Characterization of anti-endothelial cell antibodies in systemic lupus erythematosus (SLE).

IgG anti-endothelial antibodies (AEA), as measured by ELISA or immunoblotting technique could be detected in serum samples of 56 out of 64 patients with SLE (88%) and mainly occurred in monomeric form. AEA were not cell specific, because the binding reactivity was absorbed partially by both fibroblasts and peripheral blood mononuclear cells. No correlation was found between the presence of AEA and anti-nuclear antibodies. Immunoblotting revealed reactivity of AEA against endothelial antigens ranging in size from 15 to 200 kD. AEA titres were significantly higher in patients with joint or skin abnormalities, compared with patients without these abnormalities. A significant correlation was found between nephritis in SLE and the presence of AEA reactivity against endothelial membrane antigens of 38, 41 and 150 kD. These data show that the pattern of AEA reactivity in serum of SLE patients is heterogeneous, and suggest that AEA against a limited number of antigens may be involved in the pathogenesis of nephritis in SLE.     

Three clinical reports of Kikuchi's lymphadenitis combined with systemic lupus erythematosus

Summary The authors describe three cases of systemic lupus erythematosus (SLE) associated with Kikuchi's histiocitic necrotizing lymphadenitis (HNL). Two patients presented a cytomegalovirus infection concomitantly with Kikuchi's lymphadenitis; in one of them the onsets of SLE and HNL were simultaneous. In the third case an inguinal HNL was concomitant with vaginitis of unknown aetiology.     

Antibody Mediated Complete Congenital Heart Block in the Fetus

Complete congenital heart block (CCHB) affects 1:20,000–25,000 live births and is usually an atrioventricular block; 30–50% of fetuses with CCHB will have a structural anomaly, though recently attention has focused on the etiological influence of autoimmune disease, such as systemic lupus erythematosus. The diagnosis is established by detailed two-dimensional ultrasound scanning of the heart to exclude anomaly coupled with M-mode echocardiography and Doppler blood velocity patterns in the major vessels to detect the uncoupling of atrial and ventricular rhythms. Risk factors for an affected child are discussed. A previously affected child, high titers of anti-Ro antibodies, the presence of anti-Ro (SS-A) and anti-La (SS-B), and maternal HLA DR3 confer high risk. Antibody mediated CCHB is irreversible. Plasmapheresis and immunosuppression have been attempted in affected mothers, with limited success, to reduce the likelihood of the fetus being affected, and steroids have been used to reduce the inflammatory reaction in the heart. In many cases the underlying pathology of the immune system adversely affects utero-placental function requiring careful monitoring of fetal well-being. CCHB renders fetal heart rate monitoring virtually useless, in the antenatal and intrapartum periods. Alternatives are explored.     

靶向B细胞治疗系统性红斑狼疮研究进展

系统性红斑狼疮(Systemic lupus erythematosus, SLE)是一种慢性、全身多系统受累的自身免疫性疾病。其病因和发病机制尚未完全明确,有研究表明B细胞过度增殖、活化是SLE发病至关重要的环节,也是造成全身多脏器损害的病理基础。因此B细胞成为SLE治疗的新型靶点,本综述主要围绕B细胞相关靶向治疗进展进行讨论,包括靶向B细胞表面抗原、靶向B细胞因子、共刺激阻断、酪氨酸蛋白激酶抑制剂等方面,重点介绍其已经结束或正在进行的临床试验以及实际上市后的临床应用。     

细胞毒性T淋巴细胞相关抗原4融合蛋白抑制狼疮肾炎患者外周血单个核细胞B7分子表达及

目的探讨细胞毒性T淋巴细胞相关抗原4融合蛋白(CTLA-4Ig)对活动期狼疮肾炎(LN)患者外周血单个核细胞(PBMC)细胞表面B7-1(CD80)和B7-2(CD86)表达的影响及其对抗双链DNA(dsDNA)抗体和免疫球蛋白产生的影响。方法将18例活动期LN患者的抗凝血标本随机分为LN的CTLA-4Ig处理组(LN-T组9例)和普通培养组(LN-NC组9例)。另以14例正常人的抗凝血标本为对照,随机分为正常人的CTLA-4Ig处理组(NC-T组7例)和普通培养组(NC-NC组7例)。用密度梯度离心法分离PBMC。处理组加入CTLA-4Ig(10ng/L)、普通培养组加入等量普通培养基37℃孵育72h后,采用流式细胞仪技术检测PBMC细胞表面B7-1和B7-2分子的表达;ELISA法检测孵育液中抗dsDNA抗体、IgG及IgM水平。结果活动期LN患者CTLA-4Ig处理组与普通培养组比较,PB-MC表面B7-2分子表达明显下降(P<0.01);B7-1分子表达无显著变化(P>0.05);孵育液中抗dsD-NA抗体、IgG及IgM的生成均明显减少(P<0.01)。而正常人的两组间各指标差异均无统计学意义(P>0.05)。结论CTLA-4Ig可抑制活动期LN患者的PBMC表面B7-2分子的表达,并可减少其抗dsDNA抗体、IgG及IgM的分泌。     

Assessment of class-specific antibodies against denatured DNA in patients with systemic lupus erythematosus

In this retrospective study 103 serum samples from 16 females with systemic lupus erythematosus (SLE), obtained during a mean follow-up time of 2 years, were investigated for the presence of anti-denatured [single-stranded (ss)] DNA antibodies of the IgG, IgM, and IgA classes. The anti-ssDNA antibodies were determined by an enzyme-linked immunosorbent assay (ELISA), and the results were expressed in three ways: as units derived from a single serum dilution and as two parameters,E andA, calculated from the dose-response curve,E being an estimate of the effective amount of antibodies andA a function of the reaction constant between the antigen and the antibody. The simultaneous occurrence of anti-ssDNA antibodies of all three immunoglobulin classes was seen most often in the patients with the shortest duration of the disease. Clinically active disease was found to correlate with high reaction constants of the IgA anti-ssDNA antibodies. There was also an association between the IgA anti-ssDNA antibody levels and the presence of nephritis. Great fluctuations in the amounts of effective antibodies of the IgG class were seen in seven patients, in six of whom changes in the disease activity also were seen. Changes in the disease activity were unaccompanied by fluctuations in the IgG anti-ssDNA levels in four patients; two of these patients were positive for antibodies against extractable nuclear antigens. We conclude that it is of value to express the results of the anti-ssDNA ELISA as a function of the dose-response curve when monitoring patients with SLE and that immunoglobulin class-specific determinations of anti-ssDNA antibodies may provide information about the disease activity in many patients with SLE.     

Interleukin-10 (IL-10) secretion in systemic lupus erythematosus and rheumatoid arthritis: IL-10-dependent CD4+CD45RO+ T cell-B cell antibody synthesis

Interleukin-10 (IL-10) is a major immunoregulatory cytokine and has a multitude of immunomodulatory effects in the immune system. In this study, we have examined the secretion andin vitro function of IL-10 in B cell hyperactivity in antibody production in two common autoimmune diseases, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). IL-10 was detectable in serum of all active SLE and serum and synovial fluid samples of all RA patients but in none of the normal controls. B cells and CD4+CD45RO+ memory T cells secreted highly enhanced levels of IL-10 in SLE and RA versus normals. Increased IgM and IgG production by B cells-CD4+CD45RO+ T cells in SLE and RA was IL-10 dependent, since neutralization of IL-10 cytokine by anti-IL-10 antibody drastically reduced Ig synthesis in these coculture experiments. B cell hyperactivity in autoantibody production in SLE and RA may be a function of IL-10-dependent CD4+CD45RO+ Th2 cell activation. Therefore, IL-10 may play an important role in highly disturbed immune system and B cell-T cell function in these immune disorders.     

Fine specificity of autoantibodies to calreticulin: epitope mapping and characterization

Extracellular calreticulin (CRT) as well as anti‐CRT antibodies have been reported in patients with various autoimmune disorders and CRT has been implicated in ‘epitope spreading’ to other autoantigens such as the Ro/SS‐A complex. In addition, antibodies against parasite forms of the endoplasmic reticulum chaperone, CRT, have been found in patients suffering from onchocerciasis and schistosomiasis. In this study, we screened sera for anti‐CRT antibodies from patients with active and inactive systemic lupus ertythematosus (SLE) and primary or secondary Sjögren’s syndrome. Approximately 40% of all SLE patients were positive for anti‐CRT antibodies. The antigenic regions of CRT were determined using full length CRT and fragments of CRT prepared in yeast and Escherichia coli, respectively. Synthetic 15mer peptides corresponding to the major autoantigenic region of CRT (amino acids 1–289), each one overlapping by 12 amino acids, were used to map the B cell epitopes on the CRT protein recognized by autoimmune sera. Major antigenic epitopes were found to be associated with the N‐terminal half of the protein in 69% of the SLE sera from active disease patients, while the C‐domain was not antigenic. Major epitopes were found to be reactive with antibodies in sera from SLE patients with both active and inactive disease, spanning different regions of the N and P‐domains. Sera from both healthy and disease controls and primary Sjögren’s syndrome patients were non‐reactive to these sequences. Limited proteolysis of CRT with two major leucocyte serine proteases, elastase and cathepsin G, demonstrated that an N‐terminal region of CRT is resistant to digestion. Interestingly, some of the epitopes with the highest reactivity belong to the fragments of the protein which bind to C1q and inhibit complement activation. Whether C1q association with CRT is a pathological or protective interaction between these two proteins is currently under investigation.     

系统性红斑狼疮临床特征与HLA—DR,DQ基因的相关研究

采用聚合酶链反应结合顺序特异物寡核苷酸（ＰＣＲ／ＳＳＯ）探针杂交方法对ＨＬＡ－ＤＲ，ＤＱ亚区作ＤＮＡ分型，分析了系统性红斑狼疮（ＳＬＥ）的各种临床特征与ＨＬＡ－ＤＲ、ＤＱ基因的关联，结果发现汉族ＳＬＥ中肾脏损害与ＤＲ２相关，而与ＤＲ４呈负相关，口、鼻腔粘膜溃疡与ＤＲ１２相关，未发现ＳＬＥ的其他临床特征与ＤＲ、ＤＱ基因有关，发病年龄小于３５ａ者，ＤＲ２，ＤＱ６阳性率高，而ＤＲ３则多见于发病年龄大于３