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关键词： Autoimmune disease   B-cell activating factor   Bispecific antibody   Interleukin-17   Systemic lupus erythematosus  

摘要： BACKGROUND: This study aimed to develop and evaluate a bispecific single-chain variable fragment (bsscFv) targeting B-cell activating factor (BAFF) and interleukin-17 (IL-17) for the treatment of systemic lupus erythematosus (SLE). METHODS: The bsscFv was engineered by linking single-chain variable fragments (scFvs) specific for BAFF and IL-17 with a flexible peptide linker. It was expressed in E. coli BL21 and purified using affinity chromatography. Binding affinities to BAFF and IL-17 were assessed by enzyme-linked immunosorbent assay (ELISA). In vitro neutralization assays were conducted using Raji and HT-29 cell cultures. In vivo therapeutic efficacy was evaluated in an MRL/lpr mouse model of SLE, with 10 mice per group. Statistical significance was determined using a Student's t-test for comparison of two groups. RESULTS: The bsscFv demonstrated strong binding to both BAFF and IL-17 in ELISA. In vitro, it inhibited BAFF-induced B-cell survival, proliferation, and immunoglobulin production, as well as IL-17-induced inflammatory cytokine secretion in HT-29 cells. In the MRL/lpr mouse model, bsscFv treatment significantly reduced autoantibody levels (p < 0.05), proteinuria, renal pathology, and cytokine expression in a dose-dependent manner compared to controls. CONCLUSIONS: The bsscFv exhibited potent neutralizing activity in vitro and therapeutic efficacy in vivo, suggesting it as a promising bispecific therapeutic agent for the treatment of SLE. Further studies are warranted to explore its clinical potential. © 2025. The Author(s).

关键词： 巯基化透明质酸   巨噬细胞   炎症   白介素-13  

摘要： 目的:制备一种负载IL-13的巯基化透明质酸(hyaluronic acid、HA)水凝胶,旨在通过介导巨噬细胞的极化来调控伤口修复过程中的炎症和增殖阶段。方法:应用巯基改性HA制得巯基化透明质酸水凝胶(thiolated hyaluronic acid hydrogel,HA-SH),并对凝胶的可注射性、力学性能和吸水性进行表征。通过加入白介素-13(interleukin-13,IL-13)制备得到IL-1 3/HA-SH水凝胶,对IL-13/HA-SH水凝胶介导巨噬细胞极化进行探究。结果:理化性能表征结果显示,6%的HA-SH性能最好,成胶时间短,孔隙分布均匀紧密,有良好的力学性能和吸水能力。IL-13/HA-SH水凝胶培养的巨噬细胞M2:M1比例最高,促进了抑炎因子IL-10和TGF-β的分泌,上调Arg-1和TGF-β的基因表达水平,同时降低了促炎因子TNF-α和IL-1β的分泌,下调TNF-α和CD80的基因表达水平。结论:IL-13/HA-SH水凝胶能够介导巨噬细胞向M2型极化,降低炎症反应,在伤口敷料领域有较好的应用前景。

关键词： Rheumatoid arthritis   IL-37   Missense variant   Real-time PCR   Susceptibility  

摘要： Background Rheumatoid arthritis (RA) is an autoimmune disorder, in which anti-inflammatory cytokines are proposed to play a key mediating role. Interleukin (IL)-37, a recently assigned anti-inflammatory member of IL-1 cytokine family, has been linked to RA pathogenesis. Interestingly, two IL37 missense single nucleotide polymorphisms (SNPs: rs3811046 G > T and rs3811047 A > G) have been suggested to influence susceptibility to some inflammatory and autoimmune disorders, while their relationship to RA risk has not been well defined. Therefore, 120 Iraqi females with RA and 110 control females were enrolled in a case-control study to explore IL-37 role in RA etiopathogenesis in terms of serum levels and two polymorphisms (rs3811046 and rs3811047). IL-37 concentrations were quantified using an ELISA kit, while SNPs were genotyped using a method based on real-time PCR principles. IL-37 concentrations were presented as median and interquartile range (25-75%), and significant differences were assessed using Mann-Whitney U test or Kruskal-Wallis test (for comparison between two or more groups, respectively). SNP-disease association analysis was presented using odds ratio (OR) and 95% confidence interval (CI). Results Patients showed significantly higher IL-37 concentrations compared to controls (88.8 [79.1-100.0] vs. 59.5 [44.1-78.6] ng/L;probability [p] < 0.001), and IL-37 showed a reliable discriminatory area under the curve of 0.758 (95% CI = 0.691-0.826;p < 0.001) as demonstrated by receiver operating characteristic curve analysis. Association analysis disclosed that T (rs3811046) and G (rs3811047) alleles, as well as homozygous genotypes (TT and GG, respectively), were significantly linked to a lower RA susceptibility (OR [95% CI] = 0.52 [0.36-0.76], 0.37 [0.24-0.55], 0.30 [0.14-0.64], and 0.15 [0.06-0.38];adjusted p = 0.005, 0.001, 0.01, and 0.001, respectively). Additionally, G-A and T-G haplotypes (rs3811046-rs3811047) were associated with higher (OR [95% CI] = 2.7

关键词： annexin A5   anti-TNF-alpha nanobodies   Escherichia coli Nissle 1917   inflammatory bowel disease   targeted drug delivery  

摘要： The probiotic Escherichia coli Nissle 1917 (EcN), clinically used for ulcerative colitis (UC) due to its safety and genetic tractability, exhibits limited therapeutic efficacy owing to poor targeting and colonization at inflamed sites. Phosphatidylserine (PS) exposure increases on apoptotic colon epithelial cells during UC progression, suggesting PS-targeting could enhance EcN localization. Here, EcN is engineered to surface-display Annexin A5 (ANXA5), a PS-binding protein, to improve inflammation targeting and colonization. Since TNF-alpha drives UC pathogenesis and anti-TNF-alpha biologics face cost and safety limitations, the secretion-hindering lpp gene is concurrently knocked out in ANXA5-expressing EcN, creating the inflammation-targeted, secretion-enhanced EcN Delta lpp::A5. This base strain is further modified to secrete an anti-TNF-alpha nanobody (aTN), generating EcN Delta lpp::A5-aTN. Both engineered strains demonstrate significantly stronger colonic colonization versus wild-type EcN, effectively attenuating oxidative stress-mediated epithelial apoptosis, restoring mucosal barriers, improving immune-microbiota balance, and alleviating murine colitis. EcN Delta lpp::A5-aTN shows superior efficacy to EcN Delta lpp::A5. This study develops an engineered EcN system with enhanced targeting, colonization, and secretion. By efficiently delivering anti-TNF-alpha nanobodies, EcN Delta lpp::A5-aTN exhibits strong therapeutic potential for UC, overcoming limitations that hinder the clinical application of wild-type EcN.

关键词： 来那度胺   难治性复发慢性淋巴细胞白血病   疗效   安全性  

摘要： 分析难治性复发慢性淋巴细胞白血病(CLL)患者用来那度胺治疗后的疾病缓解情况和药物安全性数据。方法 从我院2023年1月至2025年1月收治的难治性复发CLL患者中选取60例参与本次调研,按治疗时间差异分为两组,且两组均采用来那度胺治疗,区别在于给药周期,参照组(n=30)间歇给药方案(用药21天,停药7天),分析组(n=30)持续给药方案(连续用药28天),比较两组的疗效、安全性以及对免疫功能、炎症指标等影响。结果 分析组临床疗效显著高于参照组(P<0.05)。分析组不良反应发生率显著低于参照组(P<0.05)。治疗前、治疗后两组CD4⁺/CD8、IgG、IgA比较均无显著差异(P>0.05)。治疗前两组NLR、PLR比较无显著差异(P>0.05),治疗后分析组显著低于参照组(P<0.05)。结论 采用28天连续给药方案的来那度胺治疗可显著提升难治性复发CLL患者的临床获益,主要体现在显著提高疾病缓解率、降低不良反应发生率、有效改善患者炎症指标以及维持免疫功能稳定方面,该给药方案较传统间歇给药模式展现出更优的临床价值。

关键词： 防己黄芪汤   他克莫司   肾病综合征   补体C3   补体C4  

摘要： 本研究试图观察防己黄芪汤与他克莫司联合医治肾病综合征过程中对患者补体C3、C4水平的影响,评判其临床疗效与免疫学相关作用,为肾病综合征治疗供给新的疗法与理论支撑。方法 本研究为回顾性队列研究,选取2024年1月至2024年12月期间,因肾病综合征入住我院的60例患者,患者按治疗方案分为两组:实验组30例给予防己黄芪汤联合他克莫司治疗,对照组30例给予常规治疗,治疗前后分别检测患者的补体C3、C4水平,并进行临床疗效评估,数据收集过程中,所有患者均接受常规的临床和免疫学检查,治疗后随访观察疗效并记录不良反应,所有数据通过SPSS22.0统计软件进行分析,计量资料采用t检验,计数资料采用卡方检验。结果 治疗后,实验组患者的补体C3、C4水平明显升高(C3从0.65±0.12g/L增至0.91±0.15g/L,C4从0.14±0.04g/L增至0.21±0.05g/L),与对照组相比差异具有统计学意义(P<0.05),在临床疗效方面,实验组的有效率为86.7%,明显高于对照组的66.7%(P<0.05),此外,实验组患者的不良反应发生率较低,且没有严重不良反应出现。结论 防己黄芪汤协同他克莫司治疗肾病综合征,能显著提高患者补体C3、C4水平,展现出理想的临床治疗效果,且安全系数相对较高,该联合治疗方案为肾病综合征患者给予了一种有效的治疗方案,宜在临床推广运用。

关键词： 系统性红斑狼疮   来氟米特   环磷酰胺   糖皮质激素  

摘要： 探析来氟米特联合环磷酰胺及糖皮质激素在系统性红斑狼疮治疗中的应用效果及其对CRP、IL-8、IL-10的影响。方法 选取本院72例系统性红斑狼疮患者(2024年2月-2025年1月),按照不同疗法分为对照组(环磷酰胺联合糖皮质激素治疗)与观察组(来氟米特联合环磷酰胺、糖皮质激素治疗),针对临床指标进行比较分析。结果 观察组治疗后SLEDAI评分是(8.14±1.15)分,对照组是(11.59±2.27)分,观察组更低(P<0.05)。治疗后,观察组IL-8是(0.25±0.04)pg/ml,CRP是(15.18±5.34)mg/L,IL-10是(27.29±3.36)pg/ml,对照组分别是(0.32±0.08)pg/ml、(22.69±7.35)mg/L、(36.18±4.45)pg/ml,观察组更低(P<0.05)。观察组较对照组治疗后IgG、ANA显著降低,而补体C3明显提高(P<0.05)。观察组治疗后Scr是(99.59±28.17)μmol/L,24h尿蛋白是(1.21±0.52)g,ALB是(37.72±4.25)g/L,对照组分别是(118.28±28.16)μmol/L、(1.85±0.59)、(30.26±4.31)g/L,观察组治疗后显著降低(P<0.05)。不良反应总发生率方面,两组差异较小(P>0.05)。结论 来氟米特、环磷酰胺联合糖皮质激素有助于系统性红斑狼疮患者免疫功能、炎性反应、肾功能等改善,控制病情发展,且安全性高。

关键词： 益生菌   美沙拉嗪   炎症性肠病   疗效   安全性   炎症因子  

摘要： 分析益生菌、美沙拉嗪联合干预对炎症性肠病患者的治疗效果。方法 选取2024年1月~2025年3月本院收治的炎症性肠病患者120例,其中,60例对照组接受美沙拉嗪单药治疗,60例研究组接受益生菌、美沙拉嗪联合治疗干预,比较两组的治疗效果。结果 与对照组相比,研究组的疗效、炎症因子水平、肠道菌群水平、症状改善时间、不良反应发生率均更优(P<0.05)。结论 针对炎症性肠病患者实施益生菌联合美沙拉嗪的干预治疗方案,能够收获较好的治疗效果。

关键词： Immunodeficiency   JAK-inhibitors   macular edema   retinal pigment epithelium   STAT3-GOF syndrome  

摘要： PurposeThe IL-6 R/JAK/STAT3 signaling pathway is implicated in non-infectious uveitis-associated macular edema, and its inhibition using monoclonal anti-IL-6 receptor therapy has been associated with clinical improvement. However, the underlying pathogenic mechanisms remain unclear. In this study, we investigated the pathological effects of a STAT3 gain-of-function (GOF) variant p.L387R identified in a family with immune dysregulation syndrome and severe retinal vasculitis and macular *** retinal pigment epithelial (RPE) cells were transduced with STAT3 wildtype (WT), the retinal disease-associated familial STAT3 GOF variant p.L387R, or another pathogenic STAT3 GOF variant (p.Y360C) linked to immune dysregulation without retinal involvement. Cells were subsequently stimulated with IL-6 and IFN-alpha. RNA sequencing was performed to analyze gene expression differences, particularly related to cytokines, chemokines, and factors associated with RPE barrier permeability. Additionally, the expression of tight junction proteins involved in the blood-retinal barrier integrity was assessed. The efficacy of JAK inhibitors to modulate hyperactivation of the IL-6 R/JAK/STAT3 pathway was also *** with WT and STAT3 p.Y360C variant-expressing cells, those expressing STAT3 p.L387R variant produced significantly elevated levels of IL-6, CCL2, and VEGF-A, which are known contributors to vascular leakage in retinal endothelial cells. Treatment with JAK1/2 inhibitors effectively reduced SOCS3 overexpression in STAT3 GOF RPE *** pathogenic STAT3 p.L387R GOF variant enhances inflammatory cytokine production in human primary RPE cells, potentially exacerbating retinal vascular leakage and macular edema. These effects can be mitigated by JAK1/2 inhibition, highlighting a promising therapeutic strategy for retinal inflammation and associated edema.

摘要： The progression of cancer strongly depends on the tumor microenvironment and immune surveillance. Tumor necrosis factor alpha (TNFα), a key inflammatory cytokine, can drive both tumor elimination and promotion, depending on its dose and the type of cancer. Colorectal cancer cell lines HCT 116, HT-29, and melanoma cells A375 engineered to stably overexpress the human TNFα gene were used to induce experimental subcutaneous tumors in two immunodeficient mouse strains: athymic Balb/c-nu/nu and SCID/bg mice. In athymic mice, TNFα-overexpressing cells completely lost their tumorigenicity. In SCID/bg mice, with no mature T and B cells and defective NK cells, the TNFα overexpressing cells formed rudimentary flat ulcerous xenografts with rapidly reduced size, with tumor penetrance of 50-85%. Histopathological analysis revealed necrotic lesions, a more differentiated phenotype of tumor cells forming pseudoglandular structures, and more abundant stromal cells. Intratumoral infiltration of immune cells increased in TNFα-secreting tumors. Positivity of cytokeratins 7 and 20 in colorectal cancer xenografts was decreased. Paradoxically, the expression of ALDH1A1 and ALDH1A3 isoforms, which are important for disease prognosis, was increased. Our study suggests that careful modulation of the tumor microenvironment to a tumor-suppressive one using cytokine TNFα and controlled stimulation of antitumor immunity can contribute to the improvement of cancer treatment.