Functional Relevance for Associations between Genetic Variants and Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a serious prototype autoimmune disease characterized by chronic inflammation, auto-antibody production and multi-organ damage. Recent association studies have identified a long list of loci that were associated with SLE with relatively high statistical power. However, most of them only established the statistical associations of genetic markers and SLE at the DNA level without supporting evidence of functional relevance. Here, using publically available datasets, we performed integrative analyses (gene relationship across implicated loci analysis, differential gene expression analysis and functional annotation clustering analysis) and combined with expression quantitative trait loci (eQTLs) results to dissect functional mechanisms underlying the associations for SLE. We found that 14 SNPs, which were significantly associated with SLE in previous studies, have cis-regulation effects on four eQTL genes (HLA-DQA1, HLA-DQB1, HLA-DQB2, and IRF5) that were also differentially expressed in SLE-related cell groups. The functional evidence, taken together, suggested the functional mechanisms underlying the associations of 14 SNPs and SLE. The study may serve as an example of mining publically available datasets and results in validation of significant disease-association results. Utilization of public data resources for integrative analyses may provide novel insights into the molecular genetic mechanisms underlying human diseases.     

系统性红斑狼疮合并甲状腺功能减退症50例临床分析

目的:分析系统性红斑狼疮合并甲状腺功能减退症50例临床症状和治疗效果.方法:选取2010年6月至2012年6月间于我院接受诊断和治疗的系统性红斑狼疮合并甲状腺功能减退症患者50例作为观察组,同时选取同期入院的单纯系统性红斑狼疮患者50例作为对照组,分析两组临床症状的差异.观察组患者分别给予系统性红斑狼疮合并甲状腺功能减退症联合治疗和甲状腺功能减退症单独治疗,观察比较治疗前后甲状腺功能差异.结果:观察组患者关节病变发病率为64.00％明显高于对照组的22.00％(P＜0.05):观察组患者雷诺现象的发病率为36.00％明显高于对照组的6％(P＜0.05).联合治疗患者治疗后促甲状腺素水平明显低于单独治疗(P＜0.05),联合治疗患者治疗后游离甲状腺素和游离甲状腺三碘原氨酸水平均明显高于单独治疗(p＜0.05).结论:系统性红斑狼疮合并甲状腺功能减退症患者的关节病变和雷诺现象发病率明显较高,联合治疗后甲状腺功能减退症恢复较佳.     

Carbohydrate specificity of IgM autoantibodies to CD45 in Systemic Lupus Erythematosus

Patients with SLE develop IgM autoantibodies to different isoforms of CD45, the major surface membrane protein tyrosine phosphatase on lymphocytes and other nucleated hemopoietic cells. Because such autoantibodies could have a potential role in the development of immune dysfunction in this disorder, we performed a series of experiments to characterize their antigenic specificity further. Blots of recombinantE. coli fusion proteins encoded by exons 3–7 of the p220 and p180 isoforms were uniformly non-reactive with SLE IgM, suggesting that anti-CD45 autoantibodies in SLE are directed against conformational and/or carbohydrate epitopes, rather than linear polypeptide epitopes. This issue was examined further using chemically and enzymatically modified CD45 purified from T cells by lectin affinity chromatography as substrates. Treatment of CD45 with 25 mM sodium-m-periodate, sufficient to abrogate binding to various lectins, abolished the reactivity with SLE anti-CD45 autoantibodies. On the other hand, digestion of CD45 with neuraminidase enhanced the binding of anti-CD45 autoantibodies from some of the SLE sera. This result probably reflects decreased steric hindrance or charge repulsion because the binding of mouse monoclonal antibodies directed against linear polypeptide epitopes of CD45 was similarly enhanced. Digestion of CD45 with N-glycosidase F had no effect on autoantibody staining. Taken together, these data suggest that IgM anti-CD45 autoantibodies in SLE recognize non-sialylated carbohydrate determinants in the highly O-glycosylated polymorphic domains of CD45.Abbreviations SLE systemic lupus erythematosus - SBA soybean agglutinin - RCAI Ricinus communis agglutinin - SNL Sambucus nigra lectin - MBP maltose binding protein - mAb monoclonal antibody - WGA wheat germ agglutinin     

系统性红斑狼疮病人的临床护理及出院指导

目的:探讨系统性红斑狼疮患者的护理经验。方法:回顾性分析45例系统性红斑狼疮患者临床及护理资料;在护理过程中采用心理护理、对症处理及出院指导等护理措施,强调加强心理护理和健康教育指导,根据不同年龄、不同性格、不同文化和社会背景,分别给予耐心解释和心理疏导。结果:改变了病人的心理状态和认知能力,使病人保持平和心态,树立坚持长期治疗,战胜疾病的信心。45例病人中除3例因经济问题放弃治疗,其余患者均达到临床缓解。经定期复查,70%的病人得到长期缓解。结论:本组病例采取的护理措施切实可行,行之有效。     

BLyS与系统性红斑狼疮

淋巴细胞刺激因子BLys是肿瘤坏死因子家族的新成员,对于B细胞的发育增殖具有重要的作用。狼疮小鼠及系统性狼疮患体内BLys水平增高,阻断BLys的作用可以使使狼疮小鼠的病情缓解,存活时间延长。因此,BLys拮抗剂可能对系统性红斑狼疮患具有治疗作用。     

Treatment of Patients with Systemic Lupus Erythematosus including Nephritis with Chlorambucil

Six female patients with systemic lupus erythematosus (S.L.E.) have been treated with chlorambucil. In five the decision was taken after failure by corticosteroids to control progressive renal disease in the face of unacceptable corticosteroid toxicity. After the introduction of chlorambucil renal function improved and all patients remain well six, six, five, three, and two-and-a-half years later, respectively. On renal biopsy five had focal proliferative glomerulonephritis. Repeat biopsy in two cases showed quantitative improvement. The sixth patient was treated with chlorambucil because of failure by corticosteroids to control peripheral vascular lesions and haemolysis and she remains well four years later. In four patients is it probable that amenorrhoea was related to chlorambucil treatment, but there were no other important side effects although one patient developed a degree of marrow depression during treatment. Chlorambucil may hold advantages over the immunosuppressive drugs normally recommended in this condition, azathioprine and cyclophosphamide, as it appears less liable to cause important marrow suppression and, unlike cyclophosphamide is not associated with alopecia and haemorrhagic cystitis.     

Acute Renal Failure in Systemic Lupus Erythematosus

Acute anuric renal failure complicating systemic lupus erythematosus does not usually respond to treatment with corticosteroids and immunosuppressive agents. We describe four cases treated by dialysis, corticosteroids, and heparin in anticoagulant doses in which there was remarkable improvement in renal function after prolonged anuria. One patient died later from a gastric haemorrhage. The other three were alive and well 55, 54, and 30 months from the onset of anuria. In two cases a second renal biopsy showed a striking improvement in the lesions. Large doses of corticosteroid and heparin may be the best treatment in acute anuric lupus nephritis.     

ANCA与SLE临床表现的相关性及其意义

目的:探讨系统性红斑狼疮(Systemic Lupus Erythematosus,SLE)患者抗中性粒细胞胞浆抗体(Anti-neutrophil Cytoplasmic Antibodies,ANCA)与肾炎及其他临床表现和实验室检查的相关性及其意义.方法:采用前瞻性研究收集77例系统性红斑狼疮患者,用间接免疫荧光法(IIF)检测患者血清ANCA、ELISA法检测ANCA抗原,检测其他免疫学指标如抗核抗体、抗dsDNA抗体等.结果:77例SLE患者中ANCA阳性28(36.4%)例,ANCA阳性组浆膜炎、肾损害、神经精神症状、皮肤血管炎、抗dsDNA抗体阳性、抗Sm抗体阳性、补体下降以及血清IgG升高的发生率明显高于阴性组(P＜0.05).52例LN患者中,25例(48.1%)ANCA阳性,其中P-ANCA阳性者22例(88%).3例(12%)为a-ANCA均出现在RPGN,无一例出现c-ANCA.非LN组25例患者中,仅3例(12%)p-ANCA阳性,且均为抗-MPO.正常对照组无一例ANCA阳性.77例SLE患者中,14例(18.2%)为抗-MPO;13例(16.9%)为抗LF,且只见于DPGN、FPGN和RPGN伴有新月体形成者;10例(13%)为抗-CG,但在非狼疮肾炎患者未检测到抗-LF及抗-CG.在各种临床表现中,抗-MPO与肾脏和皮肤表现有关;而抗-LF与肾脏、关节炎及浆膜炎有关;抗-CG可见于各种临床表现.结论:ANCA可作为评价SLE疾病及鉴别血管炎和狼疮肾炎的一个重要指标.     

Animal Models of Human Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a human autoimmune disease of unknown etiology. Clinical, serologic, immunologic, and pathologic findings are highly variable in different patients and at different times in the same patient. Murine and canine animal models of SLE have been found with clinicopathologic abnormalities resembling those observed in humans. Each animal model has unique characteristics; taken together they reflect the spectrum of disease in human SLE.Investigations in the animals have suggested that genetic, hormonal, immunologic, viral, and other environmental factors contribute to and modify the expression of disease. Where analogous studies are available for humans, the same factors have been found to modify disease expression in a similar fashion. Together, these studies have helped to clarify the multifactorial basis for SLE.The best characterized abnormalities are immunologic. These include excessive B cell function with the formation of large amounts of autoantibodies, and T cell abnormalities which include defects in T cell regulatory function as well as certain T cell effector functions.The animal models of SLE also serve as convenient test subjects for newer therapeutic modalities. It is hoped that further study of the animal models will provide a more rational approach to therapeutic modulation of disease in humans with SLE.     

Chinese Systemic Lupus Erythematosus Treatment and Research Group Registry VI: Effect of Cigarette Smoking on the Clinical Phenotype of Chinese Patients with Systemic Lupus Erythematosus

Objectives

Our study aimed to investigate the effect of cigarette smoking on the clinical phenotype of patients registered in the Chinese Systemic Lupus Erythematosus (SLE) Treatment and Research (CSTAR) group registry database, the first online registry of Chinese patients with SLE.

Methods

A prospective cross-sectional study of Chinese SLE patients was conducted using the CSTAR. Our case-control analysis was performed on age- and gender-matched subjects to explore the potential effect of cigarette smoking on the clinical manifestation of SLE.

Results

Smokers comprised 8.9% (65/730) of patients, and the ratio of females/males was 19/46. Thirty-nine patients were current smokers, and 26 were ex-smokers. Data showed significant differences between smokers and nonsmokers in the following areas: nephropathy (58.5% vs. 39.2%; p = 0.003), microscopic hematuria (30.8% vs. 19.1%; p = 0.025), proteinuria (53.8% vs. 34.4%; p = 0.002), and SLE Disease Activity Index(DAI) scores (12.38±8.95 vs. 9.83±6.81; p = 0.028). After adjusting for age and gender, significant differences between smokers and nonsmokers were found with photosensitivity (35.9% vs. 18%; p = 0.006), nephropathy (59.4% vs. 39.8%; p = 0.011), and proteinuria (54.7% vs. 35.2%). Although smokers tended to have greater disease severity compared with nonsmokers (SLEDAI scores: 12.58±8.89 vs.10.5±7.09), the difference was not significant (p = 0.081).

Conclusions

Cigarette smoking triggers the development and exacerbation of SLE, especially with respect to renal involvement. Chinese smokers with SLE should be advised to discontinue cigarette use.     

Molecular Characterization of Circulating Plasma Cells in Patients with Active Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a generalized autoimmune disease characterized by abnormal B cell activation and the occurrence of increased frequencies of circulating plasma cells (PC). The molecular characteristics and nature of circulating PC and B cells in SLE have not been completely characterized. Microarray analysis of gene expression was used to characterize circulating PC in subjects with active SLE. Flow cytometry was used to sort PC and comparator B cell populations from active SLE blood, normal blood and normal tonsil. The gene expression profiles of the sorted B cell populations were then compared.SLE PC exhibited a similar gene expression signature as tonsil PC. The differences in gene expression between SLE PC and normal tonsil PC and tonsil plasmablasts (PB) suggest a mature Ig secreting cell phenotype in the former population. Despite this, SLE PC differed in expression of about half the genes from previously published gene expression profiles of normal bone marrow PC, indicating that these cells had not achieved a fully mature status. Abnormal expression of several genes, including CXCR4 and S1P₁, suggests a mechanism for the persistence of SLE PC in the circulation. All SLE B cell populations revealed an interferon (IFN) gene signature previously only reported in unseparated SLE peripheral blood mononuclear cells. These data indicate that SLE PC are a unique population of Ig secreting cells with a gene expression profile indicative of a mature, but not fully differentiated phenotype.     

血β2微球蛋白水平在系统性红斑狼疮中的临床意义

目的：探讨系统性红斑狼疮（systemic lupus erythematosus,SLE）患者血β2-MG水平与疾病活动的相关性及其临床意义。方法：随机抽取2012年2月-2012年7月我科收治的62例SLE患者（SLE组）和同期在我院门诊体检的健康体检者40例（对照组）,检测和比较两组血清β2-MG、自身抗体、补体水平,并对SLE患者进行SLEDAI评分,分析SLE患者血清β2-MG水平与自身抗体、补体水平和SLEDAI评分的相关性。结果：SLE组血β2-MG水平（3．11±0．40μg／mL）显著高于对照组（2．23±0．23μg/mL）,差异有统计学意义（P〈0．05）;其中发生口腔溃疡、浆膜炎及蛋白尿的SLE患者的血β2-MG水平与无此三种表现的患者相比显著升高,差异有统计学意义（P〈0．05）。SLE患者的血β2-MG水平与抗ds—DAN抗体、SLEDAI均呈显著正相关（分别为r=0．289,r=0．361,P〈0．01）,与C3呈负相关（r=-0．271,P〈0．05）。结论：SLE患者血β2-MG水平高于正常,可作为SLE疾病活动指标用于监测疾病活动。     

Glycation end-products specific auto-antibodies in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease, which is highly inflammatory. Compared to a healthy control group, SLE patients exhibit a higher concentration of advanced glycation end products (AGEs) and a lower concentration of receptors for AGEs (RAGE) in serum, however, the exact aetiology is still unclear. In the present study, non-enzymatic glycation induced modification of human serum albumin (HSA) has been studied by biophysical techniques. Glycated HSA (G-HSA) was used as an antigen, and serum autoantibody levels were estimated in SLE and normal humans (NH) against it, using direct binding ELISA and competitive inhibition ELISA. Compared to N-HSA, remarkable structural modifications were observed in G-HSA. Modified HSA also showed increased pentosidine fluorescence (213.7 ± 13.4 AU). Glycation of HSA induced a conversion of α-helix and random coil to β-sheet and β-turns. Serum immuno assays results exhibited significantly (p < 0.001) higher binding of G-HSA with serum autoantibodies from SLE patients when compared with native HSA (N-HSA). Furthermore, competitive ELISA results showed significantly (p < 0.001) high percent inhibition of serum IgG from SLE patients with modified antigen. Chronic inflammation with excessive oxidative stress in SLE patients could be a possible reason for structural alterations in blood proteins, generating highly immunogenic unique new-epitopes. These in turn induce the generation of specific autoantibodies against G-HSA that may serve as a potential biomarker for SLE pathogenesis.