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关键词： IL‐6R   YTHDF2   fibroblast‐like synoviocytes   inflammation   rheumatoid arthritis  

摘要： This study examined YTHDF2's role in modulating IL-6R signaling to regulate synovial fibroblast inflammation and bone damage in rheumatoid arthritis (RA). Synovial tissues of RA patients were collected. Human fibroblast-like synoviocyte (FLS), MH7A cell line, was induced with TNF-α and transfected. Cell proliferation was assessed using MTT and EdU assays; apoptosis was measured with flow cytometry, and migration and invasion were evaluated through scratch and Transwell assays. Lentiviral vectors designed to overexpress YTHDF2 or IL-6R were created to study their effects in mice with collagen-induced arthritis (CIA). Pathological changes of ankle joints in mice were observed, and TNF-α, IL-1β, and IL-6 contents were determined. MMP3 and MMP9 levels were detected by Western blot, while YTHDF2 and IL-6R were detected by RT-qPCR and Western blot. The binding relationship between YTHDF2 and IL-6R was studied. YTHDF2 in synovial tissues of RA patients was down-regulated. Elevating YTHDF2 inhibited TNF-α-induced MH7A cell proliferation, migration, invasion, and pro-inflammatory factors; Knocking down YTHDF2 showed the opposite effect. Upregulating YTHDF2 improved synovial inflammation and bone damage in CIA mice. IL-6R in synovial tissues of patients was significantly up-regulated and negatively correlated with YTHDF2 expression. YTHDF2 reduced IL-6R mRNA stability in a m6A-dependent manner. Overexpressing IL-6R impaired the anti-proliferating and anti-inflammatory effect of YTHDF2 on TNF-α-induced MH7A cells. In CIA mice, overexpression of IL-6R reversed the benefits on synovial inflammation and bone injury mediated by up-regulating YTHDF2. YTHDF2 inhibits inflammation and bone damage in RA synovial fibroblasts by reducing the mRNA stability of IL-6R.

关键词： 坐骨神经痛   LncRNA Gm14461   辅助性T细胞17   调节性T细胞   促炎-抗炎失衡  

摘要： 目的 探讨坐骨神经痛患者血清LncRNA Gm14461表达与T淋巴细胞亚群及促炎-抗炎失衡的关系。方法 选择124例坐骨神经痛患者,其中男性59例,女性65例;年龄29～75岁,平均年龄65.1岁;身体质量指数24.3～26.4 kg/m2,平均身体质量指数24.9 kg/m2;病程4～65个月,平均病程9.1个月;腰椎间盘突出41例。采用疼痛视觉模拟量表（VAS）评分对患者坐骨神经痛严重程度进行评分,并根据评分将患者分为轻度组（1～3分）、中度组（4～6分）和重度组（7～10分）。腰椎功能采用Oswestry功能障碍指数（ODI）问卷表。采用实时荧光定量聚合酶链式反应（qRT-PCR）检测血清LncRNA Gm14461,流式细胞术检测辅助性T细胞17（Th17）和调节性T细胞（Treg）百分比,酶联免疫吸附分析（ELISA）检测促炎因子白细胞介素（IL）-17、IL-6、γ干扰素（IFN-γ）和肿瘤坏死因子α（TNF-α）及抗炎因子IL-10。结果 采用VAS评分将患者分为轻度组30例、中度组66例和重度组28例。轻度组、中度组和重度组LncRNA Gm14461、Th17百分比、IL-17、IL-6、IFN-γ和TNF-α水平逐渐升高,而Treg百分比和IL-10水平逐渐降低（P<0.05）。Pearson检验显示,VAS和ODI评分与LncRNA Gm14461、Th17百分比、IL-17、IL-6、IFN-7和TNF-7水平呈显著正相关,与Treg百分比和IL-10呈负相关（P<0.05）。LncRNA Gm14461与Th17百分比、IL-17、IL-6、IFN-γ和TNF-α水平呈显著正相关（r=0.502、0.643、0.754、0.558、0.632）,与Treg百分比和IL-10呈负相关（r=-0.542、-0.530）(P<0.05)。124例患者治疗后与治疗前相比,LncRNA Gm14461、Th17百分比、IL-17、IL-6、IFN-γ和TNF-α水平明显降低[0.89±0.07vs 1.46±0.15、（0.75±0.07）%vs（1.39±0.18）%、（7.05±0.86） pg/mL vs （11.25±1.52） pg/mL、（36.52±7.85） pg/mL vs （67.23±18.02） pg/mL、（10.02±2.42） pg/mL vs（19.93±4.23） pg/mL、（27.65±3.12） pg/mL vs （43.56±5.98） pg/mL],Treg百分比和IL-10明显升高[（6.13±0.98）%vs（4.45±0.92）%、（46.65±3.52） pg/mLvs（37.12±3.24） pg/mL]（P<0.05）。结论 坐骨神经痛患者血清LncRNA Gm14461表达与Th17、Treg及促炎-抗炎失衡紧密相关,与疼痛和临床症状严重程度相一致。

关键词： GADD45A   interferon-β   peste des petits ruminants virus   TANK-binding kinase 1   V protein  

摘要： Peste des petits ruminants virus (PPRV) is a highly contagious pathogen that severely impacts goats and sheep due to its high contagiousness and pathogenicity. Viruses rely on host proteins for their pathogenicity and replication, but the specific mechanisms facilitating PPRV replication by host proteins remain poorly understood. In this study, we identified goat growth arrest and DNA damage protein 45A (GADD45A) as a positive regulator of PPRV replication. Overexpression of GADD45A enhances PPRV replication, while its knockdown significantly inhibits PPRV replication. Furthermore, GADD45A suppresses SeV- or Poly(I:C)-induced IFN-β promoter and ISRE activation in a dose-dependent manner, as well as the transcription of interferon-stimulated genes (ISGs). We also demonstrate that goat GADD45A interacts with TANK-binding kinase 1 (TBK1), leading to the downregulation of TBK1 expression. Co-immunoprecipitation and confocal microscopy confirmed that GADD45A interacts with the PPRV V protein. Both GADD45A and V synergistically inhibit IFN-β promoter activation and TBK1 expression, thereby promoting PPRV replication. Our findings suggest that GADD45A promotes PPRV replication by downregulating TBK1, offering new insights into host proteins that counteract innate immune responses during PPRV infection. These findings offer valuable insights into the role of host proteins in viral replication and immune evasion, shedding new light on how PPRV antagonizes innate immunity.

关键词： ALTR   ALVAL   arthroplasty   metal allergy   pseudotumour   ‘at risk’ genotype  

摘要： PURPOSE:Immune-mediated adverse local tissue reactions (ALTRs) to implanted metallic devices are an increasingly recognised orthopaedic concern. Recent research has identified a critical HLA genotype associated with increased risk of ALTR development around in situ arthroplasty implants. Carriage imparts a > 700% increased relative-risk of high-grade peri-prosthetic lesion development, associated with pain and joint dysfunction and likely contributing to an increased burden of complex revision surgery. Despite being first reported in 2017, the 'at risk' genotype has only subsequently been described in selected metal-on-metal and revision arthroplasty cohorts and no population-level prevalence data has been reported. This novel epidemiologic pilot investigation aimed to explore allele-variant carriage frequencies of the previously-described 'at risk' HLA genotype in an undifferentiated orthopaedic population to inform larger screening investigations. METHODS:One hundred consecutive patients were prospectively recruited. Targeted HLA class II genotyping was performed using a medium-resolution Luminex-based approach, and secondary screening was performed to identify the presence of four specific alleles previously-associated with immune-mediated reactions to implanted metal devices. RESULTS:Our findings, in a non-differentiated orthopaedic cohort, suggest a carrier rate of the previously-defined 'at risk' allele of 38%, with 29% of those sampled carrying the defined 'at risk' genotype. CONCLUSION:Our results show a higher-than-anticipated incidence of the 'at risk' gene and genotype. As genotype-associated ALTRs may contribute to patient dissatisfaction following primary joint replacements, the impact of this result may be greater than had previously been considered. While acknowledging the preliminary nature of these data, they may guide future screening applications of the genotyping analysis and will provide a foundation contribution-to-knowledge for future endeavou

关键词： HLA-C*01:257N   next-generation sequencing   novel allele  

摘要： HLA-C*01:257N differs from the HLA-C*01:02:01:01 allele by one nucleotide substitution in exon 4.

关键词： estimated glomerular filtration rate (eGFR)   genetic association study   HLA   kidney function   polymorphisms  

摘要： HLA allelic polymorphisms are associated with a variety of kidney-related traits in different populations. Although Taiwanese-specific genetic variants associated with kidney function have been reported, the role of HLA alleles is unclear. In this study, the association between eGFR and genetic variations in the HLA region was explored in a cohort of 59,448 Taiwanese subjects. A total of 448 genetic variations in the HLA region are significantly associated with eGFR. HLA-C*03 is associated with decreased eGFR, while HLA-DQA1* 03, HLA-DQB1* 03:03 and HLA-DQB1* 03:03:02 demonstrated protective effects. Moreover, amino acid changes on HLA-C and HLA-DRB1 are significantly associated with eGFR. Finally, the eGFR-associated single nucleotide variations (SNVs) and insertions and deletions (indels) are enriched in the HLA-DQB1 gene. After conditional analysis, we identified two independent signals, including rs2853941, rs3830060. In summary, this study highlights the role of HLA-C , HLA-DQA1 , HLA-DQB1 and HLA-DRB1 variations in kidney function in the Taiwan Han Chinese population.

关键词： 系统性红斑狼疮   中药   Th17细胞   白细胞介素-17   小鼠   免疫调节   肾脏疾病   抗体形成  

摘要： 目的 研究解毒祛瘀滋阴方治疗系统性红斑狼疮（SLE）样模型小鼠及对C-C趋化因子受体6阳性/C-X-C趋化因子受体5阳性辅助性T细胞17(CCR6+CXCR5+Th17)分泌白细胞介素-17（IL-17）的影响。方法 将50只SPF级BALB/c雌性小鼠适应性饲养1周后采用ALD-DNA免疫同系BALB/c小鼠造模，构建红斑狼疮样小鼠模型，随机分为空白组、解毒祛瘀滋阴方低剂量组、解毒祛瘀滋阴方中剂量组、解毒祛瘀滋阴方高剂量组、阳性对照组，每组10只，各组小鼠灌胃相应药物4周，空白组灌胃纯净水，阳性对照组灌胃醋酸泼尼松溶液。给药前及最后一次给药2周后采集小鼠24 h尿液并于颌下静脉取血分离血清，处死小鼠解剖取脾脏、胸腺及肠系膜淋巴结。实验期间观察各组小鼠的一般情况，采用双缩脲法检测尿蛋白，采用ELISA法检测血清抗双链DNA（ds-DNA）IgG抗体、IL-17，流式细胞仪检测CCR6+CXCR5+Th17细胞比例；Pearson相关法分析抗ds-DNA抗体浓度、IL-17与CCR6+CXCR5+Th17细胞比例的关系；光学显微镜观察小鼠肾脏组织病理切片。结果 解毒祛瘀滋阴方低、中、高剂量组及阳性对照组精神状态较之前活泼，活动量增加，毛发脱落减少，饮食摄入量、1 h活动总距离均升高，尿蛋白、抗ds-DNA抗体、IL-17浓度、CCR6+CXCR5+Th17细胞占比均降低（P<0.01），且解毒祛瘀滋阴方中剂量组与阳性对照组比较差异无统计学意义（P>0.05）；抗ds-DNA抗体、IL-17浓度与CCR6+CXCR5+Th17细胞占比呈正相关性（r=0.603，0.518，P<0.001）；肾脏组织病理形态学显示解毒祛瘀滋阴方中剂量组病理情况明显改善。结论 解毒祛瘀滋阴方能够显著改善SLE模型小鼠临床症状，减轻肾脏损伤，抑制免疫反应，能够有效降低CCR6+CXCR5+Th17细胞分泌IL-17从而发挥治疗作用。

关键词： HLA-DPB1*19:01:02   next-generation sequencing   novel allele  

摘要： HLA-DPB1*19:01:02 differs from HLA-DPB1*19:01:01 by a single nucleotide substitution at position 735 C>T.

关键词： 血小板   病理性瘢痕   细胞因子   炎症   血管生成  

摘要： 病理性瘢痕是皮肤创伤愈合过程中的一种异常现象，目前病理性瘢痕的发病机制尚不明确，影响病理性瘢痕形成的因素主要包括创伤后炎症反应、血管形成、组织重塑及纤维化等过程。研究表明血小板在病理性瘢痕形成过程中发挥着重要作用。血小板是止血凝血的重要介质，活化的血小板通过脱颗粒释放细胞因子如转化生长因子-β（transforming growth factor-β，TGF-β）、血小板衍生生长因子（platelet derived growth factor，PDGF），表达膜表面蛋白如CD40配体（CD40L）、Toll样受体（Toll-like receptor， TLR）以及释放血小板微粒(platelet microparticles， PMPs)影响伤口愈合的多个阶段，其通过激活不同的信号通路，共同调控病理性瘢痕的发生与发展。近年来，研究发现抗血小板药物在缓解人体多脏器纤维化中具有积极意义，本文通过总结血小板在病理性瘢痕发病机制中的作用及研究进展，以期为病理性瘢痕的防治提供新思路。