系统性红斑狼疮的分子遗传学研究

系统性红斑狼疮（systemiclupuserythematosus,SLE）是一种复合性多基因的自身免疫性疾病。遗传因素在SLE易感性方面起重要的作用。该文介绍目前已知几个与SLE的易感性有关的遗传基因。通过对这些基因研究,有利于阐明SLE的发病机制,进一步为SLE的预防、诊断和治疗提供重要的依据。     

钙调神经磷酸酶-活化T细胞核因子与系统性红斑狼疮

系统性红斑狼疮是一种以多种自身抗体产生为特点的侵犯多系统多脏器的自身免疫性疾病,其发病机制尚未明确,目前认为T淋巴细胞异常是SLE的发病的关键.钙调神经磷酸酶-活化T细胞核因子信号通路作为T细胞内重要的生物信号转导通路,在T细胞活化中起到调节枢纽的作用,了解CaN/NFAT信号途径在SLE中的作用及目前相关主要治疗药物的研究现状可为SLE的基础研究及临床治疗提供依据.     

Current and novel therapeutics in the treatment of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with significant clinical heterogeneity. Recent advances in our understanding of the genetic, molecular, and cellular bases of autoimmune diseases and especially SLE have led to the application of novel and targeted treatments. Although many treatment modalities are effective in lupus-prone mice, the situation is more complex in human subjects. This article reviews the general approach to the therapy of SLE, focusing on current approved therapies and novel approaches that might be used in the future.     

系统性红斑狼疮自身抗体研究进展

经化学修饰的组织抗原,与正常组织成分有交叉反应的外来抗原、隔绝的体内自身成分及低分化的组织抗原等在一定条件下可刺激机体组织产生自身抗体.某些自身抗体因对系统性红斑狼疮(SLE)的判断具有高度特异性,已成为诊断SLE的血清指标或特异性抗体,有些自身抗体与疾病的活动性有相关性.因此,测定自身抗体有助于SLE的诊断,并对疾病的活动程度,观察治疗效果,指导临床用药具有重要的临床意义.     

DNaseI in pathogenesis of systemic lupus erythematosus

The aberrant activation of lymphocytes causes autoimmune diseases. Although there are many candidate molecules that are involved in the pathogenesis of autoimmune diseases, it still remains unclear how immunological tolerance is disturbed in each autoimmune disease. Recently, we discovered two patients suffering from systemic lupus erythematosus (SLE) with a defect in the DNaseI gene locus. According to immunological and genetic analysis, we hypothesize that defective antigen clearance, especially accumulation of nucleosomal antigens, is responsible for the development of SLE. In this article, we review the pathogenesis of SLE from the view of defective self-antigen clearance due to low DNaseI activity.     

B-cell-targeted therapies in systemic lupus erythematosus

Autoreactive B cells are one of the key immune cells that have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). In addition to the production of harmful auto-antibodies (auto-Abs), B cells prime autoreactive T cells as antigen-presenting cells and secrete a wide range of pro-inflammatory cytokines that have both autocrine and paracrine effects. Agents that modulate B cells may therefore be of potential therapeutic value. Current strategies include targeting B-cell surface antigens, cytokines that promote B-cell growth and functions, and B- and T-cell interactions. In this article, we review the role of B cells in SLE in animal and human studies, and we examine previous reports that support B-cell modulation as a promising strategy for the treatment of this condition. In addition, we present an update on the clinical trials that have evaluated the therapeutic efficacy and safety of agents that antagonize CD20, CD22 and B-lymphocyte stimulator (BLyS) in human SLE. While the results of many of these studies remain inconclusive, belimumab, a human monoclonal antibody against BLyS, has shown promise and has recently been approved by the US Food and Drug Administration as an indicated therapy for patients with mild to moderate SLE. Undoubtedly, advances in B-cell immunology will continue to lead us to a better understanding of SLE pathogenesis and the development of novel specific therapies that target B cells.     

Ets-1在系统性红斑狼疮中的研究进展

系统性红斑狼疮(SCE)是一种典型的系统性自身免疫性疾病,其发病机制尚未明确,其中T、B细胞功能异常起着重要作用.转录因子Ets-1作为SLE的易感基因之一在淋巴细胞分化与细胞因子调节上起重要作用.Ets-1除影响B细胞分化和功能外,对T细胞的生存、增殖、发育和功能起重要作用.虽然Ets-1在SLE发病中的确切机制仍尚未明确,但越来越多的研究表明Ets-1在SLE的发生发展中起着重要作用.     

Expression of membrane-bound human leucocyte antigen-G in systemic sclerosis and systemic lupus erythematosus

Human leucocyte antigen-G (HLA-G) is a nonclassical class I major histocompatibility complex (MHC) molecule characterized by complex immunoregulatory and tolerogenic functions. Membrane-bound HLA-G is expressed on the surface of different cell populations in both physiological and pathological conditions. Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by widespread tissue fibrosis, vascular lesions and immunological alterations. Systemic lupus erythematosus is the prototypic systemic autoimmune disease affecting virtually any organ system, such as skin, joints, central nervous system, or kidneys. In SSc and SLE patients, the membrane expression of HLA-G on monocytes (0.88 ± 1.54 and 0.43 ± 0.75, respectively), CD4+ (0.42 ± 0.78 and 0.63 ± 0.48, respectively), CD8+ (2.65 ± 3.47 and 1.29 ± 1.34, respectively) and CD4+ CD8+ double-positive cells (13.87 ± 15.97 and 3.79 ± 3.11, respectively) was significantly higher than in healthy controls (0.12 ± 0.07; 0.01 ± 0.01; 0.14 ± 0.20 and 0.32 ± 0.38, respectively) (p < 0.0001). Our results show that in SSc and SLE the membrane expression of HLA-G by different subpopulations of peripheral blood mononuclear cells (PBMC) is increased, suggesting a potential role of HLA-G molecules in the complex immunological pathogenesis of these two autoimmune disorders.     

系统性红斑狼疮患者血清泌乳素水平的检测及其临床意义

目的：探讨系统性红斑狼疮(SLE)患者血清泌乳素(PRL)水平检测的临床意义。方法：应用免疫放射量度分析法测定了75例SEE患者与25例健康人血清PRL水平。结果：SLE患者血清PRL水平明显高于正常对照组，且活动期升高更明显；高泌乳素血症(HPRL)发生率为40％，伴HPRL的患者肾损害发生率明显高于血清PRL正常者；血清PRL水平与SLEDM评分、抗ds-DNA抗体滴度倒数呈正相关，与C3呈负相关。结论：SLE患者血清PRL水平升高与病情活动相关，其检测可作为监测狼疮病情活动性的指标之一；血清PRL水平升高与肾脏损害相关，提示PRL可能在SLE肾损害中起作用。     

Hepatitis B antigen and systemic lupus erythematosus

Summary Sera from 22 patients with systemic lupus erythematosus (SLE) were examined for the presence of hepatitis B antigen (HBsAg) by a complement fixation (CF) test, by an immunoelectrophoretic method (counterelectrophoresis-CEP), and by radioimmunoassay (RIA). The sera from 8 patients gave positive results using CF. However, the same sera and sera from 28 additional SLE patients, when tested with CEP and RIA, were not shown to contain HBsAg.Additional studies were carried out in order to characterize the factor responsible for the false positive CF of the 8 SLE sera. It was shown that the sera also fixed complement in presence of normal serum previously submitted to freezing and thawing or heating at 65°C. The complement fixing factor was readily absorbed by aggregated IgG but not by insolubilized HBsAg. Complement fixation was strongly diminished by 2-mercaptoethanol treatment of SLE serum. It thus appears that the false positive reactions for the presence of HBsAg obtained by CF are due to the occurrence of anti-antibodies reacting with aggregated IgG. There is no increased incidence of HBsAg in the serum of SLE patients.This work was supported by the Dubois-Ferrière Dinu Lipatti Foundation and the Swiss National Fund (grant no. SR 3260-0.74).     

Impaired T-cell activation in patients with systemic lupus erythematosus

Interleukin-2 (IL-2) production was studied in T lymphocytes from 32 patients with systemic lupus erythematosus (SLE) and 27 healthy volunteers. The IL-2 production by phytohemagglutinin (PHA)-stimulated cells from SLE patients was significantly depressed compared to control values, with a correlation between degree of depression and disease activity. The depressed IL-2 production by SLE T cells are largely reversed by the addition of either phorbol ester (PMA) or partially by a calcium ionophore. SLE T cells had significantly lower peak increases in intracellular free calcium ([Ca²⁺]_i) than controls after stimulation by PHA or by a monoclonal antibody against the CD3 antigen. This abnormality was found even in T cells from patients with mild disease activity or in those whose T cells produced normal amounts of IL-2. Calcium ionophore produced similar increases in [Ca²⁺]_i in SLE patients as in normals. These results suggest that a major component of the defect responsible for decreased IL-2 production by SLE lymphocytes is proximal to protein kinase C activation and may involve impaired signal transduction after activation of the antigen receptor complex.     

系统性红斑狼疮血液系统损害的特点及相关分析

目的 探讨首次诊断系统性红斑狼疮(SLE)患者的血液系统损害的特点及与疾病活动性之间的关系.方法 纳入90例初次住院并诊断SLE的患者,根据有无血液系统异常分为有血液损害组和无血液损害组,收集并分析其临床资料及相关的实验室指标,采用x2检验进行统计学分析.结果 ①90例SLE患者中77例(85.56％)存在血液系统损害的患者均有不同程度的疾病活动度,且疾病活动程度越大,其血液系统损害的概率越高.两组之间比较,有血液系统损害组的疾病活动度明显高于无血液系统损害的活动度的发生率,差异有统计学意义(x2=-3.461,P=0.001);②有血液损害患者临床表现如皮疹、黏膜溃疡、浆膜炎、关节炎、肾脏损害、神经精神症状等方面的发生率均高于无血液损害组,但无统计学意义(P＞0.05).结论 血液系统损害与狼疮的活动性之间具有明显的相关性,首次发现并确诊为SLE的患者是否出现血液系统损害与是否伴有皮疹、黏膜溃疡、浆膜炎、关节炎、肾脏损害、神经精神症状等方面无相关性.     

Immunogenetics of systemic lupus erythematosus: A comprehensive review

Our understanding of the genetic basis of systemic lupus erythematosus has progressed rapidly in recent years. While many genetic polymorphisms have been associated with disease susceptibility, the next major step involves integrating these genetic polymorphisms into the molecular mechanisms and cellular immunology of the human disease. In this review, we summarize some recent work in this area, including the genetics of the type I IFN response in SLE, including polygenic and monogenic factors, as well as epigenetic influences. Contributions of both HLA and non-HLA polymorphisms to the complex genetics of SLE are reviewed. We also review recent reports of specific gene deficits leading to monogenic SLE-like syndromes. The molecular functions of common SLE-risk variants are reviewed in depth, including regulatory variations in promoter and enhancer elements and coding-change polymorphisms, and studies which are beginning to define the molecular and cellular functions of these polymorphisms in the immune system. We discuss epigenetic influences on lupus, with an emphasis on micro-RNA expression and binding, as well as epigenetic modifications that regulate the expression levels of various genes involved in SLE pathogenesis and the ways epigenetic marks modify SLE susceptibility genes. The work summarized in this review provides a fascinating window into the biology and molecular mechanisms of human SLE. Understanding the functional mechanisms of causal genetic variants underlying the human disease greatly facilitates our ability to translate genetic associations toward personalized care, and may identify new therapeutic targets relevant to human SLE disease mechanisms.     

定量蛋白质组学在系统性红斑狼疮疾病中的应用

定量蛋白质组学的目的是对复杂的混合体系中所有的蛋白质进行鉴定,并对蛋白质量的变化进行测定,是当前生物科学研究中的重要内容.近年来,以质谱为基础的定量蛋白质组学技术在分析蛋白质组或亚蛋白质组方面取得令人瞩目的成就.对寻找和发现疾病中的特异标记物,对疾病的预防、诊断及疗效的监测方面具有重要作用.当前定量蛋白质组学在系统性红...     

Anti-ribosomal ribonucleoprotein autoantibodies in systemic lupus erythematosus

Sera from systemic lupus erythematosus (SLE) patients giving a fluorescent ribosomal pattern on tissue and cell preparations also showed precipitating autoantibodies against purified rat liver ribosomes. Ribosomal antigen is also present in rabbit thymus cellular extract (RTE), since the same sera gave precipitin lines against RTE in identity with ribosomes. Immunofluorescent staining was completely inhibited by serum absorption with ribosomes or with RTE. However ribosomal RNA and RNase or trypsin-treated ribosomes failed to react with these autoantibodies as demonstrated in immunoabsorption and immunodiffusion studies. These data suggest that these sera contain autoantibodies directed against some antigenic site composed of a portion of both RNA and ribosomal protein. Ribosomal autoantibodies were detectable at a low frequency in SLE patients characterized by an active disease and renal involvement.     

Environment and systemic lupus erythematosus: An overview

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology that manifests as a pleomorphic systemic disease mainly affecting females. The variety of autoantibodies found in the serum of patients indicate that SLE is an autoimmune disease, but the mechanisms leading to the aberrant responses are not clearly understood although it is thought that a number of genetic and environmental factors may be involved. Environmental (or non-genetic) exposures could include infectious agents, chemicals or other compounds capable of modulating immune responses such as occupational/environmental pollutants or drugs, and behavioural factors such as smoking and diet. Environmental exposures may lead to the production of autoreactive T cells and autoantibodies, the stimulation of pro- and antiinflammatory cytokines, and target end-organ damage, but are not so convincing as agents causing SLE. Exposure to viruses increases antibody titres, but these may be the result of polyclonal B cell activation. The amount and timing of exposure to different environmental factors may play a significant and complex role in the pathogenesis of SLE and other autoimmune diseases. A better understanding of the etiopathogenetic mechanism of SLE is required in order to clarify the multiple interactions between environmental exposures and genetic factors.     

The B-cell activation pathway in human systemic lupus erythematosus: Imbalancedin vitro production of lymphokines and association with serum analytical findings

Recent knowledge of B-lymphocyte physiology has clarified the role of T cell-derived lymphokines in clonal proliferation and differentiation of B-cell responses. Lymphokine production was analyzed in 19 systemic lupus erythematosus (SLE) patients and sex- and age-matched controls in relation to clinical activity and steroid treatment. Whenin vitro production of interleukin-2 (IL-2) and B-cell growth factor (BCGF) was tested, both activities were found to be diminished in the group of patients (P<0.01), while B-cell differentiation factor (BCDF) activity was higher in this group with respect to normal controls (P<0.01). Interestingly enough, thisin vitro BCDF synthesis was positively correlated with clinical activity regardless of low-dose steroid treatment. A correlation was also found between BCDF production and the levels of IgG (r=0.64,P<0.01), anti-DNA antibodies (r=0.52,P<0.05), and the IgG/IgM ratio (r=0.7,P<0.01) in serum. Implications of these abnormal T-lymphocyte functions in SLE with respect toin vivo B-cell function are discussed.     

Cytotoxic responses to alloantigens in systemic lupus erythematosus

We have studied the ability of the peripheral mononuclear cells (MNC) from patients with systemic lupus erythematosus (SLE) to generate a cytotoxic (CML) response against alloantigens. CML responses in SLE patients were significantly lower than those of normal individuals. Mixed lymphocyte reaction (MLR) assays conducted in parallel in these patients were decreased but to a lesser extent. Some of the patients exhibited parallel decreases in both CML and MLR tests, while others showed decreased CML responses but normal MLR responses. Optimal CML responses in SLE patients did not occur at a different time point than in the normals. Plasma from most SLE patients tested did not have an effect on CML and MLR responses of normal MNC; the plasma of only one patient consistently decreased the CML of normal cells. Depletion of adherent cells from MNC of SLE patients by Sephadex G-10 fractionation allowed better CML and MLR responses. Low CML responses in patients with SLE were associated with increased disease activity and increased serum DNA binding. No association between MLR responses in SLE patients and any of the above parameters was detected. SLE patients not having received any cytotoxic treatment exhibited the lowest CML responses, while these under treatment or treated in the past had higher, although not normal, responses. MLR responses were not affected by the treatment status of the patients.