increase in IL-17A in the serum of RPL patients may be due to the CD4+ population, while cell exhaustion after activation could be responsible for decreased CD8+ cell population. The number of CD4CD25 FoxP3+ cells was significantly reduced (p < 0.001), and the number of activated HLADR+ cells was significantly increased (p < 0.001) in RPL patients. The absence of differences in the genetic polymorphism compared to controls suggests that biological factors influence IL-17 levels in RPL patients. This finding has significant implications for the understanding and potential treatment of RPL. [ABSTRACT FROM AUTHOR]

Psoriasis (Ps) is a chronic inflammatory disorder marked by skin plaque formation, driven by immune dysregulation and genetic factors. Despite the available treatments, incidence of Ps is increasing in the dermatology patients. Novel strategies are crucial due to current treatment limitations. The interleukin 17 (IL-17) pathway is pivotal in Ps pathogenesis, however the expression of its putative target gene placenta expressed transcript 1 (Plet1) remains unstudied in Ps. Considering the potential anti-inflammatory properties of N-Acetylglucosamine (GlcNAc), our study explored its role in modulating Plet1 expression in an imiquimod (IMQ)-induced Ps mouse model. Our data demonstarted a significant reduction of inflammation and Psoriasis Area and Severity Index (PASI) scores, downregulation of growth factors (GFs), IL-17 A, and MAPK expression after GlcNAc treatment. In addition, GlcNAc treatment reduced neutrophils, monocyte-dendritic cells (Mo-DC) and conventional T cells (Tcons) while increasing monocyte-macrophages (Mo-Macs) and regulatory T cells (Tregs). GlcNAc treatment also downregulated Plet1 overexpression in psoriatic mouse skin and in vitro, reduced proliferation and apoptosis in IL-17 A stimulated human dermal fibroblasts (HDF), along with IL-17 A and TGF-β mRNA expression. Together, these data suggest that, GlcNAc interferes with downstream mechanisms in IL-17 pathway and downregulating Plet1 expression, presenting a promising strategy for Ps treatment. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD) is a chronic and recurrent disease of the gastrointestinal tract that enhances the chance of developing colorectal cancer. Since standard treatments such as Mesalazine have limited effectiveness and are often accompanied by numerous side effects, the use of immune modulators derived from worms has been proposed as a new immunotherapy method for inflammatory diseases such as ulcerative colitis. The aim of this study is to investigate the protective effects of D. dendriticum egg antigen on DSS-induced colitis in C57BL/6 mice. Methods: D. dendriticum egg antigen was extracted and DSS (3.5%) was used to induce colitis in mice. Treatment and prophylaxis included intraperitoneal injections of D. dendriticum egg antigen. Histopathological indicators and the disease activity index (DAI), including weight loss, rectal bleeding, stool consistency, and rectal prolapse, were used to assess the severity of colitis. Real-time PCR measured the expression of transforming growth factor-β (TGF-β) and interleukin-17 (IL-17), while ELISA determined the concentration of these cytokines. Results: Treatment with D. dendriticum egg antigen significantly improved the clinical symptoms and decreased the severity of DSS-induced colitis. Furthermore, D. dendriticum egg antigen increased the expression of TGF-β mRNA and reduced the expression of IL-17 mRNA, leading to a positive adjustment in the regulation of proteins and reduction of inflammatory proteins. As a result, the macroscopic, microscopic inflammation and activity index (DAI) of DSS-induced decreased. Conclusion: D. dendriticum egg antigen provides a promising new way to modulate the immune system and improve ulcerative colitis. [ABSTRACT FROM AUTHOR]

The pathobiology of IL‐17 in lung fibrogenesis is controversial. Here we examined the role of IL‐17A/F in bleomycin (BLM) and adenoviral TGF‐β1‐induced lung fibrosis in mice. In both experimental models, WT and IL17af−/− mice showed increased collagen contents and remodeled lung architecture as assessed by histopathological examination, suggesting that IL‐17A/F is dispensable for lung fibrogenesis. However, IL17af−/− mice responded to the BLM challenge with perturbed lung leukocyte subset recruitment. More specifically, bleomycin triggered angiocentric neutrophilic infiltrations of the lung accompanied by increased mortality of IL17af−/− but not WT mice. WT bone marrow transplantation failed to correct this phenotype in BLM‐challenged IL17af−/− mice. Conversely, IL17a/f−/− bone marrow transplantation → WT did not perturb lung leukocytic responses upon BLM. At the same time, IL17af−/− mice treated with recombinant IL‐17A/F showed an attenuated lung inflammatory response to BLM. Together, the data show that the degree of BLM‐driven acute lung injury was critically dependent on the presence of IL‐17A/F, while in both models, the fibrotic remodeling process was not. [ABSTRACT FROM AUTHOR]

Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with motor incoordination which is reproduced in hyperammonemic rats. Hyperammonemia induces peripheral inflammation which triggers neuroinflammation and enhanced GABAergic neurotransmission in cerebellum and motor incoordination. The mechanisms involved remain unknown. The aims were to assess if the early increase of peripheral IL-17 triggers motor incoordination in hyperammonemic rats and to identify some underlying mechanisms. We assessed if blocking peripheral IL-17 with anti-IL-17 at 2–4 days of hyperammonemia prevents motor incoordination and analyzed underlying mechanisms. Hyperammonemia induces a transient blood IL-17 increase at days 3–4. This is associated with increased IL-17 receptor membrane expression and activation in cerebellum, leading to NADPH oxidase activation, increased superoxide production and MLCK that induce blood–brain barrier (BBB) permeabilization by reducing occludin and ZO-1. BBB permeabilization facilitates the entry of IL-17, which increases in cerebellum and activates microglia. This increases TNFα and the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway. This enhances GABAergic neurotransmission which impairs motor coordination. Blocking peripheral IL-17 with anti-IL-17 prevents all the above process and prevents motor incoordination. Early treatment to reduce blood IL-17 may be a useful treatment to reverse motor incoordination in patients with MHE. [ABSTRACT FROM AUTHOR]

The investigation of enhancer of zeste homolog 1 (Ezh1) in the context of dengue infection immunity has been limited, necessitating further exploration to elucidate its precise role and underlying mechanisms during infections. To address this gap, we generated Ezh1 knockout mice and obtained bone marrow and spleen samples from both Ezh1 knockout mice and wild‐type (WT) counterparts. Leveraging RNA sequencing (RNA‐seq) analysis, we identified the enrichment of genes associated with the interleukin‐17 (IL‐17) signaling pathway among the differentially expressed genes (DEGs) in the spleens of male Ezh1 knockout mice when compared to WT mice. Furthermore, our results revealed that Ezh1 knockout not only curtailed the viral load in dengue virus (DENV) infections but also suppressed the expression of pivotal cytokines, including interleukin‐9 (IL‐9) and IL‐17. Additionally, utilizing high‐parameter flow cytometry, we observed alterations in the immune cell phenotype within the spleens linked to Ezh1 gene knockout. Specifically, Ezh1 knockout inhibited the expressions of programmed cell death protein 1 (PD‐1), lymphocyte‐activation gene 3 (LAG‐3), and cluster of differentiation 86 (CD86). Additionally, we noted a reduction in cluster of differentiation 62L (CD62L) expression in neutrophils following DENV infection. Our comprehensive findings collectively underscore the significant role of Ezh1 in DENV infection, suggesting that targeting Ezh1 could offer a promising antiviral strategy. [ABSTRACT FROM AUTHOR]

Infertility, defined as the inability to obtain pregnancy after 12 months of regular unprotected sexual intercourse, has increased in prevalence over the past decades, similarly to chronic, allergic, autoimmune, or neurodegenerative diseases. A recent ARIA-MeDALL hypothesis has proposed that all these diseases are linked to dysbiosis and to some cytokines such as interleukin 17 (IL-17) and interleukin 33 (IL-33). Our paper suggests that endometriosis, a leading cause of infertility, is linked to endometrial dysbiosis and two key cytokines, IL-17 and IL-33, which interact with intestinal dysbiosis. Intestinal dysbiosis contributes to elevated estrogen levels, a primary factor in endometriosis. Estrogens strongly activate IL-17 and IL-33, supporting the existence of a gut–endometrial axis as a significant contributor to infertility. [ABSTRACT FROM AUTHOR]

Background: Psoriatic arthritis (PsA) is a chronic inflammatory disease that causes pain and fatigue, reduces physical function, and negatively impacts health-related quality of life (HRQoL). In the phase III BE OPTIMAL and BE COMPLETE studies, bimekizumab demonstrated clinical efficacy and meaningful improvements in patient-reported outcome (PRO) measures in biologic disease-modifying antirheumatic drug (bDMARD)-naïve patients, and those who had prior inadequate response/intolerance to tumor necrosis factor inhibitors (TNFi-IR). Objectives: To examine the association between achieving increasingly stringent clinical disease control criteria and improvements in PRO measures in patients with active PsA receiving bimekizumab. Design: Post hoc analysis of two phase III studies. Methods: BE OPTIMAL and BE COMPLETE assessed subcutaneous bimekizumab 160 mg every 4 weeks in bDMARD-naïve and TNFi-IR patients with active PsA. Disease control was assessed using American College of Rheumatology (ACR) response criteria, Minimal Disease Activity, Disease Activity Index for Psoriatic Arthritis, and the composite outcome of ACR50 and 100% improvement in Psoriasis Area and Severity Index. Associations between clinical disease control criteria and PRO measures of pain, fatigue, physical function, and HRQoL were assessed at week 16 and week 52/40 (BE OPTIMAL/BE COMPLETE). Results: Achievement of increasingly stringent clinical disease control criteria was generally associated with sequentially greater improvements in all PRO measures, including pain. At week 52/40, 94.7% of bDMARD-naïve and 97.6% of TNFi-IR patients achieving ACR70 reported ⩾50% improvements in pain from baseline, and the greatest numerical improvements (−48.5 bDMARD-naïve; −54.7 TNFi-IR). This pattern was evident as early as week 16 and sustained when assessed at week 52/40 across the majority of clinical disease control criteria and PRO measures reported. Conclusion: The achievement of increasingly stringent thresholds of disease control was associated with corresponding greater improvements in PROs, for patients receiving bimekizumab treatment, irrespective of prior TNFi use. Trial registration ClinicalTrials.gov: NCT03895203, NCT03896581, and NCT04009499. [ABSTRACT FROM AUTHOR]

Background: Calprotectin, a calcium-binding protein, plays a crucial role in inflammation and has been associated with various inflammatory diseases, including asthma. However, its regulation and impact on steroid hyporesponsiveness, especially in severe asthma, remain poorly understood. Methods: This study investigated the regulation of calprotectin proteins (S100A8 and S100A9) by IL-17 and its role in steroid hyporesponsiveness using in vitro and in vivo models. Calprotectin expression was assessed in primary bronchial fibroblasts from healthy controls and severe asthmatic patients, as well as in mouse models of steroid hyporesponsive lung inflammation induced by house dust mite (HDM) allergen and cyclic-di-GMP (cdiGMP) adjuvant. The effects of IL-17A stimulation on calprotectin expression and steroid response markers in bronchial epithelial and fibroblast cells were examined. Additionally, the therapeutic potential of paquinimod, a calprotectin inhibitor, in mitigating airway inflammation and restoring steroid response signatures in the mouse model was evaluated. Results: The results demonstrated upregulation of calprotectin expression in asthmatic bronchial fibroblasts compared to healthy controls, as well as in refractory asthma samples compared to non-refractory asthma. IL-17 stimulation induced calprotectin expression and dysregulated glucocorticoid response signatures in lung epithelial and fibroblast cells. Treatment with paquinimod reversed IL-17-induced dysregulation of steroid signatures, indicating the involvement of calprotectin in this process. In the HDM/cdiGMP mouse model, paquinimod significantly attenuated airway inflammation and hyperresponsiveness, and restored steroid response signatures, whereas dexamethasone showed limited efficacy. Mechanistically, paquinimod inhibited MAPK/ERK and NF-κB pathways downstream of calprotectin, leading to reduced lung inflammation. Conclusion: These findings highlight calprotectin as a potential therapeutic target regulated by IL-17 in steroid hyporesponsive asthma. Targeting calprotectin may offer a promising approach to alleviate airway inflammation and restore steroid responsiveness in severe asthma. Further investigations are warranted to explore its therapeutic potential in clinical settings and elucidate its broader implications in steroid mechanisms of action. [ABSTRACT FROM AUTHOR]

Psoriasis, an inflammatory disease, is largely mediated by T-helper 17 cytokines. We have previously identified the immune system-released activating agent (Israa) as a novel gene that connects the nervous and immune systems. This research aims to investigate the role of the Israa gene in psoriasis in vivo using the imiquimod-induced psoriasis model. We established the model in C57BL/6 wildtype mice, which were then treated with 200 pg/mouse, 400 pg/mouse, or 800 pg/mouse of recombinant ISRAA compared to methotrexate. Subsequently, we also induced psoriasis in Israa-knockout mice to confirm the effect of Israa. Results consistently showed improvement in psoriasis in all groups receiving recombinant ISRAA. The 200 pg/mouse dose eliminated the disease, reduced the cutaneous release of IL-17 to one-third and TNF-α to one-sixth, increased IL-10 release to over 500 pg, completely resolved parakeratosis, decreased epidermal thickness to one-half, and reduced the expression of CD4 and neutrophil elastase in the skin (all p < 0.05). Israa-knockout mice exhibited less severe psoriasis in all scoring, biochemical, and histological parameters compared to wild-type mice (p < 0.05). This study highlights Israa as a crucial molecule in psoriasis and confirms its immunomodulatory role in inflammatory diseases. [ABSTRACT FROM AUTHOR]

Keloids are characterized histologically by excessive fibroblast proliferation and connective tissue deposition, and clinically by scar tissue extending beyond the original site of skin injury. These scars can cause pruritus, pain, physical disfigurement, anxiety, and depression. As a result, keloid patients often have a diminished quality of life with a disproportionate burden on ethnic minorities. Despite advances in understanding keloid pathology, there is no effective Food and Drug Administration (FDA)-approved pharmacotherapy. Recent studies have highlighted the possible pathologic role of T helper (Th)17 cells and interleukin (IL)-17 in keloid formation, as well as their implication in other inflammatory disorders. This systematic review characterizes the role of Th17 cells and IL-17 in keloid pathogenesis, highlighting this pathway as a potential therapeutic target. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive search on PubMed, Embase, MEDLINE, and Web of Science databases on June 5, 2024. The search included terms related to Th17 cells, IL-17, and keloids. Thirteen studies met the inclusion criteria, comprising basic science and bioinformatic studies focusing on Th17 cells and IL-17. Key findings include increased Th17 cell infiltration and IL-17 expression in keloids, IL-17's role in amplifying the inflammatory and fibrotic response via the promotion of IL-6 expression, and IL-17's involvement in upregulating fibrotic markers via SDF-1 and HIF-1α pathways. IL-17 also activates the transforming growth factor beta (TGF-β)/Smad pathway in keloid fibroblasts. Th17 cells and IL-17 significantly contribute to the inflammatory and fibrotic processes in keloid pathogenesis. Therefore, targeting the IL-17 pathway offers a potential new therapeutic target to improve keloid patients' outcomes. Future research could further elucidate the role of Th17 cells and IL-17 in keloid pathogenesis and assess the safety and efficacy of targeting this pathway in human studies. [ABSTRACT FROM AUTHOR]

Aim: Microbial colonization contributes to periodontitis and peri-implantitis with an increase in proinflammatory cytokines like IL 17. This has a vital role in the destructive process of tissue and bone around the implant. Type 2 diabetes mellitus has the potential to increase these microbial colonies thus becoming a risk factor. To compare and correlate the association of peri-implant sulcular microflora and salivary IL-17 between healthy and controlled diabetic individuals. Materials and Methods: A total of 30 participants who have undergone dental implant placement with screw-retained prosthesis were included in the study. Participants were divided into two groups, healthy (n = 15) and diabetic (n = 15). The subgingival plaque was collected from peri-implant sites into TE buffer vials and the salivary sample was collected into Eppendorf tubes at the 7th, 14th, and 30th day. Microbiological counts of P. gingivalis, T. denticola, T.forsythia, and F. nucleatum were evaluated by polymerase chain reaction, and salivary interleukin (IL)-17 levels were obtained by enzyme-linked immunosorbent assay. Results: The bacterial count was increased in both healthy and diabetic individuals but more prevalent in diabetes. The salivary IL-17 levels were increased in diabetic individuals which was statistically significant. Conclusion: Increased microbiota in both healthy and diabetic individuals along with increased IL-17 levels can lead to peri-implantitis which provides an insight into microbiological and immunological aspects in individuals with dental implants further acting as a predictor for peri-implantitis. [ABSTRACT FROM AUTHOR]

Background: Long noncoding ribonucleic acids (lncRNAs), small noncoding RNAs known as microRNAs (miRNAs) as well as some cytokines are recently thought to have a role in many inflammatory and autoimmune disorders including Behçet's disease (BD). This chronic multisystem disease lacks the particular histological or laboratory findings that might aid in its diagnosis. Therefore, any association with such molecules may have an impact on understanding the disease pathogenesis and/or management. The current study compared the levels of NEAT1, miR-21 and IL17 levels in sera of Egyptian BD patients and healthy individuals. The expression levels of these molecules were further investigated for their association with BD manifestations and activity aiming to explore their potential application in disease management. Results: NEAT1 & miR-21 showed down-regulation while IL-17 showed up-regulation among BD patients as compared to controls. IL-17 had significant correlation with major vessels involvement and cyclophosphamide intake. NEAT1 showed a significant negative correlation with colchicine intake. Disease activity did not correlate significantly with any of NEAT1, miR-21 or IL-17. Conclusion: NEAT1, miR-21 and IL17 might have a role in Behçet's disease pathogenesis, so more research is needed to unveil that role and their potential usage as biomarkers for the diagnosis or therapeutic targets. [ABSTRACT FROM AUTHOR]

Background/objectives: The immunological pathways that cause Multisystem Inflammatory Syndrome after SARS-CoV-2 infection in children (MIS-C) remain under investigation. Methods: The aim of this study was to prospectively compare the T-cell cytokine expression profile in unvaccinated children with acute MIS-C (MISC_A) before immunosuppression, convalescent MIS-C (one month after syndrome onset, MISC_C), convalescent COVID-19 (one month after hospitalization), and in healthy, unvaccinated controls. The intracellular expression of IL-4, IL-2, IL-17, IFNγ, TNF-α and Granzyme B, and the post SARS-CoV-2-Spike antigenic mix stimulation of T-cell subsets was analyzed by 13-color flow cytometry. Results: Twenty children with a median age (IQR) of 11.5 (7.25–14) years were included in the study. From the comparison of the flow cytometry analysis of the 14 markers of MISC_A with the other three groups (MISC_C, post-COVID-19 and controls), significant differences were identified as follows: 1. CD4+IL-17+/million CD3+: 293.0(256.4–870.9) vs. 50.7(8.4–140.5); p-value: 0.03, vs. 96.7(89.2–135.4); p-value: 0.03 and vs. 8.7(0.0–82.4); p-value: 0.03, respectively; 2. CD8+IL-17+/million CD3+: 335.2(225.8–429.9) vs. 78.0(31.9–128.9) vs. 84.1(0.0–204.6) vs. 33.2(0.0–114.6); p-value: 0.05, respectively; 3. CD8+IFNγ+/million CD3+: 162.2(91.6–273.4) vs. 41.5(0.0–77.4); p-value: 0.03 vs. 30.3(0.0–92.8); p-value: 0.08, respectively. Conclusions: In children presenting with MIS-C one month after COVID-19 infection, T cells were found to be polarized towards IL-17 and IFNγ production compared to those with uncomplicated convalescent COVID-19, a finding that could provide possible immunological biomarkers for MIS-C detection. [ABSTRACT FROM AUTHOR]

Recent discoveries have established the pivotal role of IL-9-secreting immune cells in a wide spectrum of inflammatory and autoimmune diseases. However, little is known about how IL-9 contributes to the etiology of inflammatory bone loss in PMO. We observed that IL-9 has a pathological impact on inflammatory bone loss in ovariectomized (Ovx) mice. Our in vivo temporal kinetics analysis revealed that estrogen deprivation enhanced the production of IL-9 from Th cells (majorly Th9 and Th17). Both our ex vivo and in vivo studies corroborated these findings in Ovx mice, as estrogen diminishes the potential of Th9 cells to produce IL-9. Mechanistically, Th9 cells in an IL-9-dependent manner enhance osteoclastogenesis and thus could establish themselves as a novel osteoclastogenic Th cell subset. Therapeutically neutralizing/blocking IL-9 improves bone health by inhibiting the differentiation and function of osteoclasts, Th9, and Th17 cells along with maintaining gut integrity in Ovx mice. Post-menopausal osteoporotic patients have increased IL-9-secreting Th9 cells, which may suggest a potential role for IL-9 in the development of osteoporosis. Collectively, our study identifies IL-9-secreting Th9 cells as a driver of bone loss with attendant modulation of gut-immune-bone axis, which implies IL-9-targeted immunotherapies as a potential strategy for the management and treatment of inflammatory bone loss observed in PMO. Lay Summary: Our research identifies interleukin-9 (IL-9) as a key driver of bone loss in PMO. By promoting osteoclast formation and suppressing bone formation, IL-9 significantly contributes to the disease's progression. Our findings in both animal models and human patients suggest that targeting IL-9 could provide a novel therapeutic approach to combat bone loss in postmenopausal women. Graphical Abstract [ABSTRACT FROM AUTHOR]

AIM:To observe the changes of Th17 related cytokines in tears of conjunctivochalasis(CCH)patients with liver-kidney yin deficiency treated with traditional Chinese medicine Qi Jing Mingmu decoction combined with artificial tears.METHODS:A total of 56 CCH patients(56 eyes)with liver-kidney yin deficiency of grade Ⅱ to Ⅲ were collected and randomly divided into treatment group(treated with Qi Jing Mingmu decoction combined with artificial tears)of 26 cases(26 eyes)and control group(treated with pure artificial tears)of 30 cases(30 eyes). The treatment course was 1 mo, and international ocular surface disease index(OSDI), tear film break-up time(BUT), tear meniscus height(TMH)and conjunctival congestion index of the patients were observed before and after treatment. The patients' tears were collected before and after treatment, and Th17 related cytokines in tears were detected using flow cytometry immunofluorescence luminescence method.RESULTS:After treatment, the OSDI, BUT and conjunctival congestion index of CCH patients in the treatment group and control group were significantly improved(all P0.05). After treatment, the levels of IL-6 and TNF-α in the tears of both groups of CCH patients decreased compared to those before treatment(both P

Background. Ulcerative colitis (UC) is a chronic bowel disease with a complex aetiology that includes immune, genetic and environmental factors. Its progression and severity vary greatly, suggesting that different cytokine pathways may be responsible for the heterogeneity of clinical outcomes. The purpose of the study was to investigate the state of cytokine regulation of inflammation depending on the severity of UC. Materials and methods. We examined 32 patients with UC who were treated at the Department of Intestinal Diseases of the State Institution “Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine”. Patients were divided into groups depending on disease severity determined by the Mayo index: moderate UC — 24 individuals, severe UC — 8 patients. Serum levels of interleukin (IL) 17 and IL-23 were determined by enzyme-linked immunosorbent assay. The study was performed according to the instructions for each test kit. Statistical processing of the results was done using the Statistica 6.1 software package. Results. The content of proinflammatory cytokines in the examined patients with UC was significantly higher than in the control group: IL-17 — by 9.0 times (р

The influenza A virus (IAV) damages intestinal mucosal tissues beyond the respiratory tract. Probiotics play a crucial role in maintaining the balance and stability of the intestinal microecosystem. Extracellular vesicles (EVs) derived from probiotics have emerged as potential mediators of host immune response and anti-inflammatory effect. However, the specific anti-inflammatory effects and underlying mechanisms of probiotics-derived EVs on IAV remain unclear. In the present study, we investigated the therapeutic efficacy of Lactobacillus reuteri EHA2-derived EVs (LrEVs) in a mouse model of IAV infection. Oral LrEVs were distributed in the liver, lungs, and gastrointestinal tract. In mice infected with IAV, oral LrEVs administration alleviated IAV-induced damages in the lungs and intestines, modified the microbiota compositions, and increased the levels of short-chain fatty acids in those organs. Mechanistically, LrEVs exerted their protective effects against IAV infection by blunting the pro-inflammatory IL-17 signaling. Furthermore, FISH analysis detected miR-4239, one of the most abundant miRNAs in LrEVs, in both lung and intestinal tissues. We confirmed that miR-4239 directly targets IL-17a. Our findings paved the ground for future application of LrEVs in influenza treatment and offered new mechanistic insights regarding the anti-inflammatory role of miR-4239.

Grey mullet (Mugil cephalus) is an economically valuable species but is highly susceptible to Nocardia seriolae, leading to significant mortality. The immune responses of grey mullet to N. seriolae are not well understood, limiting the development of effective prevention strategies. This study aimed to clarify the immune responses of grey mullet to N. seriolae. Immune cells were exposed to N. seriolae ex vivo for 48 h, followed by de novo transcriptome analysis. In vivo, RT-qPCR was used to compare gene expression in N. seriolae-infected fish and controls at 48 h post-infection. Transcriptome analysis identified 65,276 unigenes, with 654 differentially expressed genes associated with immune pathways, notably Th17 differentiation and IL-17 signaling. KEGG, Ingenuity Pathway Analysis, and GSEA further supported these findings, indicating that N. seriolae activates immune responses against intracellular pathogens and may evade immunity through macrophage alternative activation. The in vivo results showed similar immune responses post-infection. These insights could inform strategies to protect grey mullet from N. seriolae infection. [ABSTRACT FROM AUTHOR]

Abstract Introduction Concentrated Growth Factor (CGF), rich in CD34 + stem cells, is widely used in treatments for androgenetic alopecia and skin rejuvenation due to its immune-modulating properties. Psoriasis, a chronic inflammatory skin condition, presents significant treatment challenges, particularly for patients who cannot use biologics due to conditions such as cancer and lesions resistant to treatments. The potential of CGF in treating psoriasis is promising, given its broad immunoregulatory effects which confirmed in our previous androgenetic alopecia work. Methods We evaluated the impact of CGF on IL-17 levels in two contexts: patients treated for androgenetic alopecia and a psoriasis mouse model. Twelve patients received three monthly injections of CGF, with serum IL-17 levels measured before and after treatment. In the psoriasis mouse model, groups were treated with CGF, and outcomes were assessed using the Psoriasis Area and Severity Index (PASI), skin barrier scores, histological analysis, and RNA sequencing. Additionally, in vitro experiments applied CD34 + cells from CGF to keratinocytes to measure levels of TNF-α, IFN-γ, IL-23, and IL-17. Results In patients with androgenetic alopecia, three monthly CGF injections resulted in significantly reduced serum IL-17 levels. In the psoriatic mouse model, CGF-treated groups exhibited lower PASI scores and improved skin barrier scores compared to controls. Histological analysis revealed enhanced skin characteristics, while RNA sequencing demonstrated downregulated IL-17 and upregulated CD34 expression, as well as improved expression of barrier-related genes. In vitro, the application of CD34 + cells from CGF to keratinocytes led to a significant reduction in TNF-α, IFN-γ, IL-23, and IL-17 levels, indicating strong anti-inflammatory effects. A clinical case of a psoriasis patient unresponsive to IL-23 therapy (Guselkumab) showed significant improvement following CGF treatment. Conclusion These findings indicate that CGF could serve as an effective and versatile treatment for psoriasis, especially for patients who have already undergone biologic therapies but continue to experience resistant lesions.

Abstract Lenalidomide (LEN) is widely used immunomodulatory drug (IMiD). Nonetheless, despite its efficacy, over time patients become resistant to LEN and relapse. Due to high clinical relevance, drug resistance in MM is being thoroughly investigated. However, less is known about predictors of good response to LEN-based treatment. The aim of this study was to identify molecular pathways associated with good and long response to LEN. The study included newly diagnosed MM patients (NDMM) and MM patients treated with first-line LEN and dexamethasone (RD) who achieved and least very good partial remission (VGPR). RNA was isolated from MM cells and new-generation sequencing was performed. Obtained results were validated with qRT-PCR. A global increase in gene expression was found in the RD group compared to NDMM, suggesting the involvement of epigenetic mechanisms. Moreover, upregulation of genes controlling the interaction within MM niche was detected. Next, genes controlling immune response were upregulated. In particular, the gene encoding the IL-17 receptor was overexpressed in the RD group which is a novel finding. This should be emphasized because IL-17-related signaling can potentially be targeted, providing the rationale for future research. Establishing the molecular background associated with long-lasting and profound response to LEN may improve LEN-based chemotherapy regimens and facilitate the development of adjuvant therapies to enhance its anti-MM activity.

Abstract Background Genetic factors, including the Hedgehog Interacting Protein (HHIP) gene, play a crucial role in Chronic Obstructive Pulmonary Disease (COPD) susceptibility. This study examines the association between HHIP gene polymorphisms and COPD susceptibility, phenotypes, and serum IL-17 and IL-18 levels in a Han Chinese population. Methods A case-control study was conducted with 300 COPD patients and 300 healthy controls in Chinese Han population. Participants underwent genotyping for HHIP gene polymorphisms, pulmonary function tests, and quantitative CT scans. DNA samples were sequenced using a custom chip targeting the HHIP gene. Serum IL-17 and IL-18 levels were measured by enzyme-linked immunosorbent assay. Associations between SNPs, COPD susceptibility, and phenotypes were analyzed using logistic and multiple linear regression models, adjusting for confounders. Results Our study identified the rs11100865 polymorphism in the HHIP gene as significantly associated with COPD susceptibility (OR 2.479, 95% CI 1.527–4.024, P = 2.39E-04) after screening 114 SNPs through rigorous quality control. Stratified analyses further indicated this association was particularly in individuals aged 60 or older. Serum levels of IL-17 and IL-18 were significantly elevated in COPD patients compared to controls, with rs11100865 showing a notable association with IL-18 levels (B = 49.654, SE = 19.627, P = 0.012). However, no significant associations were observed between rs11100865 and serum IL-17 levels, COPD-related imaging parameters, or clinical phenotypes. Conclusion This study identified a significant association between HHIP gene polymorphisms and COPD susceptibility in a Han Chinese population, with connections to inflammation, but found no significant associations between this SNP and COPD-related imaging or clinical phenotypes. Trial registration www.chictr.org.cn ID: ChiCTR2300071579 2023-05-18.

Objective: To investigate the substantial changes in cell types, pathways, and cell-cell interactions occurring in the irradiation-induced alopecia and dermatitis (IRIAD) mouse model and to identify potential targets for patients experiencing skin adverse reactions to radiotherapy. Methods: Mice were irradiated at 15 ​Gy, targeting the head and neck region. After a 14-day interval, living cells were extracted from both wild-type (WT) mice and irradiated mice for single-cell RNA sequencing (scRNA-seq). The scRNA-seq data, retrieved from the GEO database (GSE201447), underwent stringent quality control using the Seurat (v4.3.0) R package. Cell type annotation relied on previously reported typical markers and CellMarker 2.0. Differentially expressed genes were calculated to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Cell-cell interactions were evaluated using the Cellchat R package. Results: The application of single-cell RNA sequencing (scRNA-seq) enabled a comprehensive characterization of the intricate cellular composition of both wild-type (WT) and irradiated mice skin. Remarkably, cells within irradiated mice skin exhibited a significant alteration in the intensity of cell-cell interactions compared to their wild-type counterparts. This change in interaction intensity was observed across various cell types, including fibroblast cells, endothelial cells, and dendritic cells. Importantly, these ''interacting cells'' shared common signaling pathways, notably the upregulation of the IL-17 pathway following irradiation. Conclusions: The modification of intercellular communication induced by irradiation primarily involves fibroblast cells, endothelial cells, and various types of immune cells. This investigation provides a novel perspective on potential targets and holds promise for enhancing the clinical management of IRIAD.

Abstract Introduction A matching-adjusted indirect comparison (MAIC) was conducted to assess the relative efficacy at 52 weeks (Wk52) of bimekizumab 160 mg every 4 weeks (Q4W) and ustekinumab 45 or 90 mg every 12 weeks (Q12W) in patients with psoriatic arthritis (PsA) who were biologic disease-modifying anti-rheumatic drug naïve (bDMARD naïve) or who had a previous inadequate response or an intolerance to tumor necrosis factor inhibitors (TNFi-IR). Methods Relevant trials were systematically identified. Individual patient data from the bimekizumab trials BE OPTIMAL (NCT03895203; N = 431) and BE COMPLETE (NCT03896581; N = 267) were matched with summary data on patients receiving ustekinumab in the PSUMMIT 1 trial (NCT01009086; 45 mg, N = 205; 90 mg; N = 204) and a subgroup of TNFi-IR patients receiving ustekinumab in the PSUMMIT 2 trial (NCT01077362; 45 mg, N = 60; 90 mg, N = 58), respectively. Patients from the bimekizumab trials were re-weighted using propensity scores to match the baseline characteristics of the ustekinumab trial patients. Adjustment variables were selected based on expert consensus (n = 5) and adherence to established MAIC guidelines. Non-placebo-adjusted comparisons of recalculated bimekizumab and ustekinumab outcomes for the American College of Rheumatology (ACR) 20/50/70 response criteria (non-responder imputation) were analyzed. Results In patients who were bDMARD naïve, bimekizumab had a greater likelihood of response than ustekinumab at Wk52 for ACR20 (odds ratio [95% confidence interval] 45 mg: 2.14 [1.35, 3.40]; 90 mg: 1.98 [1.24, 3.16]), ACR50 (45 mg: 2.74 [1.75, 4.29]; 90 mg: 2.29 [1.48, 3.55]), and ACR70 (45 mg: 3.33 [2.04, 5.46]; 90 mg: 3.05 [1.89, 4.91]). In patients who were TNFi-IR, bimekizumab had a greater likelihood of response than ustekinumab at Wk52 for ACR20 (45 mg: 4.17 [2.13, 8.16]; 90 mg: 4.19 [2.07, 8.49]), ACR50 (45 mg: 5.00 [2.26, 11.05]; 90 mg: 3.86 [1.70, 8.79]), and ACR70 (45 mg: 9.85 [2.79, 34.79]; 90 mg: 6.29 [1.98, 20.04]). Conclusions Using MAIC, bimekizumab showed greater efficacy than ustekinumab in achieving all ACR responses in patients with PsA who were bDMARD naïve and TNFi-IR at Wk52. Trial Registration NCT03895203, NCT03896581, NCT01009086, NCT01077362.

Abstract Introduction The relative efficacy of bimekizumab and risankizumab in patients with PsA who were biologic disease-modifying anti-rheumatic drug naïve (bDMARD naïve) or with previous inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi-IR) was assessed at 52 weeks (Wk52) using matching-adjusted indirect comparisons (MAIC). Methods Relevant trials were systematically identified. For patients who were bDMARD naïve, individual patient data (IPD) from BE OPTIMAL (NCT03895203; N = 431) were matched with summary data from KEEPsAKE-1 (NCT03675308; N = 483). For patients who were TNFi-IR, IPD from BE COMPLETE (NCT03896581; N = 267) were matched with summary data from the TNFi-IR patient subgroup in KEEPsAKE-2 (NCT03671148; N = 106). To adjust for cross-trial differences, patients from the bimekizumab trials were re-weighted to match the baseline characteristics of patients in the risankizumab trials. Adjustment variables were selected based on expert consensus (n = 5) and adherence to established MAIC guidelines. Recalculated bimekizumab Wk52 outcomes for American College of Rheumatology (ACR) 20/50/70 response criteria and minimal disease activity (MDA) index (non-responder imputation) were compared with risankizumab outcomes via non-placebo-adjusted comparisons. Results In patients who were bDMARD naïve, bimekizumab had a significantly greater likelihood of response than risankizumab at Wk52 for ACR50 (odds ratio [95% confidence interval]: 1.52 [1.11, 2.09]) and ACR70 (1.80 [1.29, 2.51]). In patients who were TNFi-IR, bimekizumab had a significantly greater likelihood of response than risankizumab at Wk52 for ACR20 (1.78 [1.08, 2.96]), ACR50 (3.05 [1.74, 5.32]), ACR70 (3.69 [1.82, 7.46]), and MDA (2.43 [1.37, 4.32]). Conclusions Using MAIC, bimekizumab demonstrated a greater likelihood of efficacy in most ACR and MDA outcomes than risankizumab in patients with PsA who were bDMARD naïve and TNFi-IR at Wk52. Trial Registration NCT03895203, NCT03896581, NCT03675308, NCT03671148.

Background: Genetic factors, including the Hedgehog Interacting Protein (HHIP) gene, play a crucial role in Chronic Obstructive Pulmonary Disease (COPD) susceptibility. This study examines the association between HHIP gene polymorphisms and COPD susceptibility, phenotypes, and serum IL-17 and IL-18 levels in a Han Chinese population. Methods: A case-control study was conducted with 300 COPD patients and 300 healthy controls in Chinese Han population. Participants underwent genotyping for HHIP gene polymorphisms, pulmonary function tests, and quantitative CT scans. DNA samples were sequenced using a custom chip targeting the HHIP gene. Serum IL-17 and IL-18 levels were measured by enzyme-linked immunosorbent assay. Associations between SNPs, COPD susceptibility, and phenotypes were analyzed using logistic and multiple linear regression models, adjusting for confounders. Results: Our study identified the rs11100865 polymorphism in the HHIP gene as significantly associated with COPD susceptibility (OR 2.479, 95% CI 1.527–4.024, P = 2.39E-04) after screening 114 SNPs through rigorous quality control. Stratified analyses further indicated this association was particularly in individuals aged 60 or older. Serum levels of IL-17 and IL-18 were significantly elevated in COPD patients compared to controls, with rs11100865 showing a notable association with IL-18 levels (B = 49.654, SE = 19.627, P = 0.012). However, no significant associations were observed between rs11100865 and serum IL-17 levels, COPD-related imaging parameters, or clinical phenotypes. Conclusion: This study identified a significant association between HHIP gene polymorphisms and COPD susceptibility in a Han Chinese population, with connections to inflammation, but found no significant associations between this SNP and COPD-related imaging or clinical phenotypes. Trial registration: www.chictr.org.cn ID: ChiCTR2300071579 2023-05-18. [ABSTRACT FROM AUTHOR]

Objective: To analyze the serum pertussis toxin immunoglobulin G (PT-IgG), IL-17 and IFN-y levels in children with pertussis, and their relationship with intestinal mucosal barrier function and humoral immunity. Methods: A total of 140 children with pertussis (pertussis group) who were admitted to the Department of Pediatrics at General Hospital of Ningxia Medical University from February 2020 to September 2023, and 80 children (control group) with 2 weeks or longer duration of persistent cough but without Bordetella pertussis were selected as the study subjects at the same time. Serum PT-IgG, interleukin-17 (IL-17) and interferon-gamma (IFN-y) levels in all subjects were measured by enzyme-linked immunosorbent assay. Intestinal mucosal barrier function [advanced glycation end products (AGEs), diamine oxidase (DAO) and endotoxin (ETX)] and humoral immunity [immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), complement C3 and complement C4] were evaluated. The correlation between the levels of PT-IgG, IL-17 and IFN-y and intestinal mucosal barrier function, humoral immunity in children with pertussis was analyzed. Results: Serum PT-IgG positive rate in the pertussis group was 35.00% (49/140). Serum IL-17, IFN-y, AGES, DAO, and ETX levels in the pertussis group were higher than those in the control group. Serum IgA, IgG, IgM, complement C3, and complement C4 levels in the pertussis group were lower than those in the control group (P<0.05). PT-IgG positive rate was negatively correlated with the levels of IL-17, IFN-y, AGEs and ETX in children with pertussis. PT-IgG positivity rate was positively correlated with the levels of IgA, IgM and complement C3. IL-17 and IFN-y were positively correlated with AGEs and ETX. IL-17 and IFN-y were negatively correlated with IgA and complement C3. IL-17 was positively correlated with IFN-y (P<0.05). Conclusion: Serum PT-IgG positive rate is low, while the levels of IL-17 and IFN-y are relatively high in children with pertussis. The three are related to intestinal mucosal barrier function and humoral immunity. Detecting these indicators can provide a basis for clinical decision-making. [ABSTRACT FROM AUTHOR]

Background/Objectives: Cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) represent major primary liver cancers, affecting one of the most vital organs in the human body. T regulatory (Treg) cells play an important role in liver cancers through the immunosuppression of antitumor immune responses. The current study focuses on the characterization of circulating natural killer (NK) cells and T cell subsets, including Treg cells, in CCA and HCC patients, before and after surgical tumor resection, in order to understand the effect of tumor resection on the homeostasis of peripheral blood NK cells and T cells. Methods: Whole blood assays were performed to monitor immune alterations and the functional competence of circulating lymphocytes in a group of ten healthy individuals, eight CCA patients, and twenty HCC patients, before and one month after the surgical procedure, using flow cytometry, cell sorting, and qRT-PCR. Results: Before tumor resection, both HCC and CCA patients display increased percentages of CD8+ Treg cells and decreased frequencies of circulating CD4+ Treg cells. Notwithstanding, no functional impairment was detected on circulating CD4+ Treg cells, neither in CCA nor in HCC patients. Interestingly, the frequency of peripheral CD4+ Treg cells increased from 0.55% ± 0.49 and 0.71% ± 0.54 (in CCA and HCC, respectively) at T0 to 0.99% ± 0.91 and 1.17% ± 0.33 (in CCA and HCC, respectively) at T1, following tumor resection. Conclusions: Our results suggest mechanisms of immune modulation induced by tumor resection. [ABSTRACT FROM AUTHOR]

Among several quantitative trait loci involved in tuberculosis (TB) control in mice, one was mapped within the chromosome 17 segment occupied by the H2 complex and another within the chromosome 3 segment comprising the S100A8/9 genes, which encode neutrophil inflammatory factor S100A8/9. Previously, we developed a panel of H2‐congenic mouse strains differing by small segments of the major histocompatibility complex Class II (MHC‐II) region from TB‐susceptible H2j mice transferred onto the genetic background of the TB‐resistant C57BL/6 (H2b) strain. Susceptible B6.I‐9.3 mice differ from B6 progenitors by the alleles of their only classical MHC‐II H2‐Aβ gene. The goals of the present study were to: (i) comprehensively characterise the differences in TB‐related phenotypes between mice of the two strains and (ii) decipher interactions between the H2‐Aβ and S100A8/9 genes. Here, we describe the dynamics of TB‐related phenotypes differentiating B6.I‐9.3 and B6 mice (colony forming units counts, histopathology, lung immune cell infiltration and cytokine profiles). We show that disproportionally diminished CD4+ T‐cell population, an enlarged S100A8/9‐positive neutrophil population and higher S100A8/9 serum levels in B6.I‐9.3 mice collectively form the 'susceptible' phenotype before infection. An increase in IL‐17 and a decrease in intrferon‐gamma production by CD4+ T‐cells in these mice provide a mechanistic explanation of this phenotype. Using F2 segregation analysis, we show that the number of S100A8/9‐producing neutrophils in lungs and spleens and the proportion of Th17 CD4+ T‐cells in lungs are significantly lower in the presence of the MHC‐II dominant 'resistant' b allele compared to the recessive 'susceptible' j/j genotype. This provides direct genetic evidence that MHC‐II‐regulated CD4+ T‐cell landscapes determine neutrophil abundance before infection, an important pathogenic factor in TB immunity. [ABSTRACT FROM AUTHOR]