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关键词： ERα   MHC I   male reproductive dysfunction   maternal BPB exposure   testicular immunity  

摘要： As an emerging endocrine-disrupting agent and structural analog of bisphenol A (BPA), bisphenol B (BPB) raises significant concerns due to its potential to induce male reproductive toxicity. Despite its presence in maternal bodily fluids, the effects of BPB exposure on the reproductive system and its mechanisms in adult male offspring are poorly understood. By establishing a maternal BPB exposure model in mice, we found that the exposure reduced the relative weights of seminal vesicles and preputial glands, decreased the thickness of the seminiferous epithelium, enlarged the lumen area of seminiferous tubules, and lowered testosterone concentration and synthesis, as well as sperm count in 10-week-old male offspring. Bioinformatic analyses revealed that the differentially expressed genes were significantly associated with major histocompatibility complex I (MHC I)-mediated immunological processes, including immune system processes, antigen processing and presentation of exogenous peptide antigens via MHC class I, and interleukin-2 production. Importantly, molecular docking proposed a potential mechanistic model wherein BPB bound to estrogen receptor α (ERα) suppressed its testicular expression and triggered MHC class I gene overexpression, potentially promoting macrophage infiltration, CD4+/CD8+ T cell activation, and pro-inflammatory cytokine production. Our findings provide critical insights into the adverse effects of maternal BPB exposure on male reproductive development, suggesting that impairments in testicular morphology and spermatogenesis may be attributed to MHC I-mediated immunological responses and hormonal imbalances resulting from inhibited ERα signaling. These results underscore not only the toxicological risks associated with BPB but also potential therapeutic targets for mitigating male reproductive dysfunction.

摘要： Recently long-read sequencing technologies and bioinformatics have enabled the construction of haplotype-resolved genome assemblies. Here, we present the complete and accurate de novo characterization of two challenging genomic regions, the major histocompatibility complex (MHC) and Killer-cell immunoglobulin-like receptors (KIRs), in phased haplotypic form, using the Oxford Nanopore Technology (ONT) Adaptive Sampling sequencing, and a newly developed bioinformatics pipeline. These critical regions for our immune response have been notoriously difficult to characterize due to their sequence variability and structural complexity. The key features of our approach are (i) focused sequencing of specific regions, (ii) exclusive use of ONT, and (iii) a unique phasing methodology that integrates sequencing reads, methylation signals, and a reference panel. Ten samples with known MHC and KIR haplotypes were sequenced and assembled, demonstrating the potential of our approach. We achieved efficient target enrichment resulting in 100% coverage and accuracy ranging from 99.95% to 99.99% across the MHC and KIR. Its simplicity, reproducibility, and affordability distinguish this method as a unique and effective approach for the targeted haplotypic characterization of the MHC and KIR without trios and possibly other specific genomic regions. These efforts will in turn facilitate future studies that further advance the functional deconvolution of our genome.

关键词： Cytokines   Disease activity   Interleukin 2 (IL-2)   Systemic lupus erythematosus  

摘要： ObjectiveLow-dose interleukin 2 (IL-2) administration has been shown to selectively modulate regulatory T (Treg) cell abundance and alleviate the progression of systemic lupus erythematosus (SLE). IL-2 level could be indicator of low-dose IL-2 usage in SLE patients. However, current methods for IL-2 detection are generally not sensitive to be used in clinic. This study aims to establish flow cytometry-based IL-2 detection as a feasible approach in determining IL-2 in peripheral blood of SLE *** cytometry was used to quantify the relative mean fluorescence intensity (MFI) of IL-2 in CD3+T cells and other lymphocyte subsets in peripheral blood mononuclear cell (PBMCs) from a cohort of 134 SLE patients and 112 healthy controls (HC). Correlations between IL-2 MFI and clinical or laboratory parameters in SLE patients were also *** of IL-2 represented IL-2 expression in CD3+T cells. IL-2 MFI was significantly lower in SLE patients compared to the HC group and negatively associated with anti-ribosomal protein antibodies, erythrocyte sedimentation rate (ESR), and blood urea. Conversely, it was positively correlated with IgA and hemoglobin. These associations with IgA, hemoglobin, ESR, and blood urea remained significant after adjusting for age and disease duration. IL-2 level was also positively correlated with the relative abundance of Th1, Th2, and Th17 cells. Furthermore, MFI of IL-2 recovered with effective treatment in SLE *** of IL-2 serves as a feasible marker of IL-2, which is significantly decreased in SLE patients and recovered with treatment, suggesting its potential for assessing short-term disease status and treatment response in SLE patients. Key Points center dot IL-2 MFI can be used to estimate IL-2 expression level in SLE patients. center dot IL-2 MFI is significantly reduced in SLE *** dot IL-2 MFI can serve as a marker for monitoring SLE activity and short-term status.

关键词： 哮喘   丹龙定喘汤   炎症   辅助性T细胞17   调节性T细胞  

摘要： 目的：探讨丹龙定喘汤对白蛋白（OVA）所致的支气管哮喘小鼠炎症的作用及改善机制。方法：60只SPF级BALB/c雌性小鼠，随机分为正常对照组、模型对照组、地塞米松0.63 mg/kg组、丹龙定喘汤13、27、53 g/kg组，每组10只。除正常对照组外，其他组小鼠于第1、14d腹腔注射0.2mLOVA溶液致敏，在第28d，将1%OVA生理盐水溶液超声雾化并以最大雾量吸入激发，1次/d，30 min/次，连续5d。第35d开始雾化吸入1%OVA溶液激发哮喘，每周雾化3次，同时各药物组灌胃给予相应药物，1次/d，共6w。末次给药1 h后，小鼠进行气道反应性高低的检测；检测结束后取材，摘眼球取血，全血测定血常规观察炎症细胞变化；检测血清检测白介素10（IL-10）、白介素17（IL-17）的含量；取肺泡灌洗液检测辅助性T细胞17（Th17细胞）、调节性T细胞（Treg细胞）的水平；多聚甲醛固定右肺上叶后包埋切片进行苏木精-伊红染色（HE染色）和马松染色（Masson染色）。结果：与正常对照组相比，模型对照组小鼠经不同浓度的乙酰甲胆碱刺激后Penh值显著升高，全血中白细胞和粒细胞比例显著增加，支气管周围炎症浸润与胶原沉积明显，肺泡灌洗液中Th17细胞占比、血清中IL-17含量显著增加，Treg细胞占比、血清IL-10含量明显降低（P＜0.05或P＜0.01）；与模型对照组相比，丹龙定喘汤penh值、全血中白细胞和粒细胞比例显著降低，支气管周围炎症浸润与胶原沉积情况显著改善，肺泡灌洗液中Th17细胞占比、血清IL-17含量显著降低，Treg细胞占比、血清IL-10的含量明显升高（P＜0.05或P＜0.01）。结论：丹龙定喘汤能够有效改善OVA所致的哮喘模型小鼠的气道炎症反应，其机制可能与调节Th17/Treg间细胞免疫平衡进而影响炎症反应相关。

关键词： Acute kidney injury   Drug causality   Drug reaction with eosinophilia and systemic symptoms   Human leukocyte antigens   Latency   RegiSCAR   Severe cutaneous adverse drug reactions   Vancomycin  

关键词： Adultos, Tratamiento   Adults   Hidradenitis Supurativa   Interleucina-17   Interleukin 17   Meta-Analysis   Metaanálisis   Suppurative Hidradenitis   Treatment  

摘要： BACKGROUND AND OBJECTIVE:Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that is difficult to manage, requiring the use of biologic drugs such as anti-TNFα and anti-interleukin 17 (anti-IL17). The aim of our review is to evaluate the safety and efficacy profile of anti-IL17 drugs in patients with HS. MATERIALS AND METHODS:We conducted a systematic review with subsequent meta-analysis following the population, intervention, comparison, outcome and type of study (PICOS) method. We included only randomized clinical trials with placebo (S) that included individuals with HS > 18 years old (P), and who had been on placebo (C) OR, an anti-IL17 biologic drug (I) to measure safety and efficacy outcomes (O). Search was conducted across multiple databases: PubMed, Scopus, and the Cochrane Central Register of Controlled Trials. The risk of bias of each study, publication bias, sensitivity analysis, and certainty of evidence were determined. RESULTS:A total of 320 bibliographic references were obtained, 4 of which met the inclusion criteria. Compared to placebo, the meta-analysis showed a significantly higher percentage of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR) OR, of 1.96 [1.79-2.15], a greater decrease in DLQI, MD -1.92 [-2.68,-1.16] and an increase in adverse effects; OR, 1.21 [1.09, 1.34], particularly due to Candida infections; OR, 5.61 [2.66-11.83]. CONCLUSIONS:Treatment with anti-IL17 biologic drugs is effective in patients with moderate-to-severe HS. Although these drugs are safe, they should be monitored due to the risk of infections, mainly candidiasis.

关键词： hyper-responsiveness   interleukin-6   platelets   thrombo-inflammation   thrombosis  

摘要： Interleukin-6 (IL-6) is a pleiotropic cytokine with critical roles in immune regulation, inflammation, and haematopoiesis. While its functions in host defence and tissue repair are well established, accumulating evidence suggests that IL-6 also can directly and indirectly modulate megakaryocyte and platelet biology. This review examines the mechanistic basis supporting IL-6-mediated platelet hyper-responsiveness, in addition to its effect on megakaryopoiesis and thrombopoiesis in thromboinflammatory disease states. We discuss how IL-6-mediated trans-signalling may sensitizes platelets to activation, and that this may be exclusive to glycoprotein VI (GPVI) stimulation due to Janus kinase (JAK)-signal transducer 2 crosstalk, in addition to other mechanisms that may contribute to priming platelets. We further highlight clinical evidence linking IL-6 to thrombotic complications in cardiovascular disease and infection (e.g., COVID-19 and sepsis). Given the emerging interest in IL-6-targeting therapies as anti-inflammatory and anti-thrombotic agents, a thorough understanding of how IL-6 can drive platelet responsiveness is crucial.

摘要： Chronic granulomatous disease (CGD) is an inborn error of immunity characterized by defective NAD phosphate oxidase function, leading to impaired microbial killing, recurrent infections, and granulomatous inflammation. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for CGD, particularly effective when a fully HLA-matched donor is available. However, the place of HLA-haploidentical HSCT remains less established. This retrospective multicenter study analyzed outcomes of 64 patients with CGD (53 males;46 with X-linked CGD) who underwent a first HSCT with HLAhaploidentical family donors, with either in vitro T-cell receptor (TCR)alpha beta/CD19 depletion or in vivo depletion using posttransplant cyclophosphamide (PTCY). The mean age at transplant was 5.8 years (range, 0-33). Patients exhibited a high disease burden before HSCT, with 45% experiencing infections in the 6 months before HSCT and 67% exhibiting inflammation. Outcomes in the entire cohort showed a 3-year overall survival, event-free survival (EFS), and grade 3 to 4 graft-versus-host disease (GVHD)-free EFS of 75.9%, 70.2%, and 56.1%, respectively, and were not affected by the type of depletion or age. The cumulative incidence (CI) of primary graft failure (PGF) was 20.6%. The CI of grade 2 to 4 acute GVHD was higher in the PTCY group (P = .04), whereas the CI of grade 3 to 4 GVHD was not. These results indicate that HLAhaploidentical HSCT is a feasible transplant option for patients with CGD lacking HLA-matched donors. Further refinement of transplant protocols is necessary to mitigate graft failure and acute GVHD, ultimately improving access and outcomes for this life-saving therapy.

关键词： Nanovaccine   Cancer immunotherapy   Redox-responsive polymer   Cytosolic delivery   Synergistic therapy  

摘要： Cancer vaccines have garnered significant attention in cancer immunotherapy because they trigger tumor-specific immune responses. However, their effectiveness is hindered by inefficient antigen and adjuvant delivery at the subcellular level, which is essential to stimulate a robust CD8+ T cell response. This study presents PAR/OVA, a cancer nanovaccine developed by combining imiquimod (R837)-modified polyamidoamine dendrimers with the model protein antigen ovalbumin (OVA). Within the nanovaccine, R837 is an adjuvant for the Toll-like receptor 7 (TLR7) pathway and a structural component that facilitates OVA loading. In dendritic cells (DCs), the high cytoplasmic glutathione levels triggered the breakdown of PAR/OVA, releasing OVA and R837, which induced DC activation and antigen cross-presentation. Furthermore, PAR/OVA vaccination showed a protective effect and effectively inhibited B16-OVA tumor progression, indicating its potential in cancer immunotherapy. Combining this vaccine with an immune checkpoint blockade enhanced antitumor efficacy by improving the ability of cytotoxic T lymphocytes to target cancer cells within the tumor microenvironment. These findings underscore the potential of this adjuvant/antigen-delivering nanovaccine in cancer immunotherapy. [GRAPHICS] .

关键词： Chicken   MDV   MHC   MHC-Y   N-myristoylation   YF1*7.1   immunity   lipopeptides  

摘要： Major Histocompatibility Complex I (MHC-I) and MHC-I-like molecules play a central role in mediating immunity. Through their conservation across all taxa of jawed vertebrates, the MHC-I-like proteins have adapted to present non-peptidic antigens to distinct T cell populations. While our understanding of the structure-function relationship of MHC-I and MHC-I-like molecules in humans and mice is well established, the nature of the antigens presented by MHC-I- like molecules in 'non-model' species remains unclear. Here, using a mammalian recombinant expression system combined with mass spectrometry approaches, we identified N-myristoylated peptides as endogenous ligands for the chicken MHC-I-like protein YF1*7.1. Given the importance of N-myristoylation in viral pathogenesis, we determined the crystal structure of YF1*7.1 in complex with two N-myristoylated peptides derived from Marek's disease virus (MDV), demonstrating the molecular basis that underpins the presentation of N-myristoylated peptides from MDV, a highly contagious and fatal viral neoplastic disease in chickens. Thus, the identified ligands are distinct from unmodified peptides found in classical MHC-I and -II as well as diverse amphipathic lipids captured by CD1 proteins. Collectively, our study lays the foundation for further molecular and functional characterization of YF1*7.1 and more broadly of the role of the MHC-I encoded by the MHC-Y gene cluster in protection against highly contagious viral neoplastic diseases in chickens.