Dendritic cells and the immunopathogenesis of systemic lupus erythematosus

Over the last decade, the role of dendritic cells (DCs) in the immunopathogenesis of systemic lupus erythematosus (SLE) has become apparent. As unique mediators of both tolerance and immunity, aberrant myeloid and plasmacytoid DC function can promote autoimmune responses via a number of mechanisms and proinflammatory pathways. This review provides an overview of DC function, the potential role of DCs in promoting autoimmune responses in SLE, and how other abnormalities in lupus can lead to an enhanced engagement of DCs in immune responses. How medications used to treat SLE and other autoimmune conditions may exert effects on DCs is also explored.     

Endogenous humoral autoreactive immune responses to apoptotic cells: Effects on phagocytic uptake,chemotactic migration and antigenic spread

Enhanced cell death and deficient clearance of cellular debris are thought to contribute to increased self‐antigen exposure in systemic autoimmune disease. To investigate the characteristics of early humoral autoimmune responses, six monoclonal antibodies were generated from two autoimmune prone strains of mice. All antibodies specifically bound the surface of late‐stage apoptotic cells. Similar antibody reactivities were present in the sera of patients with systemic lupus erythematosus. While IgM antibodies significantly reduced the phagocytic uptake of apoptotic thymocytes, IgG antibodies enhanced uptake. Poly‐reactivity was demonstrated in the recognition of ribonucleoproteins and lipids. An antibody reactive towards lysophosphatidylcholine reversed lysophosphatidylcholine‐mediated inhibition of LPS‐induced TNF‐α production and adversely affected the transmigration of phagocytes towards an apoptotic stimulus. In several instances, CDR were characterized by the accumulation of somatic mutations. Anti‐idiotypic antibodies generated upon immunization bound distinct cellular moieties and self‐antigens. Poly‐specific, apoptotic cell‐reactive autoantibodies can therefore directly impact upon the course of disease by influencing phagocytic uptake of apoptotic cells, by inducing a pro‐inflammatory environment through neutralization of bioactive lipids, by blinding phagocytes to the presence of dying cells through the negation of lipidic chemotactic signals, and by mediating diversification of the humoral autoimmune response via the idiotypic network.     

FcγRIIa polymorphism in systemic lupus erythematosus (SLE): no association with disease

An allotypic variant of FcγRIIa, FcγRIIa-HR (FcγRIIa-R131), has been shown in vitroto reduce the capacity of phagocytic cells to bind and internalize IgG-containing immune complexes. Our aim was to determine whether this allotypic variant was associated with susceptibility to SLE and the development of lupus nephritis, as previous studies have suggested. FcγRIIA genotype analysis was performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in 215 Caucasoid, 70 Afro-Caribbean, and 46 Chinese patients with SLE, and in 259, 77, and 49 ethnically matched controls, respectively. Distribution of FcγRIIa genotypes between the patients and ethnically matched controls was not significantly different in the three populations studied. No association between the FcγRIIa-HR allotype and nephritis was found. Our results suggest that the FcγRIIa-HR allotype is not a major factor predisposing to the development of SLE, or to lupus nephritis.     

Phenotype and function of dendritic cells of patients with systemic lupus erythematosus

Dendritic cells (DC) regulate the activation and differentiation of T cells. They are activated by signals of inflammation and tissue damage, and thus could play a role in the amplification and perpetuation of autoimmune diseases such as systemic lupus erythematosus (SLE). Here we analyzed the phenotype of circulating DC from patients with SLE and studied their differentiation from monocytes. Peripheral blood DC exhibited increased levels of activation in patients with SLE. Although their in vitro differentiation process occurred normally, their responses to activation stimuli (LPS, TNF-α plus PGE(2), anti-CD40) were abnormal when compared to DC differentiated from healthy monocytes. When incubated in the presence of IL-10, DC from patients with SLE were able to induce tolerance to allogeneic antigens in a normal manner. Our results suggest that DC from patients with SLE are abnormal, in part due to the effect of abundant pro-inflammatory signals, but also because of intrinsic cellular defects that alter their responses to activation stimuli.     

Mechanisms of systemic autoimmunity in murine models of SLE

Our laboratory has utilized spontaneous and experimentally induced models of systemic autoimmunity in mice in order to elucidate the cellular deficiencies in immunoregulation that are essential to this process. In the spontaneously autoimmune mouse strains, genetic defects in T and B cell tolerance are the primary abnormalities that drive the syndrome. The induced chronic graft-vs-host model depends on abnormal T-B interactions resulting from allogeneic recognition of major histocompatibility complex (MHC) class II. Future investigations will target the biochemistry of the loss of tolerance and the specificity of autoreactive T cells that provide help for autoantibody production.     

Soluble Fas molecule in the serum of patients with systemic lupus erythematosus

The serum level of soluble Fas (sFas) molecules in 35 patients with SLE was determined by enzyme-linked immunosorbent assay (ELISA) and its relation to other lymphocyte activation markers and clinical parameters was examined. The level of sFas increased significantly compared to that in normal subjects, consistent with previous reports. There was a significant correlation between the level of sFas and that of sCD4, suggesting some relation between sFas and activation of CD4⁺ T cells. Patients with lymphopenia tended to have low levels of sFas, making it possible to hypothesize that sFas protects against apoptosis. Although the change in the level of sFas with steroid therapy was variable, some relation to the differential activation of T cell subsets was suggested.     

FcγR Ⅱ a基因多态性、中性粒细胞胞浆抗体、循环免疫复合物在系统性红斑狼疮发病肿饔玫难芯靠

目的 通过检测系统性红斑狼疮(SLE)病人FcγR Ⅱ a受体的基因型及其分布情况,检测了血清中的中性粒细胞胞浆抗体(ANCA)、循环免疫复合物(CIC).分析三者之间的关系和其与SLE的关系,从基因表达、转录及表达产物的作用三个层次探讨了SLE的发病机制.方法 收集69例SLE病人与48例健康人的标本,采用巢式PCR对FcγRⅡa基因进行分型,RT-PCR检测该基因的转录,采用ELISA方法对血清中的ANCA和CIC进行检测.结果 FcγR Ⅱ a-R131纯和子的分布在SLE患者组与正常对照组之间有统计学意义(P<0.02).三种基因型在狼疮病人中(分别为45%Fcγ/RⅡa-R/R131、30%H/R 131和25%H/H131)与正常对照组(21%FcγR Ⅱ a-R/R131、52%H/R131和27%H/H131)之间不同.FcγRⅡ a-R/R131基因型转录产物在SLE患者组与正常对照组之间有有统计学意义(P<0.02),此结果与分型结果一致.在FcγR Ⅱ a-R/R131基因型中抗ANCA阳性率为67.9%,CIC阳性率67.4%,与FcγRⅡ a-H/R131和FcγRⅡ a-H/H131两个基因型(ANCA:21.4%H/R131和10.7%H/H131;CIC:18.4%H/R131;14.0%H/H131)之间有统计学意义(P<0.05).ANCA与CIC的阳性率在H/R131与H/H131基因型之间无统计学意义(P0.2).结论 FcγR Ⅱ a-R/R基因型可能是云南汉族SLE病人的遗传易感因素,其在体内的过度表达可能是造成SLE患者血清中ANCA和CIC含量增高进而导致SLE发生的一个重要原因.     

The Yaa gene-mediated acceleration of murine lupus: Yaa− T cells from non-autoimmune mice collaborate with Yaa+ B cells to produce lupus autoantibodies in vivo

The BXSB Y chromosome-linked mutant gene, Yaa, promotes autoimmune responses in mice predisposed to a lupus-like autoimmune disease. We have previously shown that a cognate interaction of T cells with B cells expressing the Yaa gene appears to be responsible for the accelerated production of autoantibodies. To investigate whether T cells that provide help for autoantibody production by Yaa⁺ B cells need to express the Yaa gene, we have made radiation bone marrow chimeras containing two sets of T and B cells from mice with or without the Yaa gene and differing by the Thy-1 and Igh allotypes. We then determined autoantibody production following the selective elimination of T cells of Yaa⁺ origin by treating mice with allele-specific anti-Thy-1 monoclonal antibody. Our results demonstrated that the selective production of autoantibodies by Yaa⁺ B cells in Yaa⁺-Yaa^? double bone marrow chimeras can be mediated as efficiently by T cells from non-autoimmune mice lacking the Yaa gene as by T cells from autoimmune mice bearing the Yaa gene. This indicates that T cells from non-autoimmune Yaa^? mice are capable of providing help for autoimmune responses by collaborating with Yaa⁺ B cells. These data thus strongly suggest that the Yaa gene defect is not functionally expressed in T cells, but only in B cells, and contrast with parallel experiments in the lpr model, in which defects of the Fas antigen in both T and B cells are crucial for the lpr gene-mediated promotion of autoantibody production.     

系统性红斑狼疮病人血T,B淋巴细胞Bcl—2的表达

目的：探讨Ｂｃｌ－２在系统性红斑狼疮（ＳＬＥ）发病机制中作用。方法：采用流式细胞仪双标记法检测３１例ＳＬＥ病人外周血Ｔ、Ｂ细胞Ｂｃｌ－２蛋白表达。结果：发现活动期ＳＬＥ病人活动期ＳＬＤ病人ＣＤ３＾＋、ＣＤ４＾＋和ＣＤ８＾＋Ｔ细胞Ｂｃｌ－２蛋白表达明显高于非活动期ＳＬＥ病人、其他疾病组和正常对照组。ＣＤ１９＾＋Ｂ细胞Ｂｃｌ－２蛋白表达在各组之间并无统计学差异。ＣＤ３＾＋Ｔ细胞Ｂｃｌ－２蛋白表达的平均     

杀伤细胞免疫球蛋白样受体(KIR)基因多态性与系统性红斑狼疮的关联性研究

目的 探讨杀伤细胞免疫球蛋白样受体（KIR）基因多态性与系统性红斑狼疮（SLE）的关联性。方法 采用序列特异性引物聚合酶链反应（SSP-PCR）法，分析93例SLE患者和123例无血缘关系的健康对照K／R基因位点的多态性。结果 SLE病例组KIR2DS1（P〈0．001）、KIR2DL2（P〈0．001）基因的阳性率较随机对照组显著升高。具有2个或2个以上活化性基因个体在SLE组（80．7％）较对照组（66．7％）明显增多，差异具有统计学意义（P=0．025）。SLE患者狼疮肾炎与非狼疮肾炎组K／R基因分布频率比较差异无统计学意义。按发病年龄分组后，SLE患者中不同发病年龄组间K／R基因频率分布比较差异无统计学意义。结论 KIR2DS1、KIR2DL2基因频率升高可能与SLE发病相关。     

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...     

Selective enhancing effect of the Yaa gene on immune responses against self and foreign antigens

The BXSB Y chromosome-linked mutant gene, Yaa, accelerates the progression of a lupus-like autoimmune syndrome only in mice that are predisposed to autoimmune diseases. Unlike the lpr gene, which causes the defects in the Fas antigen-mediating apoptosis, the autoimmune enhancing activity of the Yaa gene is selective, depending on autoantigens, and varies among lupus-prone mice. To obtain a better definition of the role of the Yaa gene in the acceleration of autoimmune disease, we have investigated immune responses to several foreign antigens to determine whether the Yaa gene is able to potentiate immune responses to foreign antigens in a selective manner. We report here that the Yaa gene potentiated immune responses against foreign antigens only in mice which are genetically (H-2-linked) low responding, but not high or non-responding. Moreover, studies on Yaa⁺-Yaa^? double bone marrow chimeric mice revealed that B cells from Yaa⁺ mice were selectively stimulated to produce antibodies to low-responding antigen, human IgG, while both B cell populations similarly responded to high-responding antigen, ovalbumin. Our results suggest that first, the selective immune enhancing activity of the Yaa gene may be related to differences in the capacity of T helper cells specific for given self or foreign antigens; and second, a specific cognate interaction of T helper cells with Yaa⁺ B cells is apparently responsible for the selective enhancement of immune responses to antigens, to which mice are genetically low responding.     

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.     

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.     

Prominent mucoid degeneration of the parotid gland in a patient with systemic lupus erythematosus

Lupus erythematosus (LE) can cause various cutaneous lesions including panniculitis (LE profundus), but salivary gland involvement has been extremely rare in patients with LE. Herein, we report the first documented case of systemic LE with prominent mucoid degeneration and lymphoplasmacytic infiltration in the parotid gland. A 38-year-old Japanese male with histories of autoimmune hemolytic anemia and systemic LE presented with a swelling of the bilateral cervical region. A physical examination revealed a swelling of the bilateral parotid gland and erythema of the right cheek. A biopsy specimen of the cheek demonstrated LE profundus with mucoid material deposition in the dermis. A biopsy specimen of the parotid gland showed lymphoplasmacytic infiltration and prominent mucoid material deposition within the parotid gland as well as mild lymphoplasmacytic infiltration and hyaline fat necrosis in the perisalivary tissue. Mucoid material deposition is one of the characteristic features of LE, however, this is the first case demonstrating mucoid material deposition in the salivary gland. Moreover, albeit extremely rare, lymphoplasmacytic infiltration within the lobules of the salivary gland has also been reported in patients with LE. Therefore, it is important that both lymphoplasmacytic infiltration and mucoid material deposition must be included in the differential diagnostic considerations for salivary gland tumors in patients who had been previously diagnosed as systemic or discoid LE.