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摘要： Pharmacodynamic (PD) biomarkers can support biosimilarity assessment, potentially reducing the need for comparative clinical efficacy studies. This study aimed to characterize previously identified proteomic PD biomarker candidates for Interferon beta-1a (IFN beta-1a, n = 248) and pegylated IFN beta-1a (pegIFN beta-1a, n = 528) biologics at therapeutic doses, to further evaluate the utility of proteomics in biosimilar development. Here, we reproduced the results at lower doses and characterized PD responses across multiple doses using criteria for justifying PD biomarker use in biosimilar development. We analyzed candidate proteins from longitudinal proteomics data (SomaScan (TM) Assay v4.1) from 48 healthy subjects administered intermediate or low doses of IFN beta-1a (15, 7.5 mu g) or pegIFN beta-1a (62.5, 31.25 mu g) in an FDA-sponsored study, alongside previously published therapeutic dose and placebo data. EDTA plasma samples were collected at 0, 0.125, 0.33, 0.67, 1.33, 2, 3, 4, 5, 6 days and at 9, 13 days additionally for pegIFN beta-1a. Prioritization criteria included significant differential expression at the intermediate dose vs. placebo, >= 20% response difference from placebo, significant baseline-adjusted area under the effect curve (AUEC) and a monotonic dose-response relationship across all doses. Among the candidates, 165 and 323 were differentially expressed at intermediate doses of IFN beta-1a and pegIFN beta-1a respectively. Nine PD biomarkers, including C-X-C motif chemokine 11 (I-TAC), Lymphocyte activation gene 3 protein (LAG3), and Granulins (GRN), were prioritized as common to both biologics. Most candidates followed the Emax dose-response model. I-TAC showed the strongest response, and LAG-3 showed the least variability in AUEC. Our study identified several suitable plasma PD biomarkers for IFN beta-1a and pegIFN beta-1a biologics with potential utility in biosimilar development programs.

关键词： 骨质疏松症   椎体压缩性骨折   孟德尔随机化   炎症细胞因子   危险因素   因果关系   再骨折   发病机制  

摘要： 目的 基于孟德尔随机化(MR)方法明确哪些炎症细胞因子与骨质疏松性椎体压缩骨折(OVCF)之间存在因果关系。方法 从全基因组关联研究(GWAS)的公开数据库中筛选出循环炎症细胞因子相关的SNPs作为工具变量。以OVCF为结局,进行双向MR。采用逆方差加权法(IVW)为主要分析方法来评估因果效应,进行异质性、多效性等敏感性检验。结果 正向MR分析结果显示,阿替明水平与OVCF存在负向关联(OR=0.765,95%CI:0.644～0.907,P=0.002)。β-神经生长因子(β-NGF)水平与OVCF存在负向关联(OR=0.849,95%CI:0.736～0.981,P=0.026)。白介素1α(IL-1α)与OVCF存在负向关联(OR=0.800,95%CI:0.708～0.904,P<0.001)。T细胞表面糖蛋白CD6异构体水平与OVCF存在正向关联(OR=1.118,95%CI:1.014～1.232,P=0.025)。无异质性、多效性,结果稳健。反向MR分析提示,经历OVCF的个体比未经历OVCF的患者趋化因子配体25(CCL25)水平升高(OR=1.060,95%CI:1.004～1.120,P=0.036)。结论 阿替明、β-NGF、IL-1α是OVCF的保护性因素。CD6异构体水平是OVCF的危险因素。OVCF患者CCL25水平比未经历OVCF的个体要高。

关键词： mBC2   memory   Th2   B cells   allergy  

摘要： Type 2 memory B cells (mBC2), identified in mice as IgG1+CD23+IL-4R alpha+CD38+ B cells, which require IL-4 for genesis, are precursors for IgE plasma cells (PC) and considered key in allergy. While IL-21 is critical for normal mBC differentiation, its involvement in mBC2 formation is unknown. Here, we show that although IL-21R-deficient (IL-21R-/-) mice immunized with ovalbumin generated ovalbumin-specific mBC2, their abundances were lower than in controls one-week post-immunization. This deficit was associated with the accumulation of pre-prememory GC B cells and corresponding deficiencies in pre-memory B cell exit, suggesting a defect in memory differentiation. Germinal centers waned rapidly in IL-21R-/- mice and subsequently mBC2 numbers diminished, and IgG1 PC genesis was suppressed. These data show that IL-21 is required for normal mBC2 formation, arguing against the use of IL-21 as a pan-allergy suppressor.

摘要： Achieving a cure is an urgent need for patients with advanced solid tumors. Here, we discover that oncolytic virus (OV) infection enhances IL-18 receptor expression but fails to increase IL-18 ligand expression. Therefore, we engineer armed oncolytic alphavirus M1 expressing wild-type IL-18 (wtIL-18) or a mutant variant (mutIL-18) that evades IL-18 binding protein (IL-18BP) while maintaining IL-18 receptor (IL-18R) binding. Intravenous administration of M1-mutIL-18 suppresses the growth of multiple advanced solid tumors in C57BL/6 and BALB/c mouse models and promotes long-term systemic immune memory. Mechanistically, armed M1-mutIL-18 enhances directed clonal expansion and differentiation of CD8+ T cells and sustains IFN-gamma production. Thus, armed M1-mutIL-18 promotes dendritic cell (DC) activation, priming and activation of CD8+ T cells in lymphatic organs, and infiltration of IL-18R+ CD8+ T cells in the tumor microenvironment, establishing a positive feedback loop. We further show that a PD-L1 inhibitor enhances the anti-tumor efficacy of mutIL-18 OVs. These results highlight the importance of the IL-18 pathway in oncolytic virus therapy and implicate reprogramming ligand-receptor interaction as an effective strategy for immunotherapy.

关键词： pseudorabies virus   innate immunity   neonates   peripheral blood mononuclear cells   plasmacytoid dendritic cells   interferon-alpha   Th1 immunity   immaturity  

摘要： Pseudorabies virus is a porcine alphaherpesvirus that causes devastating disease with high mortality in young piglets but much milder, mainly respiratory, problems in older pigs. Here, we report marked age-dependent differences in the cytokine response profile of primary porcine peripheral blood mononuclear cells (PBMCs) to pseudorabies virus (PRV)-infected cells. Notably, IFN-alpha and IL-12 production in response to PRV remains low to almost undetectable in piglets up to 8.5 weeks of age, followed by a marked increase in older piglets, which coincides with age-related shifts in PRV symptomatology. Additionally, we found that PBMC from newborn piglets exhibit a high IL-6 and IL-10 production which, in combination with the low IL-12 levels, suggests a suppressed Th1 immune response, similar to neonatal humans and mice. Our results reveal a remarkable age-dependent difference in PBMC cytokine response to PRV and provide a basis to identify cytokines or adjuvants that shift the neonatal immune response towards a Th1 response, potentially improving outcomes of severe viral infections in the neonatal period in both pigs and humans.

关键词： Immunology   Interferon   Gene expression signature discovery   Transcriptomics   SLE-systemic lupus nephritis   Oncology  

摘要： BackgroundAberrant interferon signaling is a key element of various diseases, but resolving gene expression signatures that stem from different types of IFNs in tissue samples is still a challenge. Most published IFN signatures comprise genes that are activated by different IFNs: they cannot discriminate type-I (IFN-I) and type-II (IFN-II) IFN stimulation. Most often such signatures were obtained from a single expression dataset that had been obtained in a specific cellular context, and their translatability to other experimental contexts has not been *** leveraged multiple RNA-seq datasets of IFN stimulation in a network meta-analysis workflow to obtain IFN gene signatures separating IFN-I and IFN-II. We validated our signatures in bulk and single cell RNA-seq datasets of various cellular contexts demonstrating similar or higher coherence than previously published signatures. Our IFN-II signature is broader applicable than other published signatures as it demonstrates strong performance in detecting IFN-II response in more cell types. In three SLE microarray datasets our IFN-I signature was highly coherent and correlated with disease severity better than most published signatures. In TCGA, our IFN-II signature produced distinct profiles compared to published IFN-I signatures and correlated strongly with published CD8+ T cell signatures. In cohorts of three different cancer types, we observed higher signature scores of our IFN-II signature in responders than in non-responders to immune checkpoint inhibitor (ICI) *** IFN-I and IFN-II response-specific gene expression signatures can inform on complex IFN responses in a more fine-grained way than previously possible. They can be used to assess type I versus II IFN response in gene expression data produced by different technologies, for different diseases and even different cell types in single cell studies. The association of high scores of our IFN-II signature with anti-tumor resp

关键词： Tofacitinib   JAK/STAT   Infectious colitis   Innate lymphoid cells   Campylobacter jejuni  

摘要： Patients with autoimmune diseases are more susceptible to foodborne infections, which can be exacerbated by immunosuppressive therapy. Tofacitinib, a JAK/STAT pathway inhibitor, was recently approved for the treatment of ulcerative colitis, yet its effects on the pathogenesis of intestinal infections remain unclear. Here, we examined the impact of oral tofacitinib treatment in a mouse model of Campylobacter jejuni ( C. jejuni ) infection. Our results show that early tofacitinib administration attenuates intestinal pathology without affecting bacterial colonization. Specifically, tofacitinib suppressed CXCL1, CXCL2, CCL2 chemokine expression by intestinal epithelial cells, limiting recruitment of monocytes and neutrophils to the gut. In addition, JAK/STAT inhibition reduced IFNγ-producing innate lymphoid cells (ILCs) and T cells in the gut. Furthermore, tofacitinib suppressed IFNγ production and ameliorated intestinal disease in humanized mice. Cell-fate mapping revealed that tofacitinib predominantly inhibited IFNγ production by NK1.1 − ILCs derived from NKp46 − progenitors and reduced NK1.1 − ILC proliferation without affecting ILC3 to ILC1 plasticity. Notably, tofacitinib ameliorated intestinal disease even in the absence of T cells. These findings suggest that tofacitinib alleviates C. jejuni -induced colitis by reducing proinflammatory cytokine production by monocytes/macrophages/epithelial cells and suppressing IFNγ secretion by ILCs and T cells, while preserving antibacterial defenses.

关键词： IRF4   IRF8   B细胞发育   自身免疫病  

摘要： 干扰素调节因子4（Interferon regulatory factor 4，IRF4）和干扰素调节因子8（Interferon regulatory factor 8，IRF8）是免疫系统发育和功能的重要调节因子，对T细胞、巨噬细胞和树突状细胞的发育和功能至关重要。最近系列研究表明IRF4和IRF8在B淋巴细胞发育和成熟过程中也起到关键作用，包括B细胞早期发育、诱导B细胞耐受途径、生发中心反应和浆细胞分化。从机制上讲，IRF4和IRF8被发现以非必要的方式控制B细胞发育的某些阶段，但它们在B细胞生物学的其他阶段中也发挥不同的特殊作用。总的来说，这些新的研究提供了对IRF4和IRF8功能的分子机制的了解，并强调了IRF4和IRF8对B细胞发育过程中的影响。本综述就IRF4和IRF8在B细胞发育中作用以及其在自身免疫病上的最新研究进展作一综述。

关键词： Apical periodontitis   Passive ultrasonic irrigation   Gingival crevicular fluid   Sonically activated irrigation   PGE2   IL-6  

摘要： The effectiveness of Passive Ultrasonic Irrigation(PUI) and Sonically Activated Irrigation(SAI) techniques was investigated in apical periodontitis(AP) patients based on changes in prostaglandin E2(PGE2), nitric oxide(NO), and interleukin-6(IL-6) levels. Sixty-six AP patients and thirty healthy controls were enrolled. Preoperative gingival crevicular fluid(preGCF) PGE2, NO and IL-6 levels were measured before treatment. After chemo-mechanical preparation, teeth were assigned into two groups according to final irrigation protocol[PUI(n:33) and SAI(n:33)]. The same markers were again measured 1 week after treatment(postGCF) and also 1st order most commonly seen bacteria(FMCB) typing was performed on microbial samples of the patients. PostGCF-PGE2 levels of the PUI group were lower than postGCF-PGE2 levels of the SAI group(p = 0.0335). Both postGCF-PE2 and IL-6 levels of the PUI group were significantly decreased after treatment(p < 0.0001), while only postGCF-PE2 levels decreased in the SAI group(p = 0.0316). The PUI system significantly reduced PGE2 and IL-6 levels by better controlling inflammation in the treatment of AP.

关键词： Small cell lung cancer   Immunotherapy   MHC-I   IFITM3  

摘要： Background Most small cell lung cancer (SCLC) patients exhibit resistance to immune checkpoint inhibitors (ICIs) and demonstrate downregulation of major histocompatibility complex class I (MHC-I) molecules. This study aimed to elucidate the regulatory mechanisms underlying MHC-I expression and potential combination strategies. Methods Single-cell and bulk RNA sequencing data from SCLC patients were analyzed. Clinical data from SCLC patients treated with PD-1/PD-L1 inhibitors were used to investigate the associations between treatment efficacy and IFITM3 expression. In vitro and in vivo functional studies were conducted to evaluate the role and mechanisms of IFITM3 in modulating tumor sensitivity to PD-1 inhibitors. Results Integrative analysis of multiple real-world SCLC cohorts confirmed a significant positive association between IFITM3 expression and MHCI. IFITM3 overexpression upregulated MHC-1-related genes, enriched antigen presentation pathways, and increased CD8+ T-cell infiltration and cytotoxicity. Elevated IFITM3 expression was significantly associated with prolonged progression-free survival (PFS) in patients receiving chemoimmunotherapy but not in those treated with chemotherapy alone. Additionally, patients with high H-scores for IFITM3, as determined by immunohistochemistry, demonstrated better clinical outcomes with chemoimmunotherapy. Inducing IFITM3 expression directly or through treatment with ethyl gallate (EG), an IFITM3 inducer, effectively sensitized tumors to PD-1 blockade in SCLC mouse models. Mechanistic studies revealed that IFITM3 upregulates NLRC5, a key transcriptional activator of MHC-I, facilitating its nuclear translocation and thereby increasing MHC-I levels. Conclusions IFITM3 is associated with MHC-I expression and can predict the efficacy of anti-PD-1/-L1 therapy in SCLC patients. IFITM3 inducers potently improved the efficacy of anti-PD1 monotherapy in SCLC.