系统性红斑狼疮与肠道菌群关系研究进展

系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种慢性进行性自身免疫疾病,可累及全身多器官。SLE的发病机制不仅与遗传易感性有关,还与环境因素有关,其中肠道菌群紊乱引起了越来越多的关注。研究表明,肠道菌群是影响自身免疫性疾病发病率的环境因素。公认的机制包括异常的微生物移位、分子拟态以及局部和全身免疫的失调。因此,肠道菌群及其代谢物影响SLE的发生发展。本文将重点探讨肠道菌群与SLE的关系,以及菌群干预作为SLE防治的新策略,为进一步研究SLE的诊断和治疗提供新的思路。     

狼疮性肾炎患者血清TBX21、SCF、Chemerin水平与病情严重程度的相关性分析

目的:研究狼疮性肾炎(LN)患者血清T-框蛋白21(TBX21)、干细胞因子(SCF)、趋化素(Chemerin)水平与病情严重程度的相关性。方法:将2016年2月~2019年12月我院收治的160例LN患者纳入研究,将其按照疾病活动度的不同分成活动期组92例,非活动期组68例。另取同期于我院接受体检的健康志愿者50例作为对照组。比较三组血清尿素氮(BUN)、红细胞沉降率(ESR)、补体C3、C4、TBX21、SCF及Chemerin水平,并作相关性分析。以受试者工作特征(ROC)曲线分析血清TBX21、SCF及Chemerin水平在LN中的诊断能效。结果:活动期组BUN、ESR水平均高于非活动期组,且非活动期组BUN、ESR水平均高于对照组(P<0.05);活动期组补体C3、C4水平均低于非活动期组,且非活动期组补体C3、C4水平均低于对照组(P<0.05)。活动期组血清TBX21、SCF及Chemerin水平均高于非活动期组,且非活动期组血清TBX21、SCF及Chemerin水平均高于对照组(P<0.05)。经Pearson相关性分析可得:LN患者血清TBX21、SCF及Chemerin水平与BUN、ESR水平均呈正相关,与补体C3、C4水平均呈负相关(P<0.05)。经ROC曲线分析可得:血清TBX21、SCF及Chemerin水平联合检测诊断狼疮性肾炎的曲线下面积为0.933、灵敏度为0.95、特异度为0.91均高于上述指标单独检测。结论:LN患者血清TBX21、SCF及Chemerin水平均存在明显高表达,且和患者的病情严重程度相关,临床工作中可能通过联合检测上述三项血清学指标,继而达到辅助诊断LN以及判断患者病情严重程度的目的。     

系统性红斑狼疮患者血小板参数、血脂、补体C3、C4水平与病情活动度的关系分析

摘要 目的：研究系统性红斑狼疮（SLE）患者血小板参数、血脂、补体C3、C4水平与病情活动度的关系。方法：将从2011年1月～2018年1月我院收治的100例SLE患者纳入研究,将其按照SEL疾病活动指数（SLEDAI）评分的不同分成活动组（SLEDAI评分≥10分）36例,非活动组（SLEDAI评分<10分）64例,另取同期于我院进行体检的健康志愿者100例作为对照组。比较三组各项血小板参数、血脂指标以及补体C3、C4水平,采用Pearson相关性分析SLE患者SLEDAI评分与各项指标的相关性。结果：活动组、非活动组血小板计数（PLT）、血小板压积、大血小板百分率低于对照组,且活动组PLT、大血小板百分率低于非活动组（P<0.05）。活动组、非活动组血小板平均容积（MPV）、血小板体积分布宽度（PDW）高于对照组,且活动组高于非活动组（P<0.05）。活动组、非活动组低密度脂蛋白胆固醇（LDL-C）均高于对照组,高密度脂蛋白胆固醇（HDL-C）均低于对照组（P<0.05）,活动组HDL-C低于非活动组（P<0.05）。活动组、非活动组补体C3、C4水平均低于对照组,且活动组补体C3、C4水平均低于非活动组（P<0.05）。经Pearson相关性分析发现：SLE患者SLEDAI评分与PLT、大血小板百分率、HDL-C以及补体C3、C4水平呈负相关,与MPV、PDW呈正相关（P<0.05）。结论：SLE患者血小板参数PLT、大血小板百分率、血脂指标HDL-C以及补体C3、C4水平与SLEDAI评分密切相关,可能作为SLE患者疾病活动性的评估指标。     

<Emphasis Type="Italic">Cis</Emphasis>-regulation of <Emphasis Type="Italic">IRF5</Emphasis>expression is unable to fully account for systemic lupus erythematosus association: analysis of multiple experiments with lymphoblastoid cell lines

Introduction  

Interferon regulatory factor 5 gene (IRF5) polymorphisms are strongly associated with several diseases, including systemic lupus erythematosus (SLE). The association includes risk and protective components. They could be due to combinations of functional polymorphisms and related to cis-regulation of IRF5 expression, but their mechanisms are still uncertain. We hypothesised that thorough testing of the relationships between IRF5 polymorphisms, expression data from multiple experiments and SLE-associated haplotypes might provide useful new information.     

Rates of, and risk factors for, severe infections in patients with systemic autoimmune diseases receiving biological agents off-label

Introduction

The purpose of this observational study was to analyze the rates, characteristics and associated risk factors of severe infections in patients with systemic autoimmune diseases (SAD) who were treated off-label with biological agents in daily practice.

Methods

The BIOGEAS registry is an ongoing Spanish prospective cohort study investigating the long-term safety and efficacy of the off-label use of biological agents in adult patients with severe, refractory SAD. Severe infections were defined according to previous studies as those that required intravenous treatment or that led to hospitalization or death. Patients contributed person-years of follow-up for the period in which they were treated with biological agents.

Results

A total of 344 patients with SAD treated with biological agents off-label were included in the Registry until July 2010. The first biological therapies included rituximab in 264 (77%) patients, infliximab in 37 (11%), etanercept in 21 (6%), adalimumab in 19 (5%), and 'other' agents in 3 (1%). Forty-five severe infections occurred in 37 patients after a mean follow-up of 26.76 months. These infections resulted in four deaths. The crude rate of severe infections was 90.9 events/1000 person-years (112.5 for rituximab, 76.9 for infliximab, 66.9 for adalimumab and 30.5 for etanercept respectively). In patients treated with more than two courses of rituximab, the crude rate of severe infection was 226.4 events/1000 person-years. A pathogen was identified in 24 (53%) severe infections. The most common sites of severe infection were the lower respiratory tract (39%), bacteremia/sepsis (20%) and the urinary tract (16%). There were no significant differences relating to gender, SAD, agent, other previous therapies, number of previous immunosuppressive agents received or other therapies administered concomitantly. Cox regression analysis showed that age (P = 0.015) was independently associated with an increased risk of severe infection. Survival curves showed a lower survival rate in patients with severe infections (log-rank and Breslow tests < 0.001).

Conclusions

The rates of severe infections in SAD patients with severe, refractory disease treated depended on the biological agent used, with the highest rates being observed for rituximab and the lowest for etanercept. The rate of infection was especially high in patients receiving three or more courses of rituximab. In patients with severe infections, survival was significantly reduced. Older age was the only significant predictive factor of severe infection.     

Polymorphisms in STK17A gene are associated with systemic lupus erythematosus and its clinical manifestations

Systemic lupus erythematosus (SLE) is an autoimmune disorder with several clinical manifestations. SLE etiology has a strong genetic component, which plays a key role in disease's predisposition, as well as participation of environmental factors, such and UV light exposure. In this regard, we investigated whether polymorphisms in STK17A, a DNA repair related gene, encoding for serine/threonine-protein kinase 17A, are associated with SLE susceptibility. A total of 143 SLE patients and 177 healthy controls from Southern Brazil were genotyped for five STK17A TagSNPs. Our results indicated association of rs7805969 SNP (A and G/A genotype, OR = 1.40 and OR = 1.73, respectively) with SLE predisposition and the following clinical manifestations: arthritis, cutaneous and immunological alterations. When analyzing haplotypes distribution, we found association between TGGTC, TAGTC and AAGAT haplotypes and risk to develop SLE. When considering clinical manifestations, the haplotypes TGGTT and TAGTC were associated with protection against cutaneous alterations and the haplotype TAGTC to hematological alterations. We also observed association between SLE clinical manifestations and ethnicity, with the European-derived patients being more susceptible to cutaneous and hematological alterations.     

The association between Interleukin (IL)-4 gene intron 3 VNTR polymorphism and alopecia areata (AA) in Turkish population

Objective

Alopecia areata (AA) is hypothesized to be an organ-specific autoimmune disease of hair follicles mediated by T cells. As immunological and genetic factors have been implicated in the pathogenesis of AA, the purpose of the present study was to investigate possible associations between the functional Interleukin (IL)-4 gene intron 3 VNTR polymorphism and AA susceptibility and disease progression in Turkish population.

Methods

The study group consisted of 116 unrelated patients with AA and 125 unrelated healthy controls. Genomic DNA was isolated and IL-4 gene 70 bp VNTR polymorphism determined by using polymerase chain reaction (PCR) with specific primers.

Results

No association was observed between AA patients and controls according to genotype distribution (p = 0.051). The allele distribution of IL-4 gene intron 3 VNTR polymorphism was statistically different between AA patients and control group (p = 0.026). The frequency of P1 allele in patients was significantly higher than that in the control group. When the P2P2 genotype was compared with P1P2 + P1P1 genotypes, a statistically significant difference was observed between patients and controls (p = 0.036). Intron 3 VNTR polymorphism in the IL-4 gene was found to be associated with AA susceptibility in Turkish population.

Conclusion

The results suggest that IL-4 VNTR polymorphism in the intron 3 region may be a risk factor for the development of AA among Turkish population. This is the first to report that intron 3 VNTR polymorphism in the IL-4 gene is associated with AA susceptibility.     

人BAFF转基因斑马鱼的构建及早期免疫基因表达检测

目的建立人BAFF转基因斑马鱼模型,探讨其在自身免疫性疾病发病中的作用。方法RT-PCR法由人淋巴瘤细胞克隆了人BAFF基因全长855bp蛋白编码区域,构建表达人BAFF重组质粒Tol2-hBAFF,体外细胞转染并通过免疫印迹法验证蛋白表达。重组载体经显微注射斑马鱼受精卵后,GFP荧光跟踪并筛选阳性鱼。qPCR法检测早期免疫相关基因表达情况。结果人BAFF-GFP融合蛋白可成功表达,利用Tol2-hBAFF重组质粒显微注射斑马鱼受精卵可获得表达人BAFF的转基因斑马鱼,且表达人BAFF斑马鱼1dpf胚胎中TCRAC明显高表达,而Ikaros则表达量显著降低,表明在斑马鱼胚胎中表达人BAFF蛋白会造成早期淋巴系统中基因的过早表达。结论建立的表达人BAFF的转基因斑马鱼,可为系统性红斑狼疮等与BAFF功能亢进密切相关的自身免疫性疾病的治疗,及相关机制研究提供一种具有诸多优点的新型工具。     

Changes of frequency and expression level of CD161 in CD8+ T cells and natural killer T cells in peripheral blood of patients with systemic lupus erythematosus

Immunologic abnormalities of natural killer (NK) cells and T cells play a role in the pathogenesis of systemic lupus erythematosus (SLE). CD161 is expressed on most of the NK cells and on some T cells. The quantities of CD161-expressing cells and expression levels of CD161 were analyzed in T cells and NK cells from patients with SLE compared with normal controls. The expression of CD161 on NK cells, NKT cells, CD4⁺ T cells, and CD8⁺ T cells in peripheral blood from patients with inactive SLE and active SLE, and from the normal controls group were determined using flow cytometry. The frequency and expression level of CD161 in the lymphocyte subsets and its relationship with the quantity of regulatory T cells, anti-double stranded DNA antibody, and the titer of antinuclear antibody were evaluated. Both the percentages of the CD161⁺ subpopulation and the mean fluorescence intensities (MFIs) of CD161 in CD8⁺ T cells and NKT cells decreased significantly in SLE patients compared with normal controls (P < .001). The CD161 expression in CD8⁺ T cells and NKT cells also decreased in the anti-dsDNA (+) group (P < .05). The counts of Treg cells were lower in SLE patients and were weakly correlated with the percentage of the CD161 subpopulation (r = 0.229, P = .016) and the MFIs of CD161 expression in CD8⁺ T cells (r = .232, P = .014). The frequencies and levels of CD161 expression on CD8⁺ T cells and NKT cells were reduced in SLE patients, suggesting that an abnormality of these cells was related to the pathogenesis of SLE.