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关键词： IFN-γ   复发性流产   Meta分析  

摘要： 目的:系统评价不明原因复发性流产(URPL)患者外周血或绒毛组织中IFN-γ水平的变化。方法:在PubMed、Web of science、Cochrane Library、中国知网及万方等数据库中检索相关文献,使用固定效应模型或随机效应模型进行meta分析。结果:最终纳入29篇文献,共2603例患者。非孕期URPL组外周血清IFN-γ水平高于健康非妊娠组(SMD=0.39,95%CI:0.18～0.60,P=0.001)。孕早期URPL组外周血清IFN-γ水平高于健康早孕组(SMD=1.30,95%CI:1.16～1.45,P=0.000)。孕早期URPL组外周血血浆IFN-γ水平高于健康早孕组(SMD=2.07,95%CI:1.81～2.33,P=0.000)。孕早期URPL组外周血清IFN-γ水平高于健康非妊娠组(SMD=3.86,95%CI:3.39～4.33,P=0.000)。孕早期URPL组绒毛组织中IFN-γmRNA水平高于健康早孕组(SMD=0.74,95%CI:0.39～1.10,P=0.000)。结论:与健康女性相比,URPL患者的外周血或绒毛膜绒毛组织中IFN-γ水平较高。高水平的IFN-γ可能与URPL患者疾病的发生和妊娠丢失有关。

关键词： acute graft-versus-host disease   haematopoietic stem cell transplantation   HLA antibody   non-donor-specific HLA antibody   unrelated donor  

摘要： The clinical relevance of de novo HLA antibodies in haematopoietic stem cell transplantation (HSCT) is yet incompletely defined. This prospective, single-centre study recruited adult patients with malignant haematological diseases receiving their first unrelated donor HSCT. Serum samples from 124 patients were screened for HLA antibodies before and after HSCT. It was found that 29 out of 61 females (47.5%) and 8 out of 63 males (12.7%) had HLA antibodies prior to HSCT. After HSCT, 31 out of 37 patients retained HLA antibody positivity, whereas 72 out of 87 maintained HLA antibody negativity. The 21 remaining patients changed their status: six turned HLA antibody-negative, while 15 became HLA antibody-positive. No donor-specific HLA antibodies (DSA) were identified prior to HSCT. One patient generated a single DSA together with the batch of non-donor-specific HLA antibodies (NDSA) after HSCT. The remaining 14 patients developed only de novo NDSA. Univariable Cox regression analysis revealed that the presence of all de novo HLA antibodies was associated with an elevated risk of Grade III-IV aGVHD (p = 0.012;HR 3.286) at 180 days after HSCT and neared statistical significance for delayed neutrophil engraftment (p = 0.056;HR 3.836). Multivariate Cox regression analysis indicated that only de novo HLA antibodies are an independent prognostic factor for the increased incidence of Grade III-IV aGVHD. The limited size of our cohort and the varied range of haematological malignancies have limited confidence in our findings. Thus, additional data obtained from larger patient cohorts is essential for the correct evaluation of the clinical relevance of de novo DSA and NDSA on HSCT outcomes.

关键词： DQ   HLA   new eplet   transfection   transplantation  

摘要： The target of an anti-HLA antibody is an epitope on the surface of the antigen, and in particular the polymorphic eplet of its core, which contains one or a few polymorphic residues accessible to the molecule surface. The HLA Eplet Registry database references more than 550 HLA eplets thus deduced from AA sequence alignments. However, not all eplets have yet been verified and this list is not exhaustive. We performed a systematic analysis of sequence alignment of DQ antigens, to identify polymorphic amino acids so far not proposed as candidate eplets. From this, we describe and validate 3 DQB1 eplets targeted by sera of organ-transplanted patients and explore a new eplet overlapping the DQA1*03 and DQB1*03 chains. Serum antibody profiles using LABScreen, Lifecodes and a complementary DQ Luminex single antigen bead panel all showed a concordant pattern incriminating these residues. Moreover, antibodies were adsorbed and eluted using human splenic mononuclear cells and HLA-DQ transfected murine cell clones, thereby validating these four eplets. Their localisation by 3D modelling revealed uncertain accessibility of some residues implicated. The protrusion and accessibility of an eplet on the HLA surface may ultimately not always be sufficient to predict antibody binding, since the dynamic flexibility of the molecule can modify these parameters. Our strategy, combining Luminex single antigen assays, cell adsorption/elution and in silico prediction of surface exposure, altogether concur to ascertaining the realness of candidate eplets in the highly complex HLA system.

关键词： IL-1 beta   NF-kappa B   p62   chondrocytes   mitophagy  

摘要： Interleukin-1 beta (IL-1 beta) is a central proinflammatory cytokine implicated in osteoarthritis (OA), but its precise role in chondrocyte apoptosis remains to be fully elucidated. In this study, we demonstrate that IL-1 beta triggers mitophagy in chondrocytes by promoting Parkin translocation and p62 recruitment to damaged mitochondria, thereby reducing mitochondrial dysfunction and apoptosis. Loss of p62 resulted in impaired mitophagy, excessive mitochondrial superoxide accumulation, and increased cell death. Mechanistically, IL-1 beta enhanced NF-kappa B (RelA) phosphorylation at Ser276 and Ser536, accompanied by elevated Mitogen and stress-activated kinase-1 (MSK1) expression. Inhibition of MSK1 selectively suppressed Ser276 phosphorylation without affecting Ser536, leading to reduced p62 expression and disrupted mitophagy. These findings reveal a previously unrecognized intrinsic regulatory mechanism by which IL-1 beta limits its own apoptosis-promoting effect through activation of the NF-kappa B (RelA) Ser276-p62-mitophagy axis. This pathway facilitates the clearance of damaged mitochondria and preserves chondrocyte viability, offering potential therapeutic insight into inflammation-associated cartilage degeneration in OA.

关键词： the AhR/IL-22 pathway   chronic intestinal inflammation   immune response   AhR   IL-22  

摘要： Chronic inflammatory bowel diseases, including Crohn's disease (CD), ulcerative colitis (UC), and post-infectious irritable bowel syndrome (PI-IBS), are characterized by immune-mediated intestinal inflammation and epithelial barrier dysfunction. Research indicates that the aryl hydrocarbon receptor (AhR)/interleukin-22 (IL-22) pathway is critical for intestinal homeostasis. This pathway can be activated by ligands from dietary and microbial sources (such as tryptophan metabolites), and AhR signaling in immune cells (particularly type 3 innate lymphoid cells (ILC3s) and T cells) is the primary driver of IL-22 production. IL-22 protects the intestinal barrier and regulates inflammatory responses by promoting epithelial repair, enhancing mucus and antimicrobial defenses, and strengthening tight junctions. Dysregulation of this pathway plays a key role in the pathogenesis of chronic intestinal inflammation, leading to exacerbated inflammatory processes and mucosal damage. Given its central role in barrier defense and repair, targeting the AhR/IL-22 pathway has emerged as a novel therapeutic direction for restoring intestinal homeostasis. This review summarizes the mechanisms of action of this pathway in chronic intestinal inflammation and explores its potential as a novel therapeutic target.

关键词： anti-TNF   Crohn disease   inflammatory bowel disease   pregnancy outcomes   ulcerative colitis   ustekinumab  

摘要： Background:Inflammatory bowel disease (IBD) frequently affects women of reproductive age. While the safety of anti-tumor necrosis factor (TNF) agents during pregnancy is well established, data on the safety of ustekinumab remain limited. We aimed to compare the safety of ustekinumab versus anti-TNF therapy in pregnant patients with IBD in terms of pregnancy ***:We systematically searched PubMed, Embase, and Cochrane databases. Studies comparing ustekinumab and anti-TNF agents and reporting key pregnancy outcomes were included. Pooled analyses were performed using random-effects ***:Four studies, encompassing 3308 pregnancies (592 ustekinumab, 2716 anti-TNF) were included. The majority of patients (2914;88.2%) had Crohn disease, and the median disease duration ranged from 6.5 to 14 years. There was no significant difference between ustekinumab and anti-TNF therapy in major pregnancy outcomes, including live birth rates (67.2% vs 67.7%;odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.39-1.37), spontaneous abortion rates (5.9% vs 4.2%;OR = 1.51, 95% CI = 0.74-3.36), preterm delivery rates (6.6% vs 7.4%;OR = 0.50, 95% CI = 0.15-1.61), low birth weight rates (4.6% vs 7.1%;OR = 0.68, 95% CI = 0.23-1.98), and cesarean section rates (30.0% vs 30.1%;OR = 1.11, 95% CI = 0.85-1.45).Conclusion:Ustekinumab appears comparable to anti-TNF agents regarding major pregnancy outcomes in pregnant patients with IBD, suggesting its potential safety during pregnancy.

关键词： 高原鼢鼠   MHC-DRB外显子2   多态性   遗传多样性   选择作用  

摘要： 为了解高原鼢鼠（Eospalax baileyi）不同地理种群的遗传多样性和适应性进化机制，本文对高原鼢鼠8个不同地理种群121只个体的MHC-DRB基因外显子2进行PCR扩增及克隆。结果发现，高原鼢鼠MHC-DRB基因外显子2具有较高的多态性，种群间遗传分化明显，地理隔离是各种群分化的关键因素，碱基使用方面存在密码子偏好性，中性检测表明高原鼢鼠种群近期未发生过种群扩张现象且维持遗传多态性的驱动力主要为选择作用。本研究结果将为进一步研究高原鼢鼠的MHC基因的遗传适应性和种群有效管理提供理论依据。

关键词： Interleukin (IL)-11   italic>Trypanosoma cruzi   Cellular immune response   Cardiomyopathy   DTUs   Chagas disease  

摘要： Chagas disease (CD), caused by Trypanosoma cruzi, leads to cardiomyopathy in approximately 20-30% of infected individuals. Interleukin-11 (IL-11) has been implicated in cardiac fibrosis, although its immunological role in this context remains unclear. This study investigated the temporal dynamics of IL-11 and its receptor, IL-11R alpha, expression in the hearts of C57BL/6 mice infected with 1,000 trypomastigote forms of the Y or Colombian strains of T. cruzi. Mice were euthanized at 5, 15, 30, 60, and 120 days post-infection (dpi). Survival, parasitemia, and body and heart weights were monitored. Cardiac tissue was analyzed for parasite nests, myocarditis, collagen deposition, and expression of the IL-11 receptor alpha (IL-11R alpha). Cytokine profiles were evaluated by ELISA and Cytometric Bead Array. Histopathological analysis revealed more intense myocarditis, parasite load, and collagen deposition in mice infected with the Colombian strain. Both strains induced IFN-gamma, TNF-alpha, and IL-6 in cardiac tissue;however, IL-10, IL-4, and IL-17 were detected only in the Y strain, indicating a more balanced immune response. Despite the absence of significant IL-11 upregulation in either infection, IL-11R alpha expression was progressively increased over time and positively correlated with collagen deposition. These findings suggest that IL-11R alpha may play a role in cardiac remodeling and fibrosis independently of IL-11 upregulation. The results reinforce the importance of T. cruzi strain variability in disease outcome and highlight the IL-11/IL-11R alpha axis as a potential target for further investigation in Chagas *** AbstractThe kinetics of IL-11 and IL-11R alpha expression in the heart during experimental Trypanosoma cruzi infection reveal striking differences between the Y and Colombian strains over time (5, 15, 30, 60, and 120 days post-infection). The shaded areas in green and orange represent IL-11R alpha expression and IL-11 productio

关键词： ADP-ribosylation   PARP   macrodomain   coronavirus   HSV-1   VSV   LCMV   interferon   interferon-stimulated genes  

摘要： PARP14 is a 203 kDa multi-domain protein that is primarily known as an ADP-ribosyltransferase and is involved in a variety of cellular functions, including DNA damage, microglial activation, inflammation, and cancer progression. In addition, PARP14 is upregulated by interferon (IFN), indicating a role in the antiviral response. Furthermore, PARP14 has evolved under positive selection, again indicating that it is involved in host-pathogen conflict. We found that PARP14 is required for increased IFN-I production in response to coronavirus infection lacking ADP-ribosylhydrolase (ARH) activity and poly(I:C);however, whether it has a direct antiviral function remains unclear. Here, we demonstrate that the catalytic activity of PARP14 enhances IFN-beta and IFN-gamma responses and independently restricts ARH-deficient murine hepatitis virus (MHV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. To determine if PARP14's antiviral functions extended beyond CoVs, we tested the ability of herpes simplex virus 1 (HSV-1), a DNA virus, vesicular stomatitis virus (VSV), a negative-sense RNA virus, and lymphocytic choriomeningitis virus (LCMV), an ambisense RNA virus, to infect A549 PARP14 knockout (KO) cells. While LCMV infection was unaffected, HSV-1 replication was increased in PARP14 KO cells, and VSV replication was decreased. These results indicate that PARP14 restricts HSV-1 replication but enhances the replication of VSV. A PARP14 active site inhibitor had no impact on HSV-1 or VSV replication, indicating that its effect on these viruses was independent of its catalytic activity. These data demonstrate that PARP14 promotes IFN production and has both proviral and antiviral functions targeting multiple *** antiviral response is largely regulated by post-translational modifications (PTM), including ADP-ribosylation. PARP14 is an ADP-ribosyltransferase that is upregulated by interferon and is under positive selection, indicating t

关键词： PD-1单克隆抗体   质量监测   风险评估  

摘要： 目的 以某程序性死亡受体-1（PD-1）单克隆抗体注射液为例，建立该类药品质量监测和风险评估工作模式，为监管部门对风险品种进行监督管理提供参考。方法 依据该品种注册质量标准，结合国内外参考指南，对27批检品开展关键质量属性的检验和质量监测。同时围绕药品的安全性、稳定性和质量标准可控性开展风险评估工作，开展基于高分辨质谱技术的宿主细胞蛋白残留鉴定，低内毒素回收考察、风险物质等多维度研究。结果27批检品关键质量属性检验结果均为合格（100.00%）。各批次检品均检出蛋白磷脂酶B-2，存在宿主细胞蛋白（HCPs）残留风险；各批次单抗检品的可结晶片段（Fc）受体亲和力一致，具有一定的Fc端效应活性，提示质控过程中应对糖基化水平给与关注；该品种存在低内毒素回收（LER）风险；各批次检品中组氨酸含量与处方量接近，生产批间差异较小；未发现本品存在抗生素残留、元素杂质及抗氧剂风险；加速试验结果提示本品生物学活性等关键质量属性无明显变化，稳定性良好。另在质量分析方法方面，将《中国药典》通则3127用于该品种十二烷基硫酸钠毛细管电泳（CE-SDS）纯度的检验，发现其结果在非还原纯度与企业方法有显著性差异；新建高效液相-蒸发光检测器方法作为吐温80含量测定方法的补充。结论 建立了基于风险的某PD-1单克隆抗体注射液的质量监测和风险评估工作模式；该品种质量总体良好，现行质量标准基本可行，但仍需提高和完善。