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关键词： CRSwNP   EGPA   eosinophilic asthma   hyper-eosinophilic syndrome hyper-eosinophilia   IL-5   mepolizumab   NUCALA  

摘要： The Interleukin-5 (IL-5)-mediated pathogenic role of eosinophils in airway disorders including severe eosinophilic asthma (SEA), chronic rhinosinusitis with nasal polyps (CRSwNP), eosinophilic granulomatosis with polyangiitis (EGPA), and rare hyper-eosinophilic syndrome (HES) is well established. Mepolizumab, an IL-5-targeting humanised antibody, is approved as an add-on maintenance therapy for SEA, EGPA, CRSwNP, and HES. Here, we review the safety and efficacy findings of mepolizumab in clinical trials and real-world evidence studies in patients with SEA, CRSwNP, EGPA, and HES. We specifically explore the data on mepolizumab that support early initiation of IL-5-targeted therapy to maximise its corticosteroid-sparing effect. This review consolidates the clinical data on mepolizumab, highlights other promising IL-5-targeting agents, and supports the IL-5 pathway as the key therapeutic target across eosinophilic indications.

关键词： Inflammatory bowel disease (IBD)   Human mesenchymal stem cells (MSCs)   Bone marrow (BM)   Uterine myometrium (Ut) MSCs   Major Histocompatibility Complex (MHC)   Interferon-gamma (IFN-gamma)  

摘要： The clinical efficacy of mesenchymal stem cell (MSC) therapy for inflammatory bowel disease (IBD) is inconsistent and often fails to match promising preclinical findings. To improve outcome, we compared MSCs isolated from human uterine myometrium (Ut), a readily-available tissue source from a unique immune niche, to bone marrow (BM) MSCs, the most common source, in a murine IBD model with mechanisms underlying differential effects. In this study, human BMMSCs and UtMSCs were intravenously administered to mice with dextran sulfate sodium-induced colitis and evaluated for disease activity, microbiome composition, and cellular immunity. Bioinformatics analyses including patient data were performed to further specify involved mechanisms with subsequent functional validation performed. We found that UtMSC but not BMMSC treatment significantly reversed disease parameters by improving microbiome and reducing mesenteric lymph node IFN-gamma and IL-17Asecreting T cells. Transcriptomic analysis revealed UtMSCs had reduced MHC II pathway activation compared to BMMSCs. Functional validation confirmed UtMSCs compared to BMMSCs expressed lower IFN-gamma receptors, prevent MHC II-mediated human unstimulated T cell activation, and modulated stimulated T helper (Th) cells away from effector phenotypes while increasing regulatory T cells (Tregs) and IL-10 levels. Bioinformatics from IBD patients resistant to non-T cell-specific therapies implicated persistent MHC II-mediated Th1/Th17 activation as key drivers of disease. Overall, UtMSCs outperformed BMMSCs in improving microbiota, avoiding IFN-gamma responses, and modulating overall Th responses, suggesting this MSC source may offer more significant effectiveness for IBD and Th1/Th17-mediated conditions. Our findings also highlight that understanding MSC sourcespecific therapeutic mechanisms is crucial for optimizing clinical therapies.

关键词： antibody-mediated rejection   HLA class II DSA   paediatric liver transplantation   T cell-mediated rejection  

摘要： To evaluate the clinical relevance of post-transplant anti-HLA class II donor-specific antibodies (DSA) in paediatric liver transplantation (LT) recipients. We performed a retrospective cohort study including 346 paediatric patients who underwent LT between January 2019 and December 2022 at our centre. Based on the HLA class II DSA status, we divided the patients into the class II DSA-positive (n = 74) and class II DSA-negative (n = 272) groups. Demographic data, biopsy-proven rejection, DSA characteristics, clinical outcomes, and post-transplantation complications data were compared between groups. Our study consisted of 346 eligible paediatric LT recipients. Of these patients, 74 (21.4%) patients were positive for class II DSA and 272 (78.6%) were negative for class II DSA. The median and interquartile range between LT and class II DSA assessment was 12 (3-24) months post-transplant. Compared with the class II DSA-negative patients, post-transplant class II DSA was associated with a significantly increased risk of T cell-mediated rejection (p = 0.033) and antibody-mediated rejection (p = 0.045). Postoperatively, the incidence of cytomegalovirus infection (p = 0.003) and fungal infection (p = 0.007) was higher in the class II DSA-positive group than in the class II DSA-negative group. The frequency of adverse events, including biliary complications (p < 0.001) and intestinal flora alteration (p = 0.007), occurred more frequently in the class II DSA-positive group. Multivariable analyses showed that post-transplant class II DSA was an independent risk factor for T cell-mediated rejection (OR 2.027, 95% CI: 1.109-3.706, p = 0.022). Within the class II DSA-positive group, 22 (30.6%) patients developed T cell-mediated rejection post-transplant, 5 (6.9%) for DSA against HLA-DR, 12 (16.2%) for DSA against HLA-DQ, and 5 (6.7%) for DSA against HLA-DR + HLA-DQ. The MFI value for class II DSA was not significantly higher for patients with T cell-mediated rejection than for t

关键词： DADA2   immune repertoire   BCR   TCR   immune archi-tecture   autoimmunity   machine learning   TNF  

摘要： Background: Adenosine deaminase 2 deficiency (DADA2) is a genetic disorder caused by biallelic hypomorphic or loss-of-function mutations in the ADA2 gene, which encodes a protein deaminase regulating extracellular adenosine metabolism. Clinical features encompass inflammatory vasculopathy, early-onset strokes, and a complex presentation involving both immunodeficiency and autoinflammation/autoimmunity. Objective: Our aim was to determine a DADA2-specific adaptive immune architecture. Methods: We profiled immunoglobulin levels and peripheral Band T-cell phenotypes in 47 previously reported and 5 unreported patients with DADA2. Levels of 21 cytokines and chemokines were quantified in patients with or without anti-TNF treatment. To characterize the DADA2 immune architecture, we performed T-and B-cell receptor immunosequencing. We trained a binary LightGBM classifier to distinguish DADA2 T-and B-cell immune repertoires from healthy individuals. Results: We detected hypogammaglobulinemia in 65% of patients with DADA2 (34 of 52) and cytopenias in 48% (25 of 52). Flow cytometric profiling revealed contraction of Band T-cell memory compartments. In addition, we observed elevated levels of TNF, IL-8, several interferons, a proliferation-inducing ligand (APRIL), B-cell activating factor (BAFF), and soluble CD40 ligand (sCD40L). High serum levels of TNF, BAFF, and sCD40L persisted under anti-TNF therapy. Next-generation immunosequencing of peripheral lymphocytes showed restricted T-cell receptor repertoires and B cells, which were particularly skewed toward immunoglobulin heavy chain V4-34 rearrangements. With high accuracy, our machine learning algorithm separated individuals with DADA2 from healthy individuals on the basis of immunogenetic parameters regarding B-cell clone fraction, CDR3 length, and selected Kidera factors. Conclusions: Our findings underscore the significant influence of ADA2 on the adaptive immune system, which results in a highly specific immunogenetic si

关键词： Familial Mediterranean fever   FMF   Colchicine   Canakinumab   Anakinra   Autoinflammatory diseases   Safety  

摘要： Introduction: The majority of currently available data on familial Mediterranean fever (FMF) come from retrospective national or international studies. Methods: An observational study collected data on the Eurofever international FMF cohort. Patients fulfilling genetic and clinical Eurofever criteria were considered as FMF+. Patients not fulfilling clinical and/or genetic (one VUS or benign variants or negative for MEFV variants) criteria were considered as FMF-. Data on compliance to treatment and quality of life were also recorded. Results: Since November 2024, 876 FMF patients (466 M, 410 F) were enrolled, with a mean follow-up of 2.9 +/- 3.1 years. 730 (84 %) patients were classified as FMF+, 146 (16 %) as FMF-, with significant differences in the prevalence of clinical manifestations and treatment response between the two groups. At the last follow-up, 433 patients (50.6 %) still had some disease activity. At the last follow-up 749 (85.5 %) patients received colchicine with a relative under dosage of the drug. Anti-IL-1 treatment was reported in 133 patients (15.2 %), mostly canakinumab (117, 13.4 %). Treatment compliance was generally satisfactory, and adverse events were generally mild. Conclusions: Patients with an FMF-like phenotype who lack genetic confirmation display significant differences in clinical features and duration of attacks and show a less response to treatment during their disease course in respect, and thus, should be considered as FMF-mimics and investigated for other causes. Longitudinal data provides a more detailed comprehension of the long-term burden of FMF and the impact of treatment on disease activity and patients' quality of life.

关键词： AKI   chemokine   CKD   macrophages   renal tubular epithelial cells  

摘要： Key PointsMacrophage-derived IFN- contributes to tubular epithelial cell polyploidization after *** IFN- induced tubular epithelial cell polyploidization by regulating inorganic pyrophosphatase-mediated yes-associated protein (YAP) *** Delayed blockade of the IFN-beta response attenuated persistent polyploidization and kidney *** is recognized as a common risk factor of CKD. Renal tubular epithelial cell polyploidization after AKI is closely associated with maladaptive repair, while the regulatory and molecular mechanisms remain poorly understood. In this study, we set out to investigate the mechanism of tubular epithelial cell polyploidization and their role in AKI-to-CKD *** change characters of polyploid tubular epithelial cells and macrophages after AKI were detected by flow cytometry and immunofluorescence. The underlying mechanism was explored by RNA-sequencing analysis, immunofluorescence, and Western blot. The role of tubular epithelial cell polyploidization in AKI-to-CKD transition was evaluated by transgenic mice and drug *** discovered that tubular epithelial cells underwent polyploidization after AKI, and polyploid tubular epithelial cells exhibited greater fibrotic phenotypes than nonpolyploid cells. Furthermore, we revealed an upregulated IFN-beta response feature within tubular epithelial cells after AKI and identified that macrophage-derived IFN-beta bound to IFN-I receptor 1 of tubular epithelial cells and induced their polyploidization. Mechanistically, IFN-beta, secreted by macrophages through activation of the cyclic guanosine monophosphate-AMP synthase-stimulator of IFN genes pathway, acted on tubular epithelial cells and facilitated inorganic pyrophosphatase binding to yes-associated protein (YAP), which mediated YAP dephosphorylation and subsequent nuclear translocation, culminating in p21 expression and polyploidization. Importantly, delayed blockade of the IFN-b

关键词： Nanobody screening   IL-12B   Phage display technology   Fluorescence resonance energy transfer  

摘要： Aims: IL-12B, a subunit of the IL-23 family of cytokines, plays a crucial role in various diseases such as viral infections, autoimmune disorders, and tumors. This study aimed to identify high-affinity nanobodies that bind to distinct epitopes of IL-12B to and assess their potential for therapeutic and diagnostic applications, particularly through fluorescence resonance energy transfer(FRET) to evaluate their ability to target IL-12B. Methods: IL-12B protein was expressed in eukaryotic cells and used to immunize camels to induce an immune response. Camel-derived anti-IL-12B nanobodies were isolated and screened via phage display to identify those with high specificity and affinity for IL-12B. Binding affinity and epitope interactions were further analyzed using high-performance liquid chromatography (HPLC) and ForteBio Octet assays. A FRET-based assay was developed to evaluate protein interactions for precise therapeutic targeting. Results: Several high-affinity nanobodies targeting IL-12B were successfully generated. These nanobodies exhibited strong binding to various epitopes of IL-12B. Screening by HPLC and ForteBio Octet confirmed their high specificity and affinity, while fluorescence analysis demonstrated efficient energy transfer between thenanobodies, indicating successful interactions. Conclusions: This study identified high-affinity nanobodies against IL-12B and used FRET to characterize their interactions. These nanobodies show promise for therapeutic potential targeting IL-12B-related diseases, including viral infections, autoimmune disorders, and cancer. However, further clinical studies are needed to fully explore their potential for diagnostic and therapeutic applications.

关键词： Methotrexate   Dabigatran   Inflammation   Coagulation   Endothelial dysfunction   Hepatotoxicity  

摘要： This study examines Dabigatran's (Dab) capacity to mitigate methotrexate (MTX)-induced coagulation disorders and endothelial dysfunction, while exploring its effects on oxidative stress and inflammatory pathways (NF-kB/IL-1 beta/MCP-1, TLR4/NLRP3) in reducing hepatotoxicity. Rats were assigned to four groups: a control group receiving saline intraperitoneally (i.p.);an MTX group with a single MTX dose (20 mg/kg, i.p.) to induce hepatotoxicity;and two pretreatment groups receiving Dab orally at 15 mg/kg and 25 mg/kg for seven days before and 4 days after MTX administration. MTX-treated rats showed significant increases in liver enzymes (ALT, AST, ALP) and reductions in antioxidant enzymes (SOD, GSH), along with elevated coagulation parameters (tissue factor (TF), thrombin, fibrin, plasminogen activator inhibitor-1 (PAI-1)), leading to coagulation disorders. Endothelial dysfunction was evident with reduced eNOS expression, while inflammation increased through elevated iNOS, ICAM-1, and pro-inflammatory cytokines (MPO, NF-kB, TNF-alpha, IL-1 beta, MCP-1), alongside activation of the TLR4/NLRP3 inflammasome pathway and decreased IL-10 (p < 0.05). Immunohistochemistry revealed increased cytochrome c and caspase-3 expression, with histopathological damage. Dabigatran mitigated these effects, downregulating liver enzymes, modulating coagulation factors, restoring eNOS levels, and reducing histopathological and inflammatory markers. Dabigatran demonstrates significant therapeutic potential in alleviating methotrexate-induced hepatotoxicity through its antioxidant, anti-inflammatory, anticoagulant, and anti-apoptotic effects. Its regulation of coagulation parameters and endothelial function suggests a protective role against tissue damage, warranting further investigation.

关键词： HLA   HLA-A*68:331   novel allele   sequencing-based typing  

摘要： HLA-A*68:331 differs from HLA-A*68:01:02:02 by one nucleotide substitution in codon 52 in exon 2.