Antiphospholipid Antibodies and Atherosclerosis: Insights from Systemic Lupus Erythematosus and Primary Antiphospholipid Syndrome

The issue of atherosclerosis in the antiphospholipid syndrome (APS) is receiving considerable attention within and without the autoimmune settting. Measurement of arterial intima media thickness (IMT) of is an easy and surrogate means of detecting subclinical atherosclerosis. This technique has been applied to patients with systemic lupus erythematosus (SLE) nand primary APS in the attempt to unravel a possible association between antiphospholipid antibodies and premature atherosclerosis. The available data is reviewed in the light of the most recent atherogenic pathways that may differentially account for premature vascular disease in SLE and primary APS.     

Antiphospholipid Syndrome: Ultrastructure of Microvascular Endotheliocytes in Musculocutaneous Bioptates during Systemic Lupus Erythematosus

Degeneration and atrophy of the epidermis, disorganization of the connective tissue, focal atrophy of skeletal myocytes, and diffuse vasculopathy are the main pathomorphological signs found in musculocutaneous bioptates during the antiphospholipid syndrome associated with systemic lupus erythematosus. The major morphogenetic disorder is alteration of microvascular endotheliocytes accompanied by the formation of concentric perivascular mononuclear infiltrates.     

系统性红斑狼疮合并抗磷脂抗体相关性肾病的肾组织病理学特点

 摘要：目的 分析系统性红斑狼疮（SLE）患者合并抗磷脂抗体相关性肾病（APLN）的肾组织病理学表现,以促进对APLN的认识。 方法 回顾性分析北京协和医院2000年至2005年期间155例SLE肾活检患者中APLN及APLN样肾组织病理学表现特点,及其与APL的关系。分为2组：抗磷脂抗体（APL）阳性组（37例,23.9％)和APL阴性组(118例,76.1％)。结果 155例SLE患者中APLN及APLN样肾组织病理学表现共55例（35.5%）,包括急性表现（即血栓性微血管病, 9.0％）和慢性表现（29.7%）。慢性表现中纤维性肾内动脉增生46例（29.7％）、纤维性或细胞纤维性肾内动脉阻塞12例（7.7％）、局灶性肾皮质萎缩共3例（1.9%）、肾小管甲状腺样化8例（5.2％）。其中APL阳性组 的APLN肾组织病理学表现共23例（占阳性组62.1%）,APL阴性组共32例（占阴性组27.1%）。Logistic回归分析表明,APL阳性组的APLN肾组织学表现发生率（62.1% vs 27.1%）及慢性表现和急性表现的发生率均显著高于APL阴性组（P均<0.05）。结论 SLE患者合并APLN的肾组织病理学表现发生率较高,APLN的肾组织病理学表现与APL存在显著相关性。     

系统性红斑狼疮患者自身抗体检测及意义

目的：探讨自身抗体在系统性红斑狼疮（SLE）中的意义。方法：采用放射免疫分析检测50例SLE患者血清中的抗双链DNA（dsDNA）抗体,采用德国IMTEC公司抗核抗体谱线性印迹法检测抗核小体抗体（AnuA）、抗组蛋白抗体（AHA）、抗StuD1等其他自身抗体。结果：抗StuD1阳性率最高（82％）,其次是抗R060KD抗体（80％）和AunA（72％）;抗dsDNA、AHA、抗U1-RNP、抗R052KD、抗SSB的阳性率分别为44％、32％、58％、48％、24％。其他三种自身抗体阳性率很低。结论：SLE患者血清中可出现大量的自身抗体,同时检测多种自身抗体能提高对SLE的鉴别诊断。     

系统性红斑狼疮患者的Th细胞亚群平衡失调的初步研究

为分析Th亚群平衡失调在系统性红斑狼疮 (SLE )发生发展中的变化特点 ,以ELISA法检测血清IL 10、IL 12水平 ,以细胞内细胞因子的流式细胞术检测SLE患者PBMC的不同Th细胞亚群分泌细胞因子的变化特点 ,应用三色荧光标记技术分析Th1/Th2细胞表型。结果显示 :SLE患者血清IL 10水平显著高于正常人 ,而IL 12呈低水平表达。SLE患者CD4 + IFN γ IL 10 + 细胞亚群百分率显著高于正常人 ,IFN γ+ IL 10 与IFN γ IL 10 + 细胞亚群的比值明显降低 ,IFN γ+ IL 10 + 双阳性的CD4 + T细胞亦显著增多。SLE患者的CD4 + CCR5 CCR3+ 细胞亚群百分率与正常人比较显著升高 ,CD4 + CCR5 + CCR3 细胞亚群与正常人比较 ,示发现有显著差异 ,CD4 + CCR5 + CCR3 /CD4 + CCR3+ CCR5 比值显著低于正常对照组。这些结果提示 :SLE高水平IL 10与IL 12的低水平表达呈负相关 ;患者体内分泌IL 10的Th细胞数增多 ;Th细胞表面趋化因子受体的表达提示SLE存在CCR5 CCR3+ 细胞亚群的优势活化、数量增多 ,CCR5 + CCR3 /CCR3+ CCR5 细胞比例失调 ,从而导致免疫网络平衡被破坏。     

系统性红斑狼疮与遗传性补体缺陷相关性探讨

本文报道了二例经实验证实为补体 C_4缺陷的系统性红斑狼疮患者,长期追踪观察的结果表明,二例患者持续血清 C_4低水平,一例伴有 C_(3)缺陷的患者反复肺部感染.本文并对补体与系统性红斑狼疮间的相互关系进行了简要分析.     

Ultrastructural and Biosynthetic Characteristics of Glomerular Endotheliocytes and Periglomerular Arterioles during Systemic Lupus Erythematosus

We studied ultrastructural characteristics of renal cortical cells in patients with systemic lupus erythematosus. Endotheliocytes in periglomerular arterioles underwent primary and most pronounced changes. Examination of glomerulocytes revealed early alterations in endotheliocytes, compensatory proliferation of mesangial cells, overproduction of the mesangial matrix, and metaplasia of podocytes. Biosynthetic reactions reflected the structural and functional heterogeneity of endotheliocytes associated with their damages and regeneration.     

系统性红斑狼疮患者血清IV型胶原和层粘连蛋白测定的意义

为探讨血清IV型胶原 (IV C)和层粘连蛋白 (LN)在系统性红斑狼疮 (SLE)患者中的临床意义 ;我们采用放射免疫法(RIA)对 34例SLE和 6 3例正常人的血清IV C和LN含量进行了测定 ,并进行治疗前后对比以及血清IV C和LN水平与其它临床指标间的直线相关关系分析。结果发现SLE组血清IV C和LN均较对照组显著升高 (P <0 0 0 0 1) ;治疗后随病情缓解较治疗前明显降低 (分别为P <0 0 0 1;0 0 0 5 )。血清LN与血清白蛋白呈显著负相关 (P <0 0 0 1) ,与 2 4h尿蛋白定量、血清免疫球蛋白M和补体C3水平之间呈明显的正相关 (P <0 0 5 ) ;血清IV C与血沉呈显著正相关 (P <0 0 5 )。上述结果提示血清IV C和LN水平在SLE患者中普遍升高 ,是评估SLE患者病情活动的重要指标     

SLE患者检测血清ANCA的临床价值

目的 探讨抗中性粒细胞胞浆抗体（ANCA）在系统性红斑狼疮（SLE）患者中检测的临床意义.方法 通过间接免疫荧光法（IIF）检测57例SLE患者血清中的ANCA,对ANCA阳性血清采用免疫斑点法检测抗髓过氧化物酶（MPO）和蛋白酶3（PR3）抗体;同时以35例正常健康者作为对照组.回顾性分析SLE临床表现和实验室检查结果,SLE患者以SLE disease activity index（SLEDAI）分组（SLEDAI≥10为疾病活动组、〈10为疾病非活动组）,分析ANCA与其的相关性.结果 SLE患者中ANCA 阳性率为22.8%,其中核周型（pANCA）阳性12例,阳性率为 21.1%,胞浆型（cANCA）1例,阳性率为 1.7%,靶抗原均为非MPO、PR3;ANCA阳性组与ANCA阴性组SLE活动性存在显著性差异（P〈0.05）,ANCA阳性组患者的补体C3的下降、血沉（ESR）的增高、抗dsDNA抗体的阳性以及皮肤血管炎和肾脏损伤与ANCA阴性组比较,差异有统计学意义（P〈0.05）.结论 ANCA在SLE中有一定阳性检出率,对疾病活动性判断有一定的临床价值.     

系统性红斑狼疮皮肤表皮抗核抗体的探讨

本文对１９１例ＳＬＥ患者的“正常”皮肤进行了免疫荧光的研究，结果发现６．８％（１３／１９１）的患者伴有“体内”ＡＮＡ或称ＥＮＳ，其中以Ｓ型ＩｇＧ在表皮细胞核内沉积最为多见。同时与其他检测结果做了比较，未发现ＥＮＳ的核型或荧光强度受血清ＡＮＡ，抗ｄｓ－ＤＮＡ抗体，ＢＭＺ荧光染色的影响，因此我们认为，ＥＮＳ的出现对ＳＬＥ具有协助诊断价值。     

Genetic Contribution to Carotid Vascular Disease in Patients with Systemic Lupus Erythematosus

Objective We investigated whether stromelysin, a candidate gene in atherogenesis, plays a role in atherogenesis of systemic lupus erythematosus (SLE), a leading cause of mortality in SLE. Patients and Methods A genetic study using polymorphism located in the promoter region of stromelysin was performed in 55 Italian patients with SLE. Carotid intimal-medial thickness (IMT) was evaluated by B mode ultrasonography. Results All patients with an “abnormal” (≥0.9 mm) IMT carried at least one 6A allele, and the degree of IMT was significantly greater in patients carrying at least one 6A allele (0.63 ± 0.22 vs 0.43 ± 0.04 mm, 5A/6A + 6A/6A vs 5A/5A, p = 0.018). Conclusion Our data show that polymorphism of stromelysin promoter may be relevant for SLE-related cardiovascular disease.     

Anti-neutrophil Cytoplasmic Antibodies in New-onset Systemic Lupus Erythematosus and Lupus Nephritis

This study aims to investigate the role of Antineutrophil cytoplasmic antibodies (ANCA) in patients with new-onset systemic lupus erythematosus (SLE). Sixty SLE patients, 28 of whom had lupus nephritis (LN), and 60 normal controls were enrolled; Serum ANCA was measured by enzyme linked immunosorbent assay (ELISA). The clinical and laboratory parameters of the patients were also recorded. Results show that twenty SLE patients were seropositive for ANCA, which was significantly higher than in normal controls. LN patients had significantly higher positive rate of ANCA than patients without nephritis. Compared with ANCA-negative patients, the ANCA-positive patients had significantly higher incidence of nerves system disorder, myocarditis, renal involvement and serositis. The positive rate of gamma-globulin, anti-dsDNA and anti-Sm antibodies were significantly higher in ANCA-positive patients. Elevated IgG and ESR, decreased serum C3/C4 appeared more often in ANCA-positive patients. In addition, serum ANCA level correlated positively with disease activity. Taken together, ANCA might be used as a potential complementary parameter to differentiate LN from SLE without nephritis. In addition, ANCA may serve as a useful marker of the disease activity of SLE.     

FAS mRNA editing in Human Systemic Lupus Erythematosus

FAS/FASL system plays a central role in maintaining peripheral immune tolerance. Human Systematic Lupus Erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by expansion of autoreactive lymphocytes. It remains unclear whether a defective FAS/FASL system is involved in the pathogenesis of SLE. In this study, we have discovered a novel nucleotide insertion in FAS mRNA. We demonstrate that this novel FAS mutation occurs at mRNA levels, likely through a site-specific mRNA editing process. The mRNA editing mutation is unique for human FAS because the similar mRNA editing event is absent in other human TNF receptor (TNFR) family genes with death domains (DR5, DR6, and TNFR1) and in murine FAS. The adenine insertion mutation in the coding region message causes the alteration of human FAS mRNA reading frame. Functionally, cells expressing the edited FAS (edFAS) were refractory to FAS-mediated apoptosis. Surprisingly, cells from SLE patients produced significantly more edFAS products compared to cells from normal healthy controls. Additionally, we demonstrated that persistent engagement of T-cell receptor increases human FAS mRNA editing in human T cells. Our data suggest that the site-specific FAS mRNA editing mutation may play a critical role in human immune responses and in the pathogenesis of human chronic inflammatory diseases.     

Programmed Death-1 Gene Polymorphisms in Patients With Systemic Lupus Erythematosus in Taiwan

To investigate the role of programmed cell death-1 (PD-1) gene polymorphisms in the development of systemic lupus erythematosus (SLE) in Taiwan, 109 patients with SLE and 100 healthy controls were enrolled in this study. The PD-1 gene polymorphisms were determined by the method of polymerase chain reaction/restriction fragment length polymorphism. This study showed that the genotype distributions of PD-1 7209 C/T polymorphisms were significantly different between the patients with SLE and controls (P=0.002, Pc=0.018). The frequencies of the PD-1 7209 C/C genotype and PD-1 7209 C allele were significantly higher in the patients with SLE than those of the controls (P=0.001, OR=2.6, 95% CI=1.5–4.6, and P=0.002, OR=2.1, 95% CI=1.3–3.4, Pc=0.018, respectively). Moreover, the association of PD-1 7209 C with susceptibility to SLE was independent of the PD-1 ligand. This study also showed that the PD-1-536 A 7146 G 7209 C 7499 G haplotype was associated with the development of SLE in Taiwan.Both Authors Contributed equally to this work     

Expression of CTLA-4 Molecule in Peripheral Blood T Lymphocytes from Patients with Systemic Lupus Erythematosus

CTLA-4 is a cell surface molecule expressed on activated T cells that is suggested to deliver a negative signal for T cell activation. Since CTLA-4 might be a negative regulator of autoimmune diseases, we investigated its expression on T cells from 20 patients with systemic lupus erythematosus (SLE) by flow cytometric analysis and RT-PCR. We found that although CTLA-4 mRNA was readily detected in all patients and controls, only a very minor subset of T cells expressed detectable surface CTLA-4 molecules in both groups. But patients with SLE had significantly increased percentages of CTLA-4-positive T cells compared with normal controls, implying at least that there was no apparent defective expression of CTLA-4 molecule in human lupus. The kinetics of CTLA-4 expression on T cells stimulated in vitro with PMA plus ionomycin were similar in normal controls and patients with SLE. The expression of CTLA-4 molecules after stimulation increased gradually and peaked at 72 hr. However, the induction of CTLA-4 expression on patients' T cells appeared to be weaker than that of normal individuals. Whether this reflects impaired down regulation by CTLA-4 molecules in SLE patients needs to be clarified further.     

Contribution of Toll-Like Receptor 9 Gene Single-Nucleotide Polymorphism to Systemic Lupus Erythematosus in Egyptian Patients

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease, with multiple genetic and environmental factors involved in its etiology. The toll-like receptor 9 (TLR9) gene has been reported to have important roles in the development and progression of SLE. In this case-control study, the effect of TLR9 polymorphism on susceptibility to SLE was investigated in Egyptian patients.

Methods: We studied the distribution of the TLR9 rs352139 (G + 1174A) single nucleotide polymorphism (SNP) by allele-specific polymerase chain reaction (PCR) in 104 Egyptian patients with SLE and 108 age-, sex-, and ethnically matched controls.

Results: There was no statistically significant difference in the distribution of the AA genotype and alleles between SLE patients and the control group in our study; however, the GA heterozygous patients were three times more likely to develop SLE (P < 0.001). A significant association was detected between TLR9 genotypes and some of the disease manifestations as myositis (p = 0.032), psychosis (p = 0.014), photosensitivity (p = 0.002), and pleurisy (p = <0.001). Moreover, we observed a significant association between the TLR9 AA and GA genotypes and the presence of antinuclear antibodies (ANA) (p = 0.038).

Conclusion: The G + 1174A SNP in the toll receptor 9 gene may contribute to the genetic susceptibility of SLE in Egyptian patients. Also, an influence for this polymorphism on disease manifestations has been elucidated.     

系统性红斑狼疮患者心理状况调查

目的 调查SLE患者的心理状况。方法 67例SLE患者填写症状自评量表(SCL-90)及自制的SLE患者心理影响因素量表。结果 SLE患者与中国常模比较，SCL-90阳性项目数、阳性均分及各种因子均高于中国常模。躯体化、强迫、人际关系、抑郁、焦虑、恐怖、精神病性7种因子与中国常模相比，有非常显著性差异；敌对、偏执与中国常模相比，有显著性差异。结论 SLE患者心理健康状况普遍较差，提示以后在药物治疗的同时，应辅以心理治疗，为患者求得更高的生活质量。     

系统性红斑狼疮病人T和B淋巴细胞凋亡的观察

为了研究SLE的T、B淋巴细胞及其亚类的凋亡情况,采用碘化丙锭染色,在流式细胞仪下观察计数:22例SLE病人淋巴细胞(包括总体淋巴细胞、CD3~+、CD4~+、CD8~+T细胞和CDl9~+B细胞)凋亡率在培养0、24、48h时均较正常组有显著增高,并以CD4~+T细胞和CDl9~+B细胞在活动期SLE病人中凋亡更突出。此外,SLE病人,自身抗体产生愈多,其细胞凋亡率愈高;疾病活动度增高,凋亡率也较高。提示;SLE病人的淋巴细胞凋亡在体外加速,与其自身抗体产生有密切关系,在其发病机制中起一定的作用。     

CD40在系统性红斑狼疮外周血淋巴细胞的表达

使用密度离心法分离SLE患者和正常人外周血单个核细胞 (PBMC ) ,采用流式细胞术检测B淋巴细胞白细胞分化抗原 4 0 (CD4 0 )的表达水平 ,进行SLE患者 (活动期和缓解期 )和正常人之间的比较 ;并进行B淋巴细胞CD4 0表达水平和血清抗dsDNA抗体水平及狼疮活动指数 (SLEDAI)的相关分析。结果表明 ,活动期SLE患者外周血B淋巴细胞比例 (% )和其表达CD4 0的比例 (% )均明显高于缓解期SLE患者和对照组 ,其表达CD4 0的平均荧光强度 (MFI)在活动期SLE患者最高 ,缓解期SLE患者稍低 ,对照组最低 ;相关分析结果表明 ,活动期SLE患者B淋巴细胞CD4 0的表达比例 (% )和强度 (MFI)均与血清抗dsDNA抗体及SLEDAI呈正相关 ,后两者呈高度相关 ;缓解期SLE患者B淋巴细胞表达CD4 0的强度 (MFI)和SLEDAI呈正相关。CD4 0在活动期SLE患者B淋巴细胞的表达增加 ,其水平与疾病活动度有关。