Preferential Recognition of Peroxynitrite Damaged Thymidine-Monophosphate by Anti-DNA Autoantibodies in Systemic Lupus Erythematosus

This study was undertaken to investigate the role of peroxynitrite (ONOO^?) modified thymine-5′-monophosphate (TMP) in the generation of anti-DNA autoantibodies in patients with systemic lupus erythematosus (SLE). TMP was exposed to ONOO^? in vitro and challenged in vivo. TMP and ONOO^?-modified-TMP were found to be nonimmunogenic in rabbits. TMP-linked-BSA and ONOO^?-modified-TMP-BSA induced high titer antibodies. Induced antibodies against ONOO^?-TMP-BSA show crossreactions with nucleic acids conformers. A high degree of specific binding by SLE autoantibodies with ONOO^?-TMP-BSA was observed. Our novel results provide an important insight into the immunological basis of anti-DNA autoantibodies generation in SLE.     

Toll-like receptors in autoimmunity with special reference to systemic lupus erythematosus

The Toll-like receptor (TLR) family plays a fundamental role in host innate immunity by mounting a rapid and potent inflammatory response to pathogen infection. TLRs recognize distinct microbial components and activate intracellular signaling pathways that induce expression of host inflammatory genes. Several studies have indicated that TLRs are implicated in many inflammatory and immune disorders. Extensive research in the past decade to understand TLR-mediated mechanisms of innate immunity has enabled pharmaceutical companies to begin to develop novel therapeutics for the purpose of controlling an inflammatory disease. The roles of TLRs in the development of autoimmune diseases have been studied. TLR7 and TLR9 have key roles in production of autoantibodies and/or in development of systemic autoimmune disease. It remains to be determined their role in apoptosis, in the pathogenesis of RNA containing immune complexes, differential expression of TLRs by T regulatory cells.     

系统性红斑狼疮外周血单个核细胞cFLIP—L mRNA和cFLIP—S mRNA表达的研究

目的探讨系统性红斑狼疮（system lupus erythematosus,SLE）患者外周血单个核细胞（peripheral blood monouuclear cells,PBMC）中细胞型Fas相关死亡域样白介素-1β转换酶抑制蛋白（cFLIP）表达的意义。方法应用半定量RT—PCR方法检测38例SLE患者和21名正常人PBMC中cFLIP—L mRNA和cFLIP—S mRNA的表达水平,并与SLE疾病活动指数（SLEDAI）评分进行相关性分析。结果①SLE患者PBMC中cFLIP—L mRNA和cFLIP—S mRNA表达水平均明显高于正常对照组（P〈0．01）;SLE患者活动组cFLIP—L mRNA表达水平显著高于非活动组（P〈0．05）,cFLIP—S mRNA表达水平在SLE患者活动组与非活动组之间没有显著性差异（P〉0．05）。②SLE患者cFLIP—L mRNA表达水平与SLEDAI评分呈正相关（r=0．423,P〈0．01）;而eFLIP—S mRNA表达水平与SLEDAI评分无明显相关性（r=0．270,P〉0．05）。结论cFLIP—L mRNA和cFLIP—S mRNA可能在SLE发病机制中起重要作用。     

Cytological Aspects of Pleural, Peritoneal and Pericardial Fluids From Patients With Systemic Lupus Erythematosus

Serous effusions of nine of 33 patients with systemic lupus erythematosus contained lupus erythematosus (LE) cells, identifiable in Papanicolaou-stained smears, wet films stained with toluidine blue, and cell blocks stained with haematoxylin and eosin. Specimens in which LE cells were found contained at least a moderate number of polymorphonuclear neutrophilic leucocytes. Most specimens containing LE cells also contained cells that resembled LE cells (tart cells), which appeared to be small macrophages that had phagocytosed a non-homogenized nucleus of a cell that had undergone degeneration. In 34 years of cytologic practice we have recognized LE cells in serous effusions only from patients who were already diagnosed as having systemic lupus erythematosus.     

C-reactive protein functions as a negative regulator of macrophage activation induced by apoptotic DNA

C-reactive protein (CRP), an acute-phase protein with an ability to bind to nuclear antigen, has been reported to regulate cytokine secretion and modulate immune responses. We previously reported that activated syngeneic lymphocyte-derived apoptotic DNA (apopDNA) could induce macrophage activation and contribute to the initiation and progression of lupus nephritis. It is reasonable to hypothesize that CRP might regulate apopDNA-induced macrophage activation. Herein, CRP was shown to promote macrophage-mediated apopDNA uptake by binding to apopDNA (CRP/apopDNA complex). Notably, CRP/apopDNA treatment inhibited the production of inflammatory cytokines and chemokines by macrophages which could be induced by apopDNA alone. Further coculture and transwell studies revealed that CRP/apopDNA-induced macrophages prohibited apopDNA-induced macrophage activation in an IL-10 dependent manner. These results provide insight into the potential mechanism of CRP regulatory activity in macrophage activation induced by apopDNA in the context of lupus nephritis and other autoimmune diseases.     

Proteomic profiling of urine: implications for lupus nephritis

Introduction: Lupus nephritis (LN) is a common and significant manifestation, affecting 60% of adults and 80% of children with systemic lupus erythematosus, with up to 30% of patients progressing to end stage renal disease. There remains an unmet need for non-invasive markers of disease activity, damage, and response to therapy. In addition, non-invasive biomarkers that predict therapeutic efficacy are needed to enable cost-effective clinical trials of novel agents.

Areas covered: This review examines the methodological aspects of urinary proteomics, the role of proteome profiling in identifying promising urinary biomarkers in LN, and the translation of research findings into clinically useful tools in the management of LN.

Expert opinion: Targeted and unbiased proteomics have identified several promising urinary biomarkers that predict LN activity, damage (chronicity), and response to therapy. In particular, a combination of biologically plausible urinary biomarkers termed as RAIL (Renal Activity Index for Lupus) has emerged as an excellent predictor of LN activity as well as response to therapy, being able to predict efficacy within 3 months of therapy. If validated in additional large prospective studies, the RAIL biomarkers will transform the care of patients with LN, allowing for a personalized and predictive approach and improved outcomes.     

Systemic Lupus Erythematosus-associated Neutrophil Cytosolic Factor 2 Mutation Affects the Structure of NADPH Oxidase Complex

In a case-control association study with 3716 North Americans of Hispanic descent and 4867 North Americans of European descent, we show that the associations of rs17849502 (NCF2 His-389 → Gln) and rs13306575 (NCF2 Arg-395 → Trp) with systemic lupus erythematosus are independent. We have shown that His-389 → Gln disrupts the binding of NCF2 to the ZF domain of VAV1, resulting in decreased NADPH oxidase activity. With respect to Arg-395 → Trp, using protein docking and structure analyses, we provide a model for the involvement of this mutation in the structure and function of the NADPH oxidase complex. This model assigns a central role to Arg-395 in the structure and stability of the quaternary NCF2/NCF4/VAV1/RAC1 NADPH oxidase complex. Arg-395 stabilizes the C-terminal tail of NCF4 and the conformation of NCF2 loop 395–402, which in turn stabilize the evolutionarily conserved interactions of NCF2/NCF4 with the DH domain of VAV1 and RAC1 region 120–137. Our findings are consistent with the high levels of conservation of all of the residues involved in these interactions.     

Th1、Th2和Th17型细胞在类风湿性关节炎和系统性红斑狼疮中的活化特点

探讨Th1、Th2和Th17型细胞在类风湿性关节炎(RA)和系统性红斑狼疮(SLE)发病机制中的作用。收集37例RA患者、25例SLE患者和34例健康人的抗凝血,应用ELISA检测血清中IFN-γ、IL-10和IL-17的水平。与健康对照组比较,RA和SLE患者血清中IFN-γ的水平均具有统计学意义(P<0.05);SLE患者IL-10水平出现有意义的升高(P<0.05);而RA患者IL-17的升高具有统计学意义(P<0.05)。由此提示Th1、Th2和Th17细胞在自身免疫性疾病中均发挥不同的重要作用。     

利用cDNA-RDA技术研究BXSB狼疮小鼠差异表达的基因

利用近年来发展起来的代表性差异分析cDNA-RDA(cDNA-representational difference analysis)技术筛选BXSB红斑狼疮小鼠发病相关基因.发现了3个新的表达序列标签(EST)片段,在GenBank中的登录号分别为AF060113, AF060111, AF060110,同时发现了一些已知与自身免疫病相关的基因如逆转录病毒衣壳蛋白、Line-1逆转录酶等.通过RDA技术可能发现系统性红斑狼疮发病相关新基因,为自身免疫病的理论研究提供新的思路和方法.     

血清胱抑素C作为新型肾功指标在狼疮肾炎中的临床意义

目的:探讨血清胱抑素C在狼疮肾炎的诊断及治疗监测中的临床意义。方法:检测106名狼疮肾炎患者的血清胱抑素C(sCysC)、血清肌酐(sCr)、尿素氮(BUN)、肾小球滤过率(GFR) 24小时尿蛋白(uTP)、血清白蛋白(sAlb)、C-反应蛋白(CRP)水平,分析sCysC与上述指标的相关性及其在治疗过程中的动态变化,并与传统肾功能指标(sCr、BUN)进行比较。结果:①治疗前,血清sCysC水平与uTP、sAlb、SLEDAI、CRP均显著相关,且优于sCr及BUN。②治疗中血清sCysC水平与uTP、sAlb的相关性均优于sCr及BUN。③血清sCysC水平随激素及免疫抑制剂治疗显著改善这一趋势见于BUN并未见于Scr;激素及CTX治疗结束后血清sCysC水平显著改善这一趋势见于Scr并未见于BUN。④治疗前/sCr与sCysC联合计算所得eGFR与各项指标相关性最高。结论:sCysC在狼疮肾炎早期肾损害诊断、治疗过程以及监测疗效的敏感性均优于传统sCr和BUN。sCysC单独及sCysC联合sCr计算的GFR均优于单独sCr计算获得的GFR。sCysC在LN中不仅可作为肾功能的新型评价标志物,可能也作为炎症反应的标志物。     

Special Features of the DNA-Hydrolyzing Activity of the Antibodies in Systemic Lupus Erythematosus

Two types of IgG anti-DNA antibodies exhibiting DNA-hydrolyzing activity have been isolated from blood serum of patients with systemic lupus erythematosus. This DNase activity of antibodies differs from serum DNases by the non-processive mode, temperature resistance, pH optimum, and the rate of DNA hydrolysis. It is suggested that the anti-DNA antibody molecule possessing DNase activity contains two sites: one site determines specificity of antibody-DNA interaction, whereas the other is responsible for manifestation of the catalytic activity.     

Serum protein oxidation and apolipoprotein CIII levels in people with systemic lupus erythematosus with and without nephritis

Increased oxidative stress is a hallmark of the autoimmune disease systemic lupus erythematosus (SLE). This study compares serum protein oxidation levels in SLE patients without and with renal involvement (lupus nephritis); the latter have a significantly poorer prognosis. Similar increases in protein carbonyls and decreases in protein thiols were observed in both SLE groups compared to controls. Protein carbonyl distribution, determined by Western blotting of 2D gels, was similar in both SLE groups, suggesting factors other than oxidation also play a role in SLE complications. 2D electrophoresis examined the serum proteome further. Six proteins were significantly decreased in non-renal SLE patients compared to controls; five were identified by mass spectrometry, including one isoform of pro-atherogenic apoCIII. Total apoCIII levels (assessed by ELISA) in lupus nephritis patients were significantly elevated compared to controls or non-renal SLE patients. Thus, levels of oxidized proteins and apoCIII may be useful biomarkers in SLE studies.     

Update on differences between childhood-onset and adult-onset systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease and occurs worldwide in both children and adults. The estimated annual incidence among children is 2.22/100,000 and among adults is 23.2/100,000 in the United States. There is increasing understanding about differences in disease manifestations, medication use, and disease severity between those with childhood-onset SLE as compared with adult-onset SLE. Children have a more fulminant disease onset and course than adults with SLE, resulting in two to three times higher mortality. In future years, we anticipate more insight into the genetics between childhood-onset SLE and adult-onset SLE to help delineate the best therapies for both subsets of patients.     

核周型抗中性粒细胞胞浆抗体在狼疮性肾炎中的临床意义

目的:探讨核周型抗中性粒细胞胞浆抗体( P-ANCA)在狼疮性肾炎(LN)中的临床意义.方法:应用酶联免疫吸附分析( ELISA)的方法,检测92例LN患者血清中的P-ANCA及其他自身抗体的水平,并进一步分析P-ANCA与LN的临床表现以及辅助检查结果之间的关系.结果:P-ANCA在LN中的阳性率是21.8 ％(20/92),P-ANCA阳性组LN患者合并颧部红斑、皮肤血管炎、贫血以及补体C3偏低的频率均显著高于P-ANCA阴性组LN患者(P＜0.05).结论:P-ANCA在LN中的阳性率为21.8％,且P-ANCA与SLE特定的临床表现相关,提示P-ANCA可能参与了LN的发病过程.     

Systemic lupus erythematosus associated with primary large cell carcinoma of the lung

The association between systemic lupus erythematosus (SLE) and malignancy has been controversial in the literature. We report a case of lung cancer in a 50-year-old woman with a 4-year history of SLE. She underwent surgery at a pathological stage of T2N2M0, but she eventually died of rapid recurrence of the cancer in the abdomen resulting in massive haemorrhage from the inferior vena cava (IVC). Immunological disorders related to SLE are thought to contribute to rapid progression of the malignancy.     

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。     

以假性肠梗阻为首发表现的系统性红斑狼疮2例

目的:探讨系统性红斑狼疮(SLE)罕见的临床并发症——假性肠梗阻(IPO)的临床特点。方法:回顾性分析2例SLE合并IPO患者的发病情况、临床表现、实验室检查、病程、治疗及预后等临床特点。结果:两例均以肠梗阻为首发表症,均无SLE的特异性表现,且均有肾脏、血液系统的损害,抗抗核抗体、抗dsDNA均为阳性,病程较短,其中一例死于肾功能衰竭。结论:IPO是SLE的一个罕见但严重的并发症,以肠梗阻为首发表症的SLE易被误诊,合并IPO的SLE患者病情较重且常伴有其他脏器受累,病死率较高,免疫学检查有助于早期诊断,及早诊断及大剂量激素联合丙种球蛋白治疗对于缓解病情、改善预后意义重大。     

Features of autoantigens

The major cellular antigens recognized by autoantibodies in SLE and other systemic autoimmune diseases have been identified and characterized over the past 25 years. The pioneering studies of Eng Tan demonstrate the importance of autoantibodies as diagnostic markers. However, why certain autoantibodies, such as anti-Sm, are pathognomonic of SLE, while others are markers of othe autoimmune disease subsets, remains unanswered. This central question continues to drive much current research into the pathogenesis of SLE. Features of the autoantigens recognized by autoantibodies may provide important clues to the causes of lupus. Most autoantigens in systemic autoimmunity are multicomponent nucleoprotein complexes. These particles are encountered by the immune system as units, resulting in the tandem production of autoantibodies recognizing several components of the same complex. However, the intermolecular-intrastructural spreading of autoimmunity is regulated by mechanisms that at present are defined poorly. Also unexplained is the observation that the antigenic determinants recognized by autoantibodies are restricted and frequently correspond to active sites or functional domains. Analysis of experimental models of autoimmunity suggests that altering the structure of autoantigens, due to abnormal protein-protein interactions, hapten binding, altered degradation, or other mechanisms, could help to explain both the restricted patterns of autoantibody spreading and the selective targeting of antigenic sites. This may be a worthwhile area for further investigation of the pathogenesis of systemic autoimmune diseases.Abbreviations MCTD mixed connective tissue disease - PM/DM polymyositis / dermatomyositis - SLE Systemic lupus erythematosus - SSc systemic sclerosis - SVT simian virus 40 large T antigen