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关键词： 急性肝衰竭   解毒化瘀颗粒   白细胞介素6/Janus激酶2/信号传导和转录激活因子3   免疫炎症  

摘要： 目的 急性肝衰竭(Acute Liver Failure，ALF)是一种短期内死亡率很高的急危重症疾病。解毒化瘀颗粒(JDHY)已被临床证实是治疗ALF的有效方剂，用于治疗ALF已有20余年历史，但其疗效机制尚未被完全阐明。本文旨在探讨JDHY调控白细胞介素6（Interleukin-6，IL-6）/蛋白酪氨酸激酶（Janus Kinase 2，JAK2）/信号传导和转录激活因子3（Signal Transducer And Activator Of Transcription 3，STAT3）信号通路对D-氨基半乳糖( D-Galactosamine，D-GALN)和脂多糖( Lipopolysaccharides，LPS)诱导的ALF大鼠的作用机制及JDHY的干预效应。方法 用随机数字表法将雄性SD大鼠30只分为正常对照组（Control）、模型组（D-GALN/LPS）、D-GALN/LPS+JDHY组（JDHY），每组10只。D-GALN/LPS组和JDHY组按照D-GALN 600mg/kg 和LPS 20μg/kg腹腔注射构建ALF大鼠模型，JDHY组在造模前按0.22g/ml浓度中药液灌胃，每天1次，连续3天，Control组和D-GALN/LPS组则给予等量生理盐水灌胃，造模24小时后处死老鼠收集相关样本，观察肝脏大小、外观变化；检测血清谷丙转氨酶（Alanine aminotransferase，ALT）、谷草转氨酶（Aspartate aminotransferase，AST）、总胆红素（Total bilirubin，TBIL）、凝血酶原时间（Prothrombin time，PT）；HE染色观察肝组织病理学变化，酶联免疫吸附法（Enzyme-linked immunosorbent assay，ELISA）检测血清IL-6、白细胞介素-1β(Interleukin-1β，IL-1β)、核转录因子-κB（Nuclear factor kappa-B，NF-κB）、肿瘤坏死因子（Tumor necrosis factor-alpha，TNF-α）水平；蛋白质印迹（Western Blot，WB）检测肝组织JAk2、STAT3、P-JAk2、P-STAT3和该信号通路下游蛋白B细胞淋巴瘤-2(BCL-2)、BCL-2相关X蛋白(BAX)的表达；免疫组织化学法(Immunohistochemistry，IHC) 检测JAK2、STAT3、BCL-2、BAX蛋白表达；聚合酶链式反应（Quantitative real time polymerase chain reaction，q-PCR）检测JAK2、STAT3、BAX、BCL-2的mRNA表达。结果 经JDHY提前干预后，ALF大鼠的肝功能、凝血功能得到改善、肝组织炎症浸润范围缩小，死亡率降低，血清IL-6、IL-1β、NF-κB、TNF-α炎症细胞因子水平明显降低，肝组织JAK2、P-JAK2、STAT3、P-STAT3、BCL-2、BAX蛋白表达均下调，JAK2、P-JAK2、STAT3、P-STAT3 mRNA水平下降。结论 JDHY能有效改善ALF肝损伤，降低死亡率，其机制可能与下调IL-6/JAK2/STAT3信号通路表达有关。

关键词： Antigen   Cancer   Endocrinology   Immunology   Thyroid disease  

摘要： Cancer cells present neoantigens dominantly through MHC class I (MHCI) to drive tumor rejection through cytotoxic CD8+ T-cells. There is growing recognition that a subset of tumors express MHC class II (MHCII), causing recognition of antigens by TCRs of CD4+ T-cells that contribute to the anti-tumor response. We find that mouse BrafV600E-driven anaplastic thyroid cancers (ATC) respond markedly to the RAF + MEK inhibitors dabrafenib and trametinib (dab/tram) and that this is associated with upregulation of MhcII in cancer cells and increased CD4+ T-cell infiltration. A subset of recurrent tumors lose MhcII expression due to silencing of Ciita, the master transcriptional regulator of MhcII, despite preserved interferon gamma signal transduction, which can be rescued by EZH2 inhibition. Orthotopically-implanted Ciita-/- and H2-Ab1-/- ATC cells into immune competent mice become unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+ T-cells, also abrogates response to dab/tram. These findings implicate MHCII-driven CD4+ T cell activation as a key determinant of the response of Braf-mutant ATCs to MAPK inhibition.

关键词： Axial spondyloarthritis   HLA-B27   HLA-B alleles   diffuse idiopathic skeletal hyperostosis   palmoplantar pustulosis arthritis   osteitis condensans ilii  

摘要： Objective To assess whether extended HLA-B typing, together with simple clinical indices, distinguishes axial spondyloarthritis (axSpA) from radiographic mimics in Japanese *** We retrospectively reviewed 127 patients who underwent HLA-B typing at a single centre between 2008 and 2024. Ankylosing spondylitis met the 1987 modified New York criteria, and non-radiographic axSpA met the 2009 ASAS criteria. Diffuse idiopathic skeletal hyperostosis (DISH), palmoplantar pustulosis arthritis (PAO), and osteitis condensans ilii (OCI) were identified by characteristic imaging and clinical findings. Two rheumatologists reassigned final diagnoses. HLA-B phenotypes, age at onset, sex, and initial C-reactive protein (CRP) were compared across *** A total of 25 patients satisfied axSpA criteria;80% were HLA-B27-positive. DISH, PAO and OCI showed apparent enrichment of common Japanese alleles (B52, B61/B62, B39). DISH and PAO presented later than axSpA (54.0 y and 42.5 y versus 25.2 y) and DISH had lower CRP (0.31 versus 1.51 mg/dL, P = 0.003). OCI occurred exclusively in women and was *** In Japanese practice, no single non-B27 allele reliably separates axSpA from its mimics;instead, early age at onset, male sex, and raised CRP provide the most practical safeguards against diagnostic error and unnecessary therapy.

关键词： T cells   skin   epidermis   dermis   immune cells   adaptive immunity   HLA   proteomics  

摘要： T lymphocytes in human skin play essential roles in immune surveillance and tissue homeostasis, with distinct populations residing in the epidermal and dermal compartments. To characterize the molecular basis of their compartmentalized functional specialization, we performed proteomic analysis of total T cell populations isolated from healthy human skin, combining flow cytometry and liquid chromatography-tandem mass spectrometry. We quantified 5985 proteins across epidermal and dermal T cell populations, identifying 2177 significantly differentially expressed proteins (FDR < 0.05), including 1008 with >2-fold changes. Compared with dermal T cells, epidermal T cells showed elevated intensity of tissueresidency marker CD69, co-stimulatory protein CD27, complement components (C3, C4a, and Factors B and D), and proteins involved in oxidative phosphorylation and cholesterol metabolism. Epidermal T cells also exhibited higher levels of antimicrobial S100 proteins, chemokine receptor CCR6, IL-18, and MHC class I molecules, while, in contrast, dermal T cells showed increased expression of CXCR4, IL-16, and MHC class II-related proteins. While these distinct proteomic signatures suggest compartment-specific adaptations in metabolism, immune surveillance, and antigen presentation, the results should be interpreted as exploratory, given methodological limitations. Nonetheless, this study provides a valuable molecular resource for understanding the specialization of T cells within different skin layers and offers a basis for future investigations into skin immune biology and its potential implications in disease.

关键词： IL-6R   Inflammation   Inflammatory Bowel Disease   Intestinal epithelial cells   Tregs  

摘要： Mucosal homeostasis requires coordinated immune regulation and epithelial repair. Inflammatory bowel disease (IBD) arises from disrupted coordination between the immune system and intestinal epithelium, where resolution and repair must occur in parallel. Interleukin-6 (IL-6) plays a dual role: it promotes epithelial regeneration but destabilizes regulatory T cells (Tregs). We aimed to determine the contribution of Treg IL-6 receptor (IL-6R) signaling to intestinal inflammation and epithelial integrity. We developed a conditional knockout mouse model in which IL-6R was deleted from Tregs (Treg IL-6R knockout). These mice were subjected to dextran sodium sulfate (DSS)-induced colitis and a T cell transfer model of colitis. Soluble IL-6R production by Tregs was assessed in vitro, and transcriptional changes in epithelial cells were analyzed by RNA-seq. Human colonic organoids from IBD patients were treated with IL-6 or hyper-IL-6 (IL-6/sIL-6R fusion protein) to test downstream signaling effects. Tregs lacking IL-6R improved colitis to a similar extent as control Tregs in the adoptive transfer model, indicating intact suppressive function. However, Treg IL-6R knockout mice were more susceptible to DSS colitis than controls, suggesting a physiologic role for Treg IL-6R signaling in epithelial protection. In vitro, Tregs shed soluble IL-6R, enabling IL-6 trans-signaling to epithelial cells. Intestinal epithelial cells from Treg IL-6R knockout mice compared to WTcre controls revealed widespread transcriptional downregulation of genes related to survival and repair pathways at baseline, and impaired transcriptional responses following DSS treatment. In human organoids, IL-6 trans-signaling elicited stronger STAT3 activation than IL-6 alone. These findings reveal a previously unrecognized role for Treg-derived IL-6R in promoting epithelial resilience and maintaining mucosal homeostasis.

关键词： 甘草泻心汤   白塞病   肠道菌群   IL-17A  

摘要： 目的：研究甘草泻心汤对白塞病小鼠肠道菌群及IL-17A的干预作用。方法：24只4～6周龄BALB/c小鼠随机分为空白组、模型组、中药组和阳性药组，每组6只。除空白组外，其他组小鼠采用虾原肌球蛋白致敏构建白塞小鼠模型。造模成功后，中药组给予甘草泻心汤0.163 8 g/20 g灌胃，阳性药组给予双歧杆菌四联活菌片灌胃，空白组和模型组给予生理盐水灌胃。灌胃给药第10天，收集小鼠新鲜粪便采用平皿计数法进行肠道菌群检测，并采用酶联免疫吸附（ELISA）法测定检测小鼠血清IL-17A的含量。结果：与空白组比较，模型组小鼠粪便中的双歧杆菌与乳杆菌含量显著降低（P <0.01），大肠埃希菌与肠球菌含量则显著升高（P <0.01）；与模型组比较，中药组及阳性药组小鼠的粪便中双歧杆菌与乳杆菌含量较模型组明显上升（P <0.01），大肠埃希菌与肠球菌含量则明显下降（P <0.01）。ELISA检测结果表明，与对照组比较，模型组小鼠外周血IL-17A水平显著升高（P <0.01），与模型组比较，中药组及阳性药组小鼠血清IL-17A水平显著降低（P <0.01）。结论：甘草泻心汤能降低白塞小鼠肠道内大肠埃希菌、肠球菌的数量，增加双歧杆菌、乳杆菌的数量，抑制炎症因子IL-17A的释放，从而起到治疗白塞病的作用。

关键词： cannabinoid 2   inflammatory   microglia   morphine  

摘要： BACKGROUND:Pain has a seriously effect on patients' life quality. The use of morphine for pain is common, but tolerance limits its application in clinic. However, there is no exact mechanism for tolerance. In this study, we explored the effect of microglial polarization and the role of IL(interleukin)-4 in administrating microglial polarization in reducing morphine tolerance with CB2 receptor agonist. METHOD:The cells cultivated with morphine or combined CB2R agonist AM1241, CB2R antagonist AM630, CB1R antagonist AM281, and IL-4 inhibitor (IL-4I), and mice were injected with these drugs for 7 consecutive days, and hot plate behavioral tests were performed 30 minutes after administration respectively. Mice received a single morphine injection on day 8, and samples were taken after behavioral tests. The expression of iNOS, SOCS3, IL-4 and STAT6 mRNA were detected by qPCR; the expression of iNOS, SOCS3, p-STAT6 and STAT6 protein were detected by Western blot. Inflammatory cytokines were detected with Elisa kit. RESULTS:The M1 marker iNOS increased, the M2 marker SOCS3 decreased, p-STAT6 protein did not change, and the cytokines increased after morphine treatment. The PWL value, IL-4 mRNA and p-STAT6 protein increased after AM1241 treatment, iNOS decreased and SOCS3 increased after AM1241 treatment, AM1241 decreased the pro-inflammatory cytokines, increased IL-4, IL-10 secretion. AM630 and IL-4I reversed the effect of AM1241 on PWL, M1 M2 markers. CONCLUSION:The polarization of microglia in the direction of M1 caused morphine tolerance, AM1241 increased the IL-4 mRNA and induced the phosphorylation protein of STAT6 to reduce the tolerance, and AM1241 induced microglia to polarization in the direction of M2. AM1241 regulated microglia polarization through IL-4/STAT6 pathway, thereby reducing tolerance.

关键词： IL-22   rhIL-22BP-ABD   Renaturation of inclusion body   Psoriasis  

摘要： Psoriasis is a persistent immune-mediated inflammatory disorder that adversely affects the skin. Interleukin-22 (IL-22) is integral to the development and pathophysiology of psoriasis, and targeting IL-22 may serve as a promising therapeutic approach for treating the condition. IL-22 binding protein (IL-22BP) exhibits a binding affinity for IL-22 that far surpasses that of IL-22RA1 and functions as a natural antagonist of IL-22. Traditional IL-22BP production methods predominantly rely on eukaryotic animal cell expression systems, which generally require complex processes, resulting in low yield and high production costs. This study reports the expression of long-acting IL-22BP with a high yield and purity over 90% in Escherichia coli by fusion with the albumin-binding structural domain ABD. The biological functions of rhIL-22BP-ABD were assessed utilizing cell lines and a murine model. Our findings indicated that rhIL-22BP-ABD successfully suppressed IL-22-induced proliferation of HaCaT cells in vitro and alleviated imiquimod-induced psoriasis inflammation in mice. Furthermore, rhIL-22BP-ABD can effectively inhibit the signaling of its downstream signaling pathway STAT3 and the associated inflammatory factors by binding to IL-22, which is beneficial to the recovery of psoriasis. These findings provide a basis for forthcoming extensive studies on the rhIL-22BP-ABD protein for industrial manufacturing and pharmaceutical development.

关键词： HLA-B   NGS   novel allele   null allele  

摘要： Three novel HLA-B alleles, HLA-B*08:336 N, HLA-B*18:258 N and HLA-B*51:425 N were identified in bone marrow donors.

关键词： B*07:02:01:132   B*40:70:01   B*54:51   C*01:283   HLA-B   HLA-C  

摘要： Two novel HLA-B alleles, one extended HLA-B allele, and one confirmatory HLA-C allele were reported.