Analysis of the monocyte chemoattractant protein 1 -2518 promoter polymorphism in patients with multiple sclerosis

Cytokines and chemokines like the proinflammatory chemokine, monocytechemoattractant protein 1 (MCP-1) are important for the recruitment of inflammatory cells into multiple sclerosis (MS) lesions. Recently, a nucleotide substitution from adenosine to guanosine (A-->G) at position -2518 of the MCP-1 promoter was shown to be associated with increased MCP-1 expression. We analysed MCP-1 genotypes in 634 MS patients and 405 healthy controls. The allelic frequencies were comparable between both groups. No correlation was found between genotype and disease course, disease severity or age of disease onset. Although statistically no+ significant mRNA expression and MCP-1 secretion were elevated in patients carrying the mutant allele. Thus, our data could not reveal any association between the MCP-1 -2518 polymorphism and susceptibility to or clinical disease course of MS.     

MCP-1 promoter polymorphism in Spanish patients with systemic lupus erythematosus

The possible role of the functional polymorphism located in the regulatory region of the monocyte chemoattractant protein-1 (MCP-1) gene in the susceptibility to systemic lupus erythematosus (SLE) was investigated. Two hundred and seventy-six SLE patients (among them, 99 with lupus nephritis and 55 with cutaneous vasculitis) and 194 ethnically matched healthy controls were included in the study. Genotyping for -2518 (A/G) MCP-1 gene polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. No association between -2518 (A/G) MCP-1 polymorphism and susceptibility to SLE nor to lupus nephritis was found. However, a significant increase in the frequency of genotype AG and a decrease in the frequency of genotype AA were found among patients with cutaneous vasculitis (51% of AG vs. 32% in individuals without cutaneous vasculitis; P=0.008, OR=2.2, 95% CI: 1.18-4.25; and 47% of AA vs. 64%; P=0.03, OR=0.5, 95% CI: 0.27-0.96, respectively). These results indicate an association between the presence of G at position -2518 in the MCP-1 promoter region and the presence of cutaneous vasculitis among patients with SLE. This polymorphism does not seem to influence the susceptibility to SLE nor the appearance of lupus nephritis. Further studies are necessary in order to elucidate the role of this polymorphism in the pathogenesis of other inflammatory autoimmune diseases.     

Association of MCP-1 promotor polymorphism with disease severity of Crimean-Congo hemorrhagic fever

Crimean-Congo hemorrhagic fever (CCHF) is a thick-borne viral zoonotic disease. The pathogenesis and the reasons why cases have a mild or severe course in CCHF have not yet been explained. In this study, we investigated the relationship between promoter -2518 A/G single-nucleotide polymorphism (SNP) of the MCP-1 gene and the clinical course of CCHF. The MCP-1-2518 A/G SNP (rs1024611) frequency was examined in 128 virologically/serologically confirmed CCHF patients and 181 healthy controls by using the PCR-RFLP method. When CCHF patients and controls were compared, no significant difference was found between genotype distributions and allele frequencies of the -2518 A/G SNP of MCP-1 gene (P > .05). Compared to the AA genotype, both AG (P = .016; OR = 2.57) and GG genotype (P = .039; OR = 3.43) were found with significantly higher frequencies in mild/moderate cases than in severe cases. Compared to the AG + GG genotype, AA showed a significant risk for severe CCHF (60.0% vs 38.4%, P = .02; OR = 2.41). In contrast, the AG genotype showed a significant protective effect against severe disease compared to AA + GG genotype (29.1% vs 47.9%, P = .013; OR = 2.58). Compared to mild/moderate cases, the A allele was found to be significantly higher in severe cases (0.745 vs 0.623, P = .039; OR = 1.77). However, no significant relationship was found between fatal and nonfatal cases in terms of genotype or allele frequencies (P > .05). In conclusion, both -2518 AA genotype and A allele of MCP-1 were associated with disease severity, and the AG genotype had a protective effect against a severe disease course in CCHF patients.     

雌激素受体基因多态性与狼疮性肾炎临床病理的关系

目的 了解雌激素受体（ｅｓｔｒｏｇｅｎ ｒｅｃｅｐｔｉｏｒ，ＥＲ）基因多态性在狼疮性肾炎（ｌｕｐｕｓ ｎｅｐｈｒｉｔｉｓ，ＬＮ）患者中的分布特点，以及不同ＥＲ基因型ＬＮ患者的临床病理特征。方法 用聚合酶链反应－限制性酶切长度多态性分析方法，对２４５例ＬＮ患者（男５８例，女１８７例）基因组ＤＮＡ中ＥＲ基因多态性进行观察，并比较了不同性别ＬＮ患者与正常对照间ＥＲ基因多态性的分布特点。在此基础上进一步比     

Interference of antimodified C-reactive protein autoantibodies from lupus nephritis in the biofunctions of modified C-reactive protein

Autoantibodies against modified C-reactive protein (mCRP) are frequently found in patients with lupus nephritis and are associated with disease activity, suggesting their pathogenic role in lupus nephritis. The aim of this study was to investigate the influence of anti-mCRP autoantibodies from patients with lupus nephritis on the biofunctions of mCRP. mCRP plays important roles in the clearance of apoptotic cells and immune complex-mediated injuries via binding to C1q and factor H and acting as an opsonin. In this study, we confirmed that mCRP could bind to C1q and factor H, and the binding between mCRP and C1q was mainly via the collagen-like region of C1q by enzyme-linked immunosorbent assay and surface plasmon resonance. mCRP could significantly enhance the phagocytosis of late apoptotic cells in the presence of normal human serum. Autoantibodies against mCRP, purified from immunoglobulin G fractions of 3 patients with lupus nephritis by affinity chromatography, could significantly inhibit the binding between mCRP and C1q or factor H and reduce the clearance of late apoptotic cells enhanced by mCRP. Our observations suggest that anti-mCRP autoantibodies from patients with lupus nephritis might be pathogenic in systemic lupus erythematosus and lupus nephritis through interfering with the biofunctions of mCRP.     

Involvement of spinal monocyte chemoattractant protein-1 (MCP-1) in cancer-induced bone pain in rats

In this study, we examined the involvement of chemokine monocyte chemoattractant protein-1 (MCP-1) in the spinal cord of a rat model of cancer-induced bone pain (CIBP). In this model, CIBP was established by an intramedullary injection of Walker 256 cells into the tibia of rats. We observed a significant increase in expression levels of MCP-1 and its receptor CCR2 in the spinal cord of CIBP rats. Furthermore, the intrathecal administration of an anti-MCP-1 neutralizing antibody attenuated the mechanical allodynia established in CIBP rats. Likewise, an intrathecal injection of exogenous recombinant MCP-1 induced a striking mechanical allodynia in naïve rats. These results suggest that increases in spinal MCP-1 and CCR2 expression are involved in the development of mechanical allodynia associated with bone cancer rats.     

中国苏州地区汉族人群MCP-1基因多态性与急性胰腺炎相关性研究

目的探讨中国苏州地区汉族人群单核细胞趋化因子蛋白-1(monocyte chemoattractant protein-1,MCP-1)基因-2518A/G多态性与急性胰腺炎的相关性。方法采用聚合酶链反应-限制性片段长度多态性方法检测中国苏州汉族人群急性胰腺炎(acute pancreatitis,AP)患者101例[其中包括轻症急性胰腺炎(mildAP,MAP)78例,重症急性胰腺炎(servere AP,SAP)23例]和120名健康对照的MCP-1基因-2518位点基因型分布及基因频率,并评价基因多态性与AP易感性之间的相关性。结果对照组MCP-1-2518A/G位点的AA基因型频率较SAP组和MAP组高,差异有统计学意义(P<0.01),携AG及GG基因型者患MAP的风险度约是AA基因型的5.896倍(P<0.01,OR=5.896),患SAP的风险度约为7.011倍(P<0.05,OR=7.011)。而在MAP与SAP组间AA基因型频率差异无统计学意义(P=0.997)。对照组G等位基因频率明显低于MAP(P<0.01,OR=0.318)和SAP组(P<0.01,OR=0.309)。但G等位基因频率在MAP与SAP组间基因型分布差异无统计学意义(P=0.623,OR=1.211)。结论中国苏州地区汉族人群MCP-1-2518位点AA基因型可能有助于保护机体避免发生AP,G等位基因频率较高的人可能易患AP。但AA基因型和G等位基因频率不能预测SAP的发生。     

中国北方地区汉族人群MCP-1基因多态性与肺癌相关性研究

目的 探讨中国北方地区汉族人群单核细胞趋化因子蛋白-1(monocyte chemoattrac-tant protein 1,MCP-1)基因-2518位点多态性与肺癌的相关性.方法 应用聚合酶链反应-限制性片段长度多态性(polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)的方法对中国北方地区汉族人群134例肺癌患者和82例正常对照进行MCP-1基因-2518位点基因多态性检测.结果 AA基因型和GG基因型频率在肺癌病人和对照组间差异有统计学意义.AA基因型患肺癌的相对风险度增加(OR=2.645,X~2=6.532,P=0.011),GG基因型患肺癌的相对风险度降低(OR=0.519,X~2=4.929,P=0.026).肺癌病人中非小细胞肺癌患者AA基因型和GG基因型频率在病人和对照组间差异有统计学意义,AA基因型患病的相对风险度增加(OR=3.138,X~2=8.905,P=0.003),GG基因型患病的相对风险度降低(OR=0.516,X~2=4.613,P=0.032).小细胞肺癌患者各基因型频率与对照组差异无统计学意义.结论 中国北方地区汉族人群MCP-1基因-2518位点多态性与非小细胞肺癌相关,与小细胞肺癌不相关.     

狼疮肾炎患者PBMC-CM对系膜细胞表达MCP-1的影响

目的探讨狼疮肾炎（心）患者外周血单个核细胞条件培养液（PBMC-CM）对系膜细胞表达单核细胞趋化蛋白-1（MCP-1）的影响。方法用免疫组化观察LN患者PBMC-CM对系膜细胞表达MCP-1和蛋白激酶C（PKC）的影响。结果LN患者PBMC-CM干预系膜细胞后,系膜细胞增多,培养上清Ⅳ型胶原和层黏蛋白表达增加,系膜细胞MCP-1、PKC表达增加,呈直线相关关系。结论LN患者PBMC-CM能刺激系膜细胞增殖,促进细胞外基质增多及MCP-1的表达增加,从而可能参与LN发病。     

Lack of association between the -2518G/A polymorphism of the MCP-1 gene and ischaemic heart disease: a family-based investigation

Using two recently described family-based tests of association, the possible role of the functional -2518G/A polymorphism in the promoter region of the monocyte chemoattractant protein-1 (MCP-1) gene in the susceptibility to ischaemic heart disease (IHD) was investigated in a well-defined Irish population. One thousand and twelve individuals from 386 families with at least one member prematurely affected with IHD were genotyped for the MCP-1 -2518G/A polymorphism. Using the combined transmission disequilibrium test and the pedigree disequilibrium test, no association between the MCP-1 -2518G/A polymorphism and IHD was found. Our data demonstrate that, in an Irish population, the MCP-1 -2518G/A polymorphism is not strongly associated with IHD.     

甲基强的松龙对狼疮性肾炎患者血浆中PAI-1的影响

目的 :研究甲基强的松龙对Ⅳ型狼疮性肾炎 (LN)患者血浆中 1型纤溶酶原激活物抑制物 (PAI 1)的影响。方法 :应用免疫组织化学ELISA方法检测患者血浆中PAI 1含量。结果 :①LN治疗组与对照组比较 (P <0 0 1) ;②LN患者经甲基强的松龙两次冲击治疗后与治疗前分别比较 (P <0 .0 1) ;③甲基强的松龙第二次冲击治疗后 ,与对照组比较无显著性差异 (P >0 0 5 )。结论 :甲基强的松龙通过干扰纤溶酶原激活物 (PA) 纤溶酶系统 ,使LN病人血浆中PAI 1含量明显降低 ,从而发挥治疗作用。     

狼疮性肾炎患者肾组织Epstein-Barr病毒感染状况及其致病作用初探

并感染之间以及不同病理类型之间差异均无统计学意义(P＞0.05).肾组织EBER和EBV LMP1表达阳性的LN患者的血清中anti-Sm-Ab阳性率显著高于两标记物表达阴性的LN患者(EBER:34.3%vs 8.7%,EBV LMP1:35.3%vs 9.1%,P均＜0.05).结论 肾组织EBV感染可能参与了LN的发病,其机制可能部分与诱导机体产生自身抗体anti-Sm-Ab有关.     

SLE患者检测hsCRP的临床意义

目的探讨系统性红斑狼疮(SLE)患者超敏C反应蛋白(hsCRP)与病情及补体间的关系。方法对115例系统性红斑狼疮的患者,采用系统性红斑狼疮疾病活动指数(SLEDAI)评估狼疮病情。采用比浊法检测超敏C反应蛋白和补体水平。结果 115例患者中有42例(36.5%)超敏C反应蛋白升高,超敏C反应蛋白增高与感染相关(P0.001),伴有细菌、病毒、寄生虫感染的患者超敏C反应蛋白增高。狼疮性肾炎组超敏C反应蛋白(29.21±3.82)mg/L较非狼疮性肾炎组(27.23±2.46)mg/L轻度增高,但结果无统计学意义。超敏C反应蛋白增高组的患者较正常组患者,补提水平显著减低(P=0.03)。结论超敏C反应蛋白增高与系统性红斑狼疮患者合并感染及低补体血症相关。超敏C反应蛋白可以作为评估狼疮患者是否合并感染的有效指标。     

Correlation of plasma monocyte chemoattractant protein-1 (MCP-1) and monocyte inflammatory protein-1α (MIP-1α) levels with disease activity and clinical course of sarcoidosis

MCP-1 and MIP-1α exhibit chemotactic activity toward macrophages/monocytes and induce the production of inflammatory cytokines affecting granuloma formation. Up-regulated expression of MCP-1 and MIP-1α in the affected organ of sarcoidosis has been shown; however, the relationship between their plasma levels and the clinical course of this disease has not been determined. In the present study we measured plasma MCP-1 and MIP-1α levels in 26 patients with active sarcoidosis by ELISA in order to assess the state of MCP-1 and MIP-1α in this disease. Most patients in this study (21/26) had clinical evidence of extrathoracic disease in addition to pulmonary involvement. In addition, a high proportion of patients (n = 15) showed spontaneous remission of disease, whereas five patients showed no spontaneous remission and six patients were treated with corticosteroids over the 2-year period of study. At the time of diagnosis, both plasma MCP-1 and MIP-1α levels in patients with active sarcoidosis were significantly higher than in the normal controls. The levels of these cytokines in patients with extrathoracic disease were compatible with those in patients without extrathoracic disease. A longitudinal evaluation of plasma MCP-1 and MIP-1α levels showed that the changes in both cytokines were closely related to the clinical course of sarcoidosis. These results suggest that plasma MCP-1 and MIP-1α may be useful parameters for monitoring the clinical course of sarcoidosis. In addition, plasma MCP-1 and MIP-1α may reflect subclinical evidence of extrathoracic sarcoidosis and may play a role in initiating monocyte migration into the tissue.     

Primary central nervous system lymphoma secretes monocyte chemoattractant protein 1

The majority of primary central nervous system lymphomas (PCNSL) are diffuse large B-cell lymphomas. Histologically, reactive T lymphocytes and monohistiocytic cells are found within PCNSL tissue. To clarify the mechanisms of the cellular infiltration, the presence of monocyte chemoattractant protein (MCP-1) was investigated in biopsy samples of 19 cases of PCNSL by means of immunohistochemical staining, double staining with a confocal laser microscope, and Western blot analysis. MCP-1 expression was observed in all PCNSL immunohistochemically. Western blot analysis showed that the concentration of MCP-1 in PCNSL was as high as that in a metastatic brain tumor. In normal brain tissue, MCP-1 was not detected. Confocal laser microscope revealed MCP-1 signals were present in the cells with CD20, a B-cell marker. We concluded that lymphoma cells produced MCP-1, which is an additional cytokine involved in the pathogenesis of PCNSL.     

白细胞介素-15在狼疮性肾炎活动病变中的临床意义

目的：检测狼疮肾炎(LN)患者外周血白细胞介素15（IL-15）水平，并进一步分析其与临床有关指标的关系及治疗前后的变化。方法：用酶联免疫吸附法（ELISA）方法检测外周血IL-15水平；采用梯度密度离心法分离外周血单个核细胞(PBMCs)；并研究地塞米松对体外培养的活动期LN患者PBMCs分泌IL-15、IgG和dsDNA抗体的影响。结果：（1）LN组患者血清IL-15水平显著高于正常对照组(P<0.01)，活动期LN患者血清IL-15水平显著高于缓解期患者(P<0.05)。（2）活动期LN患者血清IL-15水平与SLE活动性指数(SLEDAI)、抗dsDNA抗体、24 h尿蛋白排泄量呈正相关关系，与补体C3呈负相关关系，而与血肌酐无相关关系。（3）激素联合环磷酰胺系统治疗活动期LN患者12周，治疗后随病情缓解血清IL-15水平明显下降。（4）体外培养的活动期LN患者PBMCs分泌IL-15、IgG、dsDNA抗体均显著高于正常对照组，而且IL-15分泌与dsDNA抗体和IgG合成呈正相关关系；地塞米松可明显抑制活动期LN患者PBMCs合成IL-15、IgG、dsDNA抗体。结论：LN患者外周血IL-15水平显著增高,IL-15可能参与LN的病理生理过程；血清IL-15水平检测可作为判断LN是否活动的指标之一。     

MCP-1 gene regulatory region polymorphism in Chinese children with mild, moderate and near-fatal asthma

BACKGROUND: A polymorphism in the monocyte chemoattractant protein 1 (MCP-1) gene regulatory region has been associated with asthma in Caucasians. This polymorphism is possibly endemic to the Asian region, but its impact on Asian populations is unclear. In addition, the relationship of this marker with life-threatening asthma has not been clarified. The aim of this study was to test the genetic association between the MCP-1 -2518A/G polymorphism and asthma/atopy in a cohort of Chinese children, with particular emphasis on those patients who had experienced life-threatening asthma attacks. METHODS: Forty-eight children with near-fatal asthma, 134 mild-to-moderate asthmatics, 69 allergic-disorder cases without asthma, and 107 nonasthmatic, nonatopic control children were genotyped by a polymerase chain reaction-based assay. RESULTS: Comparison of the four groups of children (n = 358) revealed no detectable differences in genotype or allele frequencies of the MCP-1 -2518A/G polymorphism. There was no evidence of association between the polymorphism and any of the outcomes of interest including clinical severity, blood eosinophil count, atopy, total serum IgE levels, and degree of bronchial hyper-responsiveness. CONCLUSION: These results suggest that the MCP-1 -2518A/G polymorphism is not a risk factor for near-fatal asthma. Furthermore, this polymorphism seems to play no role in the development of asthma or atopy in Chinese subjects, possibly as a result of the genetic heterogeneity between Asian and Caucasian populations with respect to regulation of MCP-1 expression. Our results underscore the necessity of accounting for ethnic background in the investigation of asthma-predisposition genes.     

C1q rs292001 polymorphism and C1q antibodies in juvenile lupus and their relation to lupus nephritis

C1q deficiency is related strongly to systemic lupus erythematosus (SLE), but very few and inconsistent studies explored the single nucleotide polymorphisms of the C1q gene in relation to juvenile SLE (jSLE) and lupus nephritis (LN). The objective of this study was to analyse whether C1q rs 292001 polymorphism is associated with SLE and disease phenotype, especially nephritis, and to investigate the relation between this polymorphism and clinical data, treatment outcome, serum level of C1q protein and antibodies. Typing of C1q rs292001 polymorphism using restriction fragment length polymorphism and measuring serum levels of C1q protein and antibodies by enzyme-linked immunosorbent assay (ELISA) were performed for 130 children with SLE and 208 healthy controls. The A allele of C1q rs292001 was associated with jSLE and LN (P = 0·005 and 0·013, respectively) and the AA genotype was associated with jSLE (P = 0·036). Low serum levels of C1q protein were found in jSLE and LN (P < 0·001 and 0·009, respectively), and these levels were increased after treatment in patients with LN (P = 0·009) and active renal disease (P = 0·027). Higher titres of C1q antibodies were found in patients with LN (P = 0·015) and correlated negatively with C1q protein level (P < 0·001) and patient age (P = 0·04). The A allele and AA genotype of C1q rs292001 can be considered a susceptibility risk factor and the GG genotype could be considered protective for jSLE and LN in the studied cohort of Egyptian children. Decreased serum levels of C1q protein and increased titres of C1q antibodies may be involved in the pathogenesis of jSLE, especially LN.     

The role of Stim1 in the progression of lupus nephritis in mice

Objective: To investigate the expression of Stim1 in the kidneys of mice with lupus, and the effect of Stim1 on the progression of renal interstitial fibrosis. Methods: Mice (MRL/lpr) with spontaneous lupus nephritis (LN) and normal control mice (C57/BL) were selected. Immunohistochemistry and Masson staining were used to determine the degree of renal interstitial fibrosis in kidney tissues. The expression of Stim1 and fibronectin in tissues was measured by qRT-PCR, western blotting, and immunohistochemistry. Urine protein, blood urea nitrogen, and serum creatinine levels in the mice were analyzed, and Spearman analysis was conducted to determine the correlation with Stim1 expression levels. Mouse renal tubular epithelial cells (mRTECs) were chosen as the experimental objects. After various treatments, the cells were divided into the blank control group, lipopolysaccharide (LPS) treatment group, LPS+siRNA-NC group and LPS+siRNA-Stim1 group. Western blotting and immunofluorescence were used to measure epithelial-mesenchymal transition (EMT)-related protein levels. Results: There was significant interstitial fibrosis in the kidneys of LN mice. Compared with that in normal mice, the expression of Stim1 in the kidney tissues of LN mice was significantly increased, and Stim1 expression was positively correlated with fibronectin, urine protein, blood urea nitrogen and serum creatinine levels. LPS induced the expression of Stim1, fibronectin, and α-SMA in mRTECs and decreased the protein level of E-CA, while silencing Stim1 effectively alleviated the effects of LPS. Conclusion: Stim1 is significantly increased in the kidneys of lupus mice, and it is possible to promote EMT in renal tubular epithelial cells and renal interstitial fibrosis by elevating fibronectin, which ultimately contributes to renal damage.     

环磷酰胺冲击疗法对狼疮性肾炎血清IL—6的影响

目的探讨白介素-6(IL-6)在狼疮性肾炎(LN)发病中的作用及大剂量环磷酰胺静脉给药(IV-CTX)对IL-6产生的影响.方法应用ELISA双抗体夹心法对IV-CTX治疗前后LN患者血清IL-6水平进行检测.结果活动期LN血清IL-6水平显著高于非活动期及健康人(P＜0.001),血清IL-6水平与血沉呈显著正相关(n=22,r=0.570,P＜0.01);抗ds-DNA抗体阳性且血清IgG＞16g/L的LN患者有更高的血清IL-6水平(P＜0.05);活动期LN治疗4w后血清IL-6水平显著下降(P＜0.001).结论LN的B细胞过度活化和自身抗体产生可能与IL-6分泌过量有关.IV-CTX可能通过抑制IL-6的产生而减轻免疫损伤,血清IL-6检测有助于监视狼疮活动和免疫抑制剂疗效.