狼疮性肾炎患者血清NETs、TWEAK、外周血CD4+T/CD8+T比例与疾病活动度及肾脏预后的关系

摘要 目的：探讨狼疮性肾炎（LN）患者血清中性粒细胞胞外诱捕网（NETs）、肿瘤坏死因子样凋亡微弱诱导剂（TWEAK）、外周血分化簇（CD）4⁺T/CD8⁺T比例与疾病活动度及肾脏预后的关系。方法：选取2021年8月～2022年8月川北医学院附属医院肾内科收治的LN患者137例（LN组）,根据系统性红斑狼疮疾病活动指数（SLEDAI）-2000评分分为轻度活动组（52例）、中度活动组（45例）、重度活动组（40例）。随访1年,根据肾脏相关终点事件发生情况分为预后不良组（43例）和预后良好组（94例）,另选取同期76名体检健康志愿者（对照组）。采用酶联免疫吸附法检测血清NETs、TWEAK水平,流式细胞术检测外周血CD4⁺T/CD8⁺T比例。Spearman相关性分析LN患者血清NETs、TWEAK和外周血CD4⁺T/CD8⁺T与SLEDAI-2000评分的相关性,多因素Logistic回归分析LN患者预后不良的因素,受试者工作特征曲线分析血清NETs、TWEAK和外周血CD4⁺T/CD8⁺T对LN患者预后不良的预测价值。结果：与对照组比较,LN组血清NETs、TWEAK水平升高,外周血CD4⁺T/CD8⁺T降低（P＜0.05）。轻度活动组、中度活动组、重度活动组血清NETs、TWEAK依次升高,外周血CD4⁺T/CD8⁺T依次降低（P＜0.05）。LN患者SLEDAI-2000评分与血清NETs、TWEAK呈正相关,与外周血CD4⁺T/CD8⁺T呈负相关（P＜0.05）。慢性肾脏病分期4期、SLEDAI-2000评分升高、NETs升高、TWEAK升高为LN患者预后不良的独立危险因素,估算肾小球滤过率升高、CD4⁺T/CD8⁺T升高为独立保护因素（P＜0.05）。血清NETs、TWEAK和外周血CD4⁺T/CD8⁺T联合预测LN患者预后不良的曲线下面积为0.943,大于血清NETs、TWEAK和外周血CD4⁺T/CD8⁺T单独预测的0.790、0.788、0.799（P＜0.05）。结论：LN患者血清NETs、TWEAK水平升高,外周血CD4⁺T/CD8⁺T降低,与疾病活动度及肾脏预后不良密切相关,血清NETs、TWEAK联合外周血CD4⁺T/CD8⁺T预测LN患者肾脏预后的价值较高。     

Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial

Introduction  

Atacicept is a soluble, fully human, recombinant fusion protein that inhibits B cell-stimulating factors APRIL (a proliferation-inducing ligand) and BLyS (B-lymphocyte stimulator). The APRIL- LN study aimed to evaluate the efficacy and safety of atacicept in patients with active lupus nephritis (LN), receiving newly initiated corticosteroids (CS) and mycophenolate mofetil (MMF).     

A single-cell survey of the human glomerulonephritis

Glomerulonephritis is the one of the major causes of the end-stage kidney disease, whereas the pathological process of glomerulonephritis is still not completely understood. Single-cell RNA sequencing (scRNA-seq) emerges to be a powerful tool to evaluate the full heterogeneity of kidney diseases. To reveal cellular gene expression profiles of glomerulonephritis, we performed scRNA-seq of 2 human kidney transplantation donor samples, 4 human glomerulonephritis samples, 1 human malignant hypertension (MH) sample and 1 human chronic interstitial nephritis (CIN) sample, all tissues were taken from the biopsy. After filtering the cells with < 200 genes and > 10% mitochondria (MT) genes, the resulting 14 932 cells can be divided into 20 cell clusters, consistently with the previous report, in disease samples dramatic immune cells infiltration was found, among which a proximal tubule (PT) subset characterized by wnt-β catenin activation and a natural killer T (NKT) subset high expressing LTB were found. Furthermore, in the cluster of the podocyte, three glomerulonephritis related genes named FXYD5, CD74 and B2M were found. Compared with the mesangial of donor, the gene CLIC1 and RPS26 were up-regulated in mesangial of IgA nephropathy(IgAN), whereas the gene JUNB was up-regulated in podocyte of IgAN in comparison with that of donor. Meanwhile, some membranous nephropathy (MN) high expressed genes such as HLA-DRB5, HLA-DQA2, IFNG, CCL2 and NR4A2, which involve in highest enrichment pathway, display the cellular-specific expression style, whereas monocyte marker of lupus nephritis (LN) named TNFSF13B was also found and interferon alpha/beta signalling pathway was enriched in B and NKT of LN comparing with donor. By scRNA-seq, we first defined the podocyte markers of glomerulonephritis and specific markers in IgA, MN and LN were found at cellular level. Furthermore, the critical role of interferon alpha/beta signalling pathway was enriched in B and NKT of LN was declared.     

Mesoamerican nephropathy: a neglected tropical disease with an infectious etiology?

An outbreak of unexplained and severe kidney disease, “Mesoamerican Nephropathy,” in mostly young, male sugar cane workers emerged in Central America in the late 1990's. As a result, an estimated 20,000 individuals have died, to date. Unfortunately, and with great consequence to human life, the etiology of the outbreak has yet to be identified. The sugarcane fields in Chichigalpa, Chinandega, Nicaragua, have been involved in the outbreak, and during our initial investigation, we interviewed case patients who experienced fever, nausea and vomiting, arthralgia, myalgia, headache, neck and back pain, weakness, and paresthesia at the onset of acute kidney disease. We also observed a heavy infestation of rodents, particularly of Sigmodon species, in the sugarcane fields. We hypothesize that infectious pathogens are being shed through the urine and feces of these rodents, and workers are exposed to these pathogens during the process of cultivating and harvesting sugarcane. In this paper, we will discuss the epidemic in the Chichigalpa area, potential pathogens responsible for Mesoamerican Nephropathy, and steps needed in order to diagnose, treat, and prevent future cases from occurring.     

IL-17 与狼疮性肾炎关系的研究新进展

系统性红斑狼疮是一种涉及多系统损害的自身免疫性疾病,其主要并发症及死亡原因之一是狼疮性肾炎。研究表明,IL-17和产IL-17细胞可以浸润肾脏,与其他细胞因子协同作用,引起肾脏局部炎症反应。拮抗IL-17的生物制剂已应用于银屑病、强制性脊柱炎等免疫介导炎症性疾病,但在系统性红斑狼疮及狼疮性肾炎的研究尚少。本文对IL-17与狼疮性肾炎的关系进行综述,探讨IL-17及其抑制剂在狼疮性肾炎治疗的作用及发展前景。     

补阳还五汤联合西药治疗小儿过敏性紫癜性肾炎的疗效及对机体血管内皮功能的影响研究

摘要 目的：探讨补阳还五汤联合西药治疗小儿过敏性紫癜性肾炎的疗效及对机体血管内皮功能的影响。方法：选取我院2019年1月到2022年12月收治的86例过敏性紫癜性肾炎患儿作为研究对象,分为观察组与对照组,每组43例。对照组患儿采取常规西药治疗,观察组患儿采取补阳还五汤联合西药常规治疗,对比两组患儿临床疗效,并对比治疗前与治疗3个月后患儿的肾功能变化、炎症因子水平变化、血管内皮功能与凝血功能变化。结果：观察组治疗总有效率较对照组高（P＜0.05）;两组患儿治疗前明胶酶相关脂质运载蛋白（NGAL）、血肌酐（SCr）、血尿素氮（BUN）对比无差异（P＞0.05）,治疗后两组患儿NGAL、SCr、BUN水平均升高,观察组较对照组高（P＜0.05）;两组患儿治疗前转化生长因子-β1（TGF-β1）、白细胞介素-18（IL-18）和白细胞介素-6（IL-6）相关炎症因子水平对比无差异（P＞0.05）,治疗后观察组患儿TGF-β1、IL-18和IL-6相关炎症因子水平低于对照组（P＜0.05）;两组患儿治疗前D-二聚体、纤维蛋白原（FIB）、一氧化氮（NO）和内皮素-1（ET-1）水平对比无差异（P＞0.05）,治疗后观察组患儿D-二聚体、FIB和ET-1水平均降低,且观察组低于对照组,NO水平升高,观察组较对照组高（P＜0.05）。结论：补阳还五汤联合西药治疗小儿过敏性紫癜性肾炎临床疗效显著,能够改善患儿肾功能,降低机体炎症反应,提升凝血功能的同时,进一步改善患儿血管内皮功能,值得临床应用推广。     

Th 细胞因子IL-17、IFN-γ、IL-4 在狼疮性肾炎中的表达及意义

目的:探讨T辅助细胞(Th)相关细胞因子在狼疮性肾炎发病中的免疫机制作用。方法:64例系统性红斑狼疮患者和28例健康体检者作为对照,采用酶联免疫吸附测定法(ELISA法)检测所有受试者血清IL-17、IFN-γ、IL-4水平,并对其与SLEDAI、SDI、24小时尿蛋白量相关性进行研究。结果:狼疮性肾炎组血清IL-17水平显著高于狼疮无肾炎组和健康对照组(P<0.001),狼疮性肾炎组血清IFN-γ水平显著高于狼疮无肾炎组(P<0.05)和健康对照组(P<0.01),血清IL-4水平在狼疮性肾炎组、狼疮无肾炎组均显著高于健康对照组(P<0.01)。狼疮性肾炎组IFN-γ/IL-4比值显著高于狼疮无肾炎组(P<0.01)和健康对照组(P<0.05);狼疮无肾炎组IFN-γ/IL-4比值显著低于健康对照组(P<0.01)。SLE患者血清IFN-γ表达水平与SLEDAI积分呈正相关(r=0.402,P<0.05),血清IL-17、IL-4表达水平与SLEDAI、SDI、抗ds-DNA抗体、C3、24小时尿蛋白量均无相关性。结论:狼疮性肾炎患者外周血中IL-17、IFN-γ、IL-4等促炎细胞因子均有不同程度升高促起炎症发生及组织损伤,参与了狼疮性肾炎的免疫发病过程。     

活血解毒、益气养阴法治疗狼疮性血管炎临床及免疫研究

目的:观察活血解毒、益气养阴法对狼疮性血管炎临床疗效及免疫功能的影响。方法:选择系统性红斑狼疮患者60例,其中活动期伴血管炎40例,非活动期20例,同时选择20例健康人作为对照组,检测可溶性血栓调节素(sTM)、血管内皮生长因子(VEGF)的水平、抗中性粒细胞胞浆抗体(ANCA)的阳性率;并将40例活动期伴血管炎患者随机分为中西医结合治疗组(狼疮饮+常规西药)和对照组(常规西药),治疗6个月后观察临床疗效,并检测治疗前和治疗后第1,6个月sTM、VEGF、ANCA水平和阳性率变化。结果:中西医结合治疗组疗效优于对照组,治疗组治疗后sTM、VEGF、ANCA水平和阳性率下降优于对照组(P<0.05)。结论:中西医结合治疗可提高狼疮性血管炎的疗效,改善免疫功能。     

Prenatal TCDD causes persistent modulation of the postnatal immune response, and exacerbates inflammatory disease, in 36-week-old lupus-like autoimmune SNF1 mice

BACKGROUND: Prenatal exposure to the persistent environmental pollutant and model Ah receptor agonist, 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD), has been shown to permanently suppress postnatal cell‐mediated immunity. More recently, skewing of select adult T and B cell responses toward enhanced inflammation has also been described in C57BL/6 mice after prenatal TCDD. This raises questions about adverse postnatal immune consequences of prenatal TCDD in animals genetically predisposed to inappropriate inflammatory responses. METHODS: Lupus‐prone SNF₁ mice were exposed to 0, 40, or 80 µg/kg TCDD on gestation day (gd) 12 and examined at 36 weeks‐of‐age for immunomodulatory effects that correlated with worsened lupus pathology. RESULTS: Bone marrow pro‐ and large pre‐B cells were decreased by prenatal TCDD, in both adult male and female mice, as were pre‐ and immature B cells. Splenic CD23⁻CD1^hi and CD19⁺CD5⁺ B cells were increased in males, as were B220^hi B cells in females, further suggesting persistent disruption of B cell lymphopoiesis by prenatal TCDD. Female mice displayed decreased IL‐10 production by ConA‐activated splenocytes, while males underproduced IL‐4. Autoreactive CD4⁺Vβ17a⁺ spleen T cells were increased in both sexes by 80 µg/kg TCDD. Male mice but not females showed increased anti‐ds DNA and cardiolipin autoantibody levels. CONCLUSIONS: Prenatal TCDD augmented the hallmark indicators of SLE progression in the lupus‐prone SNF₁ mice, including renal immune complex deposition, glomerulonephritis, and mesangial proliferation. Prenatal TCDD therefore caused persistent modulation of the postnatal immune response, and exacerbated inflammatory disease, in lupus‐like autoimmune SNF₁ mice. Birth Defects Res (Part B) 92:82–94, 2011. © 2011 Wiley‐Liss, Inc.