CD147及RECK在系统性红斑狼疮发病机制及治疗中的作用
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摘要
一、研究背景
系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种多系统受累的自身免疫病,主要发生于育龄期妇女,病变累及包括关节肌肉、皮肤、肾脏等在内的多个系统的器官,严重影响人体健康。SLE的病因和发病机制迄今尚未完全明了,目前认为是具有遗传异质性的个体在环境和性激素等因素的相互影响及共同作用下,出现免疫调节功能紊乱,导致SLE的发生。
近20年来,SLE的预后已经大为改善,目前其10年生存率可达90%以上。性别、年龄、疾病严重程度、治疗方案等因素均能影响SLE患者生存率。早期干预及控制疾病损伤与提高对高血压、感染及其它临床风险的控制在改善患者预后方面卓有成效。但狼疮血管炎所造成的器官损伤仍然严重影响患者预后。因此,深入了解狼疮血管炎的发病机制及控制方法有助于寻找确切有效的治疗手段。
血管炎是SLE的基本病变之一,临床表现多种多样,可发生于病程任何阶段。在美国和加拿大多数风湿病专家所选出的狼疮活动性评价项目、英国狼疮评估小组及Liang提出的24项判断狼疮活动的指标中,血管炎均是判断SLE活动的重要指标。SLE血管炎可累及多个系统的脏器而严重威胁患者生命:累及肺最终可导致肺动脉高压;累及消化系统可致急性胰腺炎,亦可导致食道、胃、小肠、结肠组织出血、坏死或穿孔;累及中枢神经系统可因血管炎引起脑梗塞或脑出血而致患者构语障碍、偏瘫甚至出现癫痫大发作的狼疮脑病危象。
基质金属蛋白酶-9(matrix metalloproteinase 9,MMP-9)是基质金属蛋白酶(MMPs)家族成员,其主要功能是降解细胞外基质(extracellular cell matrix,ECM),在血管炎的发生中起到重要作用。越来越多的证据表明,MMP-9通过降解血管基底膜的主要成分,使内皮细胞通透性增加,炎性细胞易于侵入血管壁,引发炎症反应,从而参与系统性红斑狼疮发病的多个环节。
已有研究表明,SLE患者PBMCs分泌MMP-9的能力增强,但是关于SLE患者血清MMP-9浓度变化及其与SLE病情活动关系的研究结论并不一致,有学者研究认为血清MMP-9水平的降低是疾病活动的标志,也有研究结果显示活动期患者MMP-9水平升高。Meta分析是一种对已有具有相同研究目的的多个独立研究资料结果进行综合评价和定量合并分析的统计分析方法。因此我们对公开发表的有关SLE患者血清MMP-9浓度的研究进行了Meta分析,以期进一步明确SLE患者血清MMP-9浓度变化情况及其与病情活动的关系。
MMP-9可通过降解血管基底膜的主要成分,直接破坏血管内皮屏障,使内皮细胞通透性增加,有助于免疫细胞黏附于血管内皮分泌炎性细胞因子和MMP-9,进一步促进炎症发展;也可与TNF-α、IL-1等在SLE发病中作用已证实的细胞因子相互作用放大免疫介导的炎症反应;此外,它可以降解肾小球基底膜,促进SLE肾损害。过度产生的MMP-9可加剧内皮细胞损伤,促进炎症细胞穿过基底膜,最终导致血管炎的发生。因此,对MMP-9的抑制可防止血管炎所致SLE器官损伤。
目前,已有数种人工MMPs抑制剂初步用于一些肿瘤和自身免疫病的治疗。因为其严重的骨骼肌毒性或关节毒性,临床实验效果欠佳,应用受限。因此,对新的MMPs抑制方法的探讨十分必要。
CD147为免疫球蛋白超家族(Immunoglobulin Superfamily,IgSF)成员,曾被命名为肿瘤细胞来源的胶原酶刺激因子(tumor cell-derived collagenase stimulatory factor,TCSF)、细胞外基质金属蛋白酶诱导因子(Extracellular matrix metalloproteinasesinducer,EMMPRIN)、人白细胞活化抗原M6及基础免疫球蛋白(basic immunoglobulin,basigin)等,能诱导基质金属蛋白酶在多种细胞表面的表达和活化,参与细胞之间、细胞与基质之间的相互作用,在肿瘤的侵袭与转移及一些自身免疫病的发生发展中起到重要作用。
RECK(reversion-inducing cysteine-rich protein with Kazal motifs),是一种新的MMPs抑制剂,其分子量约为110kD,是膜表面锚定糖蛋白。它含有表皮生长因子(epidermal growth factor,EGF)样重复序列以及丝氨酸蛋白酶抑制剂样区域。RECK可抑制MMPs的分泌,其下调被认为与肿瘤血管生成和肿瘤浸润生长有关,作用机制未明。RECK在类风湿关节炎患者滑膜中的表达明显低于骨关节炎和外伤关节炎患者,但关于RECK在系统性红斑狼疮中的研究,至今尚未见报道。
二、目的
评价SLE患者血清MMP-9浓度的变化及其与病情活动性关系;检测SLE患者外周血单个核细胞(peripheral blood mononuclear cells,PBMCs)CD147、RECK的表达,分析及其与MMP-9分泌能力及患者临床特点的相关性;探讨CD147和RECK在系统性红斑狼疮发病中的作用及抗CD147单抗在治疗系统性红斑狼疮中的价值。
三、研究对象和方法
(一)研究对象
1.国内外公开发表的关于SLE患者血清浓度变化及其与病情活动关系的文献;
2.SLE患者69例,为2006年7月至2007年3月在山东省立医院风湿免疫科门诊就诊或病房住院的患者;
3.健康志愿者23例,为2006年7月至2007年3月山东省立医院查体中心健康查体者。
(二)实验方法
1.对搜索出来的文献进行严格筛选;
2.密度梯度离心法分离PBMCs;
3.用流式细胞分析术检测CD147的表达;
4.RT-PCR法检测RECK mRNA和MMP-9 mRNA的表达;
5.Western Blotting法检测RECK蛋白的表达;
6.ELISA法检测血清及细胞培养液上清中MMP-9的浓度。
(三)统计学处理
1.对所筛选文献进行Meta分析;
2.使用t检验比较SLE患者和健康对照组各指标差异;
3.对SLE患者PBMCs CD147、RECK、MMP-9的表达、MMP-9的分泌、血清MMP-9浓度及临床特点进行Pearson相关分析;
4.使用2×2析因实验方差分析,判断抗CD147单抗对PBMCs RECK和MMP-9的表达及MMP-9分泌的作用;
5.P＜0.05认为有统计学意义。
四、结果
(一)Meta分析
1.SLE患者血清MMP-9浓度与健康对照没有差异;
2.活动期SLE患者血清MMP-9浓度与非活动期SLE患者血清MMP-9浓度没有差异;
(二)SLE患者PBMCs CD147、RECK、MMP-9的表达、MMP-9的分泌、血清MMP-9浓度的变化及其临床意义
1.CD147表达
SLE患者PBMCs CD147的表达高于健康对照组且与系统性红斑狼疮疾病活动指数(Systemic lupus erythematosus disease activity index,SLEDAI)正相关,与SLE患者损伤指数(Systemic lupus erythematosus damage index,SDI)无明显相关;出现口腔溃疡、肾损伤或血清抗心磷脂抗体滴度异常SLE患者PBMCs CD147的表达高于不出现以上各临床表现的SLE患者;
2.RECK表达
SLE患者PBMCs RECK蛋白的表达低于健康对照组且与SLEDAI无明显相关,与SDI负相关;出现颧部红斑、口腔溃疡、肾损伤、血清抗Smith抗体滴度异常或血清抗心磷脂抗体滴度异常SLE患者PBMCs RECK蛋白的表达低于不出现以上各临床表现的SLE患者;
SLE患者PBMCs RECK mRNA的表达低于健康对照组且与SLEDAI及SDI均无明显相关;出现盘状红斑SLE患者PBMCs RECK mRNA的表达高于不出现盘状红斑的SLE患者;
3.MMP-9表达
SLE患者PBMCs MMP-9 mRNA的表达高于健康对照组且与SLEDAI正相关,与SDI正相关;出现口腔溃疡或血清抗核抗体滴度异常SLE患者PBMCs MMP-9mRNA的表达高于不出现以上各临床表现的SLE患者;
4.MMP-9分泌
SLE患者PBMCs分泌MMP-9的能力高于健康对照组且与SLEDAI正相关,与SDI正相关;出现颧部红斑、口腔溃疡、肾损伤、血清Smith抗体或血清抗心磷脂抗体滴度异常的SLE患者PBMCs分泌MMP-9的能力高于不出现以上各临床表现者;
5.血清MMP-9浓度
SLE患者血清MMP-9浓度与健康对照组无区别且与SLEDAI及SDI均无明显相关;出现肾损伤的SLE患者血清MMP-9浓度低于不出现肾损伤的SLE患者;
(三)SLE患者PBMCs CD147、RECK表达、MMP-9表达及分泌与血清MMP-9浓度之间的关系
1.SLE患者PBMCs CD147表达与MMP-9表达的关系
SLE患者PBMCs CD147表达与MMP-9 mRNA的表达正相关;
2.SLE患者PBMCs CD147表达与MMP-9分泌的关系
SLE患者PBMCs CD147表达与MMP-9的分泌正相关;
3.SLE患者PBMCs CD147表达与血清MMP-9浓度的关系
SLE患者PBMCs CD147表达与血清MMP-9浓度无明显相关;
4.SLE患者PBMCs RECK表达与MMP-9表达的关系
SLE患者PBMCs RECK蛋白表达与MMP-9 mRNA表达负相关,RECK mRNA表达与MMP-9 mRNA表达无明显相关;
5.SLE患者PBMCs RECK表达与MMP-9分泌的关系
SLE患者PBMCs RECK蛋白表达与MMP-9分泌负相关,RECK mRNA表达与MMP-9分泌无明显相关;
6.SLE患者PBMCs RECK表达与血清MMP-9浓度的关系
SLE患者PBMCs RECK蛋白表达与血清MMP-9浓度无明显相关,RECK mRNA表达与血清MMP-9浓度无明显相关;
7.SLE患者PBMCs CD147表达与RECK表达的关系
SLE患者PBMCs CD147的表达与RECK蛋白表达负相关,与RECK mRNA表达无明显相关;
(四)抗CD147单抗对RECK表达、MMP-9表达及MMP-9分泌的作用
对于SLE患者PBMCs,抗CD147单抗可增加RECK蛋白的表达、降低MMP-9mRNA的表达并降低MMP-9的分泌;对于健康人PBMCs,抗CD147单抗对RECK蛋白及mRNA的表达、MMP-9的表达及分泌均无明显作用,但对PHA刺激后RECK表达的降低、MMP-9 mRNA表达的增高及MMP-9分泌的增多有抑制作用。
五、结论及意义
(一)Meta分析结果显示SLE患者血清MMP-9浓度与健康对照并无显著性差异,活动期SLE患者血清MMP-9浓度与非活动期患者亦无显著性差异;血清MMP-9浓度不足以协助诊断SLE,亦不足以用作判断SLE患者的病情活动性的指标;
(二)与健康对照相比,SLE患者PBMCs CD147表达升高、RECK蛋白表达降低、RECK mRNA表达降低、MMP-9 mRNA表达升高、分泌MMP-9的能力升高;
(三)出现口腔溃疡、肾损伤或血清抗心磷脂抗体滴度异常的SLE患者与不出现上述各项表现的SLE患者相比,其CD147表达更高、RECK蛋白的表达更低、分泌MMP-9的能力更强,更容易出现血管炎而引起严重的器官损伤,临床上应予以充分重视;
(四)SLE患者PBMCs CD147的表达与病情活动正相关,可用于判断SLE病情及治疗效果;
(五)SLE患者PBMCs RECK蛋白表达与疾病损伤负相关,可用于判断疾病损伤程度及预后,指导治疗;
(六)SLE患者PBMCs MMP-9 mRNA表达与病情活动正相关,与疾病损伤正相关,可用于判断病情及预后;
(七)SLE患者PBMCs分泌MMP-9能力与病情活动正相关,可用于协助判断SLE病情及治疗效果;
(八)SLE患者血清MMP-9浓度与健康对照无区别,此浓度与病情活动及预后均无明显相关,不能用于判断病情活动及预后;
(九)SLE患者PBMCs表面高表达的CD147对RECK蛋白的表达有抑制作用,可刺激MMP-9的分泌增多,在SLE血管炎所致损伤中起到重要作用;
(一○)SLE患者PBMCs RECK蛋白表达受抑与分泌MMP-9的增多有关,增加其表达可防止SLE中血管损伤的发生发展;
(一一)抗CD147单抗可抑制SLE患者PBMCs分泌MMP-9,此抑制作用与增加RECK蛋白的表达相关,有望用于SLE的治疗。
Background
Systemic lupus erythematosus(SLE)is the most representative autoimmune disease in humans.It is characterized by the presence of activated T cells and B cells in conjunction with the development of many different auto antibodies,and chronic inflammation that can affect various parts of the body including skin and kidney,resulting in significant morbility and mortality.Despite a large number of studies,the etiology and pathogenesis of SLE are not completely understood yet.An extremely complicated and multifactorial interaction among various genetic,hormone and environmental factors is probably involved.
As a basic pathology change happened in SLE,vasculitis appears in about fifty percents of SLE patients with various clinical manifestations.It could appear at any stage of SLE and has been estimated as the most effective index of disease activity.It is most commonly recognized in the skin but may be responsible for symptoms and findings in a number of organs and its presence is associated with increased mortality.For example, pulmonary hypertension will happen if vasculitis appears in lung;acute pancreatitis or haemorrhage,perforation or necrosis of esophagus,stomach,intestine or colon will happen if vasculitis appears in digestive system;crisis of lupus encephalopathy including anepia,hemiparalysis or major epilepsy caused by cerebral infarction or cerebral haemorrhage will happen ifvasculitis appears in central nervous system.
The prognosis of patients with SLE has improved substantially over the past two decades,with a ten-year survival of more than ninety percents in some centers.The prognosis heterogeneity associated with SLE can be attributed to gender,age,genetic clinical factors and treatment.Education,earlier intervention,better disease damage control and improved general management of hypertension,co-morbid infections and other clinical risks have contributed to reduced end-organ damage and less morbidity and mortality.Nonetheless,the serious organ damage caused by vasculitis remains a challenge for physicians.Further study of the pathology and controlling methods of vasculitis in SLE helps to find new strategies to improve long-term prognostic and life quality of the SLE patients.
Members of matrix metalloproteinases(MMPs)family can degenerate components of extracellular cell matrix(ECM)and thus play an important role in vasculitis.As a member of matrix metalloproteinases family,matrix metalloprteinases-9(MMP-9)has been associated with SLE for several years since 2002.It cleaves denatured collagens and type IV collagen,the major component of the basement membranes,and thus be involved in many physical and pathological progresses such as embryonic development,repair in trauma,vasculogenesis,inflammation,infiltration and metastasis of tumor and connective tissue diseases.MMP-9 triggers inflammation directly,by tissue destruction,or indirectly, by generation of an inflammatory signal or recruitment of inflammatory cells.Thus, overproduced MMP-9 may induce microvascular damage and leakage of substances that further augment endothelial cell damage and facilitate the movement of inflammatory cells across the basement membrane,ultimately leading to various vasculities of SLE. Inhibition of MMP-9 might be beneficial to preventing organ damage in SLE caused by vasculitis.
However,studies on changes of serum concentration of MMP-9 in SLE and the correlation between serum concentration of MMP-9 and disease activity showed different results.Because recta-analysis is an efficient tool to systematically review those published articles in associated articles with different results which could lead to powerful evidence and right direction for further research,we collected the published articles and make meta-analysis of the serum MMP-9 concentration changed in SLE patients and the differences between patietns with different disease activity.
In recent years,some MMPs inhibitors such as KR-31813 and BB-1101 were studied in therapy of certain human cancer and autoimmune diseases but no clinical efficacy was demonstrated.The non-specificity of inhibition or serious skeletal muscle damage of articular damage of these inhibitors calls for a new inhibition of MMPs.A new therapy targeted on MMP-9 which can improve long-term prognostic and life quality of patients with SLE is expected.
CD147,also known as tumor cell-derived collagenase stimulatory factor(TCSF), extracellular matrix metalloproteinase inducer(EMMPIN),human leukocyte activated antigen M6,and basic immunoglobulin(Basigin),is a member of immunoglobulin superfamily(IgSF).It is capable of inducing the expression and activation of several MMPs of different cells and involves in intercellular action and interaction between cells and matrix thus play an important role in infiltration and metastasis of tumor and development of some autoimmune diseases by an as yet unknown mechanism.CD147 is highly expressed on activated T lymphocytes and was identified as an activation associated antigen on phytohemagglutinine(PHA)activated T cells.
Reversion-inducing cysteine-rich protein with Kazal motifs(RECK),a novel MMPs inhibitor,is a membrane-anchored glycoprtein of approximately 110kD that contains multiple epidermal growth factor-like repeats and serine protease inhibitor-like domains. It inhibits MMP-2,MMP-9 and membrane type-1 secretion and activity.As a new MMPs inhibitor,RECK has been shown to be a prognostic marker in several kind of human tumor and plays an important role in angiogenesis.The expression of RECK in inflamed synovial membranes of patients with rheumatoid arthritis was decreased compared to those of patients with osculoarthritis or traumatic arthritis.Downregulation of RECK has been complicated with angiogenesis and infiltration of tumor.Apart of these studies,little was known on what role it plays in SLE.
Objective
To evaluate changes of serum concentration of MMP-9 in SLE patients and the correlation between serum concentration of MMP-9 with disease activity;determine the expression of CD147,RECK protein,RECK mRNA,MMP-9 mRNA and MMP-9 secretion of PBMCs in SLE patients;analyze correlation between these factors and clinical characters of SLE patients;study the roles of CD147 and RECK played in SLE and evaluate their value in SLE therapy.
Objects and methods
1.Objects
(1)Reported articles about serum concentrations of MMP-9 and correlation between serum concentration of MMP-9 and disease activity in SLE;
(2)Sixty nine SLE patients;
(3)Twenty three healthy donors.
2.Methods
(1)Articles searched out were selected critically according to the criteria of Lichtenstein;
(2)Peripheral blood mononuclear cells(PBMCs)were isolated by Ficoll gradient centrifugation;
(3)Flow cytometry analysis(FCAS)was used to determine the expression of CD147 on PBMCs;
(4)Semi-quantitative reverse transcription-polymerase chain reaction(RT-PCR)was used to determine the expression of RECK mRNA and MMP-9 mRNA;
(5)Western blotting was used to determine the expression of RECK protein;
(6)Enzyme linked immunosorbent assay(ELISA)was used to detect the concentrations of MMP-9 in serum and culture supernatants;
(7)Statistical analysis
①Meta analysis was used to evaluate the changes of serum concentration of MMP-9 in SLE patients and correlation between serum concentration of MMP-9 with disease activity;
②Student's t test was used to analysis the differences between between variables in SLE patients and healthy donors;
③Pearson r correlation test was used to evaluate the relationship between variables;
④A 2×2 factorial experiment was designed to study the effects of anti-CD147 monoantibody on the expression of RECK,the expression of MMP-9 and secretion of MMP-9;
⑤P values of less than 0.05 were considered significant.
Results
1.Meta analysis
(1)There is no difference between serum concentrations of MMP-9 in SLE patients and healthy controls;
(2)There is no difference between serum concentrations of MMP-9 in SLE patients with different disease activity.
2.Changes of expression of CD147,RECK and MMP-9,MMP-9 secretion of PBMCs and serum concentration of MMP-9 in patients with SLE and their clinical significance
(1)CD147 expression of PBMCs from SLE patients and its relationship with clinical features
CD147 was highly expressed on PBMCs from SLE patients than on PBMCs from healthy donors.PBMCs from SLE patients with oral ulcers,renal damage,or those with abnormal serum concentration of anticardiolipin antibody were more likely to have higher expression of CD147 than those from SLE patients without such manifestation.A positive correlation between CD147 expression and SLEDAI was observed,but no correlation between CD147 expression and SDI was found.
(2)RECK expression of PBMCs from SLE patients and its relationship with clinical features
PBMCs from SLE patients expressed lower RECK protein compared with those from healthy donors.PBMCs from SLE patients with malar rash,oral ulcers,renal damage or those with abnormal serum concentration of anti-Smith antibody or anticardiolipin antibody were more likely to have much lower expression of RECK protein than those from SLE patients without such manifestation.A negative correlation between RECK protein expression and SDI was observed,but no correlation between RECK expression and SLEDAI was found.
PBMCs from SLE patients expressed lower RECK mRNA compared with those from healthy donors.PBMCs from SLE patients with discoid rash were more likely to have much lower expression of RECK mRNA than those from SLE patients without discoid rash.No correlation was found between RECK mRNA and SDI.No correlation was found between RECK mRNA and SLEDAI.
(3)MMP-9 mRNA expression of PBMCs from SLE patients and its relationship with clinical features
PBMCs from SLE patients expressed higher MMP-9 mRNA compared with those from healthy donors.PBMCs from SLE patients with oral ulcer or those with abnormal serum concentration of antinuclear antibodies were more likely to have much higher expression of MMP-9 mRNA than those from SLE patients without such manifestation. MMP-9 mRNA expression was positively correlated with SLEDAI.MMP-9 mRNA expression was positively correlated with SDI,too.
(4)MMP-9 secretion of PBMCs from SLE patients and its relationship with clinical features
PBMCs from SLE patients secreted more MMP-9 compared with those from healthy donors.PBMCs from SLE patients with malar rash,oral ulcer,renal damage or those with abnormal serum concentration of anti-Smith antibody or anticardiolipin antibody were more likely to secreted much more MMP-9 than those from SLE patients without such manifestation.MMP-9 secretion was positively correlated with SLEDAI.MMP-9 secretion was positively correlated with SDI,too.
(5)Serum concentration of MMP-9 in SLE patients and its relationship with clinical features
There is no difference between the MMP-9 serum concentrations of SLE patients and healthy donors.The concentration of MMP-9 in serum of SLE patients with renal damage was lower than those of SLE patients without renal damage.No correlation between serum concentrations of MMP-9 with SLEDAI was found.No correlation between serum concentrations of MMP-9 with SDI was found.
3.Correlation between expression of CD 147,RECK,MMP-9,secretion of MMP-9 and serum concentration of MMP-9 in patiens with SLE
(1)Correlation between CD 147 expression and MMP-9 expression
CD147 expression was positively correlated with MMP-9 mRNA expression;
(2)Correlation between CD147 expression and MMP-9 secretion
CD147 expression was positively correlated with MMP-9 secretion;
(3)Correlation between CD147 expression and serum concentration of MMP-9
No correlation was found between CD147expression and serum concentation of MMP-9;
(4)Correlation between RECK expression and MMP-9 expression
The expression of RECK protein was negatively correlated with MMP-9 mRNA expression,but no correlation was found between the expression of RECK mRNA and MMP-9 mRNA expression;
(5)Correlation between RECK expression and MMP-9 secretion
The expression of RECK protein was negatively correlated with MMP-9 secretion, but no correlation was found between the expression of RECK mRNA and MMP-9 secretion;
(6)Correlation between RECK expression and serum concentration of MMP-9
Neither of RECK protein expression nor RECK mRNA expression was correlated with serum concentration of MMP-9;
(7)Correlation between CD 147 expression and RECK expression
The expression of CD147 was negatively correlated with RECK protein expression, but no correlation was found between the expression of CD147 and RECK mRNA;
4.Effects of anti-CD147 monoantibody on expression of RECK,MMP-9 and secretion of MMP-9
(1)As to PBMCs from SLE patients,anti-CD147 monoantibody could increase RECK protein expression,decrease MMP-9 mRNA expression and decrease MMP-9 secretion;
(2)As to PBMCs from healthy donors,anti-CD147 monoantibody had no effect on expression of RECK protein,RECK mRNA,MMP-9 mRNA and secretion of MMP-9;
(3)Anti-CD147 monoantibody could decrease the effects of PHA(MMP-9 secretion increased,MMP-9 mRNA expression increased,RECK protein expression decresed)on PBMCs from SLE patients and healthy donors.
Conclusion
1.The serum concentration of MMP-9 should not be used in SLE diagnosis,neither should it be used in judgement of disease activity;
2.Compared with PBMCs from healthy donors,PBMCs from SLE patients expressed higher CD147,lower RECK protein,lower RECK mRNA,higher MMP-9 mRNA and secreted more MMP-9;
3.PBMCs from SLE patients with oral ulcers,renal damage or those with abnormal serum concentration of anticardiolipin antibody were more likely to express much higher CD147,lower RECK protein,lower RECK mRNA,lower MMP-9 mRNA and secret more MMP-9 than those from SLE patients without such manifestation.Physicians should pay more attention to those patients because serious organ damage caused by vasculitis are more likely to appear;
4.CD147 expression on PBMCs from SLE patients was positively correlated with disease activity and could be used to assess disease status and estimate the therapeutic effects;
5.RECK protein expression on PBMCs from SLE patients was negatively correlated with damage accrual and might be regarded as an indicator of the disease course allowing clinicians to anticipate the intermediate and long-term outcomes of the disease;
6.MMP-9 mRNA expression was positively correlated with disease activity and damage accrual of SLE patients and could be used to assess disease status and anticipate the prognostics of SLE patients;
7.MMP-9 secretion ability of PBMCs in SLE patients was positively correlated with disease activity and could be used to assess disease status and estimate the therapeutic effects;
8.There is no difference between serum concentrations of MMP-9 in SLE patients and healthy donors;serum concentration was correlated with neither disease activity nor damage accrual;
9.Over expression of CD147 inhibited the expression of RECK protein and this inhibition increased the secretion of MMP-9 which plays important role in SLE pathology;
10.The decreased expression of RECK was correlated with overproduction of MMP-9.Vascular damage could be prevented by increasing the expression of RECK protein.This will be benefit for development of new therapy.
11.Anti-CD147 monoantibody could inhibit MMP-9 secretion of PBMCs in SLE patients.This effect might be correlated with upregulation of RECK protein.Anti-CD147 monoantibody might be prospective in SLE treatment.
系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种多系统受累的自身免疫病,主要发生于育龄期妇女,病变累及包括关节肌肉、皮肤、肾脏等在内的多个系统的器官,严重影响人体健康。SLE的病因和发病机制迄今尚未完全明了,目前认为是具有遗传异质性的个体在环境和性激素等因素的相互影响及共同作用下,出现免疫调节功能紊乱,导致SLE的发生。
近20年来,SLE的预后已经大为改善,目前其10年生存率可达90%以上。性别、年龄、疾病严重程度、治疗方案等因素均能影响SLE患者生存率。早期干预及控制疾病损伤与提高对高血压、感染及其它临床风险的控制在改善患者预后方面卓有成效。但狼疮血管炎所造成的器官损伤仍然严重影响患者预后。因此,深入了解狼疮血管炎的发病机制及控制方法有助于寻找确切有效的治疗手段。
血管炎是SLE的基本病变之一,临床表现多种多样,可发生于病程任何阶段。在美国和加拿大多数风湿病专家所选出的狼疮活动性评价项目、英国狼疮评估小组及Liang提出的24项判断狼疮活动的指标中,血管炎均是判断SLE活动的重要指标。SLE血管炎可累及多个系统的脏器而严重威胁患者生命:累及肺最终可导致肺动脉高压;累及消化系统可致急性胰腺炎,亦可导致食道、胃、小肠、结肠组织出血、坏死或穿孔;累及中枢神经系统可因血管炎引起脑梗塞或脑出血而致患者构语障碍、偏瘫甚至出现癫痫大发作的狼疮脑病危象。
基质金属蛋白酶-9(matrix metalloproteinase 9,MMP-9)是基质金属蛋白酶(MMPs)家族成员,其主要功能是降解细胞外基质(extracellular cell matrix,ECM),在血管炎的发生中起到重要作用。越来越多的证据表明,MMP-9通过降解血管基底膜的主要成分,使内皮细胞通透性增加,炎性细胞易于侵入血管壁,引发炎症反应,从而参与系统性红斑狼疮发病的多个环节。
已有研究表明,SLE患者PBMCs分泌MMP-9的能力增强,但是关于SLE患者血清MMP-9浓度变化及其与SLE病情活动关系的研究结论并不一致,有学者研究认为血清MMP-9水平的降低是疾病活动的标志,也有研究结果显示活动期患者MMP-9水平升高。Meta分析是一种对已有具有相同研究目的的多个独立研究资料结果进行综合评价和定量合并分析的统计分析方法。因此我们对公开发表的有关SLE患者血清MMP-9浓度的研究进行了Meta分析,以期进一步明确SLE患者血清MMP-9浓度变化情况及其与病情活动的关系。
MMP-9可通过降解血管基底膜的主要成分,直接破坏血管内皮屏障,使内皮细胞通透性增加,有助于免疫细胞黏附于血管内皮分泌炎性细胞因子和MMP-9,进一步促进炎症发展;也可与TNF-α、IL-1等在SLE发病中作用已证实的细胞因子相互作用放大免疫介导的炎症反应;此外,它可以降解肾小球基底膜,促进SLE肾损害。过度产生的MMP-9可加剧内皮细胞损伤,促进炎症细胞穿过基底膜,最终导致血管炎的发生。因此,对MMP-9的抑制可防止血管炎所致SLE器官损伤。
目前,已有数种人工MMPs抑制剂初步用于一些肿瘤和自身免疫病的治疗。因为其严重的骨骼肌毒性或关节毒性,临床实验效果欠佳,应用受限。因此,对新的MMPs抑制方法的探讨十分必要。
CD147为免疫球蛋白超家族(Immunoglobulin Superfamily,IgSF)成员,曾被命名为肿瘤细胞来源的胶原酶刺激因子(tumor cell-derived collagenase stimulatory factor,TCSF)、细胞外基质金属蛋白酶诱导因子(Extracellular matrix metalloproteinasesinducer,EMMPRIN)、人白细胞活化抗原M6及基础免疫球蛋白(basic immunoglobulin,basigin)等,能诱导基质金属蛋白酶在多种细胞表面的表达和活化,参与细胞之间、细胞与基质之间的相互作用,在肿瘤的侵袭与转移及一些自身免疫病的发生发展中起到重要作用。
RECK(reversion-inducing cysteine-rich protein with Kazal motifs),是一种新的MMPs抑制剂,其分子量约为110kD,是膜表面锚定糖蛋白。它含有表皮生长因子(epidermal growth factor,EGF)样重复序列以及丝氨酸蛋白酶抑制剂样区域。RECK可抑制MMPs的分泌,其下调被认为与肿瘤血管生成和肿瘤浸润生长有关,作用机制未明。RECK在类风湿关节炎患者滑膜中的表达明显低于骨关节炎和外伤关节炎患者,但关于RECK在系统性红斑狼疮中的研究,至今尚未见报道。
二、目的
评价SLE患者血清MMP-9浓度的变化及其与病情活动性关系;检测SLE患者外周血单个核细胞(peripheral blood mononuclear cells,PBMCs)CD147、RECK的表达,分析及其与MMP-9分泌能力及患者临床特点的相关性;探讨CD147和RECK在系统性红斑狼疮发病中的作用及抗CD147单抗在治疗系统性红斑狼疮中的价值。
三、研究对象和方法
(一)研究对象
1.国内外公开发表的关于SLE患者血清浓度变化及其与病情活动关系的文献;
2.SLE患者69例,为2006年7月至2007年3月在山东省立医院风湿免疫科门诊就诊或病房住院的患者;
3.健康志愿者23例,为2006年7月至2007年3月山东省立医院查体中心健康查体者。
(二)实验方法
1.对搜索出来的文献进行严格筛选;
2.密度梯度离心法分离PBMCs;
3.用流式细胞分析术检测CD147的表达;
4.RT-PCR法检测RECK mRNA和MMP-9 mRNA的表达;
5.Western Blotting法检测RECK蛋白的表达;
6.ELISA法检测血清及细胞培养液上清中MMP-9的浓度。
(三)统计学处理
1.对所筛选文献进行Meta分析;
2.使用t检验比较SLE患者和健康对照组各指标差异;
3.对SLE患者PBMCs CD147、RECK、MMP-9的表达、MMP-9的分泌、血清MMP-9浓度及临床特点进行Pearson相关分析;
4.使用2×2析因实验方差分析,判断抗CD147单抗对PBMCs RECK和MMP-9的表达及MMP-9分泌的作用;
5.P＜0.05认为有统计学意义。
四、结果
(一)Meta分析
1.SLE患者血清MMP-9浓度与健康对照没有差异;
2.活动期SLE患者血清MMP-9浓度与非活动期SLE患者血清MMP-9浓度没有差异;
(二)SLE患者PBMCs CD147、RECK、MMP-9的表达、MMP-9的分泌、血清MMP-9浓度的变化及其临床意义
1.CD147表达
SLE患者PBMCs CD147的表达高于健康对照组且与系统性红斑狼疮疾病活动指数(Systemic lupus erythematosus disease activity index,SLEDAI)正相关,与SLE患者损伤指数(Systemic lupus erythematosus damage index,SDI)无明显相关;出现口腔溃疡、肾损伤或血清抗心磷脂抗体滴度异常SLE患者PBMCs CD147的表达高于不出现以上各临床表现的SLE患者;
2.RECK表达
SLE患者PBMCs RECK蛋白的表达低于健康对照组且与SLEDAI无明显相关,与SDI负相关;出现颧部红斑、口腔溃疡、肾损伤、血清抗Smith抗体滴度异常或血清抗心磷脂抗体滴度异常SLE患者PBMCs RECK蛋白的表达低于不出现以上各临床表现的SLE患者;
SLE患者PBMCs RECK mRNA的表达低于健康对照组且与SLEDAI及SDI均无明显相关;出现盘状红斑SLE患者PBMCs RECK mRNA的表达高于不出现盘状红斑的SLE患者;
3.MMP-9表达
SLE患者PBMCs MMP-9 mRNA的表达高于健康对照组且与SLEDAI正相关,与SDI正相关;出现口腔溃疡或血清抗核抗体滴度异常SLE患者PBMCs MMP-9mRNA的表达高于不出现以上各临床表现的SLE患者;
4.MMP-9分泌
SLE患者PBMCs分泌MMP-9的能力高于健康对照组且与SLEDAI正相关,与SDI正相关;出现颧部红斑、口腔溃疡、肾损伤、血清Smith抗体或血清抗心磷脂抗体滴度异常的SLE患者PBMCs分泌MMP-9的能力高于不出现以上各临床表现者;
5.血清MMP-9浓度
SLE患者血清MMP-9浓度与健康对照组无区别且与SLEDAI及SDI均无明显相关;出现肾损伤的SLE患者血清MMP-9浓度低于不出现肾损伤的SLE患者;
(三)SLE患者PBMCs CD147、RECK表达、MMP-9表达及分泌与血清MMP-9浓度之间的关系
1.SLE患者PBMCs CD147表达与MMP-9表达的关系
SLE患者PBMCs CD147表达与MMP-9 mRNA的表达正相关;
2.SLE患者PBMCs CD147表达与MMP-9分泌的关系
SLE患者PBMCs CD147表达与MMP-9的分泌正相关;
3.SLE患者PBMCs CD147表达与血清MMP-9浓度的关系
SLE患者PBMCs CD147表达与血清MMP-9浓度无明显相关;
4.SLE患者PBMCs RECK表达与MMP-9表达的关系
SLE患者PBMCs RECK蛋白表达与MMP-9 mRNA表达负相关,RECK mRNA表达与MMP-9 mRNA表达无明显相关;
5.SLE患者PBMCs RECK表达与MMP-9分泌的关系
SLE患者PBMCs RECK蛋白表达与MMP-9分泌负相关,RECK mRNA表达与MMP-9分泌无明显相关;
6.SLE患者PBMCs RECK表达与血清MMP-9浓度的关系
SLE患者PBMCs RECK蛋白表达与血清MMP-9浓度无明显相关,RECK mRNA表达与血清MMP-9浓度无明显相关;
7.SLE患者PBMCs CD147表达与RECK表达的关系
SLE患者PBMCs CD147的表达与RECK蛋白表达负相关,与RECK mRNA表达无明显相关;
(四)抗CD147单抗对RECK表达、MMP-9表达及MMP-9分泌的作用
对于SLE患者PBMCs,抗CD147单抗可增加RECK蛋白的表达、降低MMP-9mRNA的表达并降低MMP-9的分泌;对于健康人PBMCs,抗CD147单抗对RECK蛋白及mRNA的表达、MMP-9的表达及分泌均无明显作用,但对PHA刺激后RECK表达的降低、MMP-9 mRNA表达的增高及MMP-9分泌的增多有抑制作用。
五、结论及意义
(一)Meta分析结果显示SLE患者血清MMP-9浓度与健康对照并无显著性差异,活动期SLE患者血清MMP-9浓度与非活动期患者亦无显著性差异;血清MMP-9浓度不足以协助诊断SLE,亦不足以用作判断SLE患者的病情活动性的指标;
(二)与健康对照相比,SLE患者PBMCs CD147表达升高、RECK蛋白表达降低、RECK mRNA表达降低、MMP-9 mRNA表达升高、分泌MMP-9的能力升高;
(三)出现口腔溃疡、肾损伤或血清抗心磷脂抗体滴度异常的SLE患者与不出现上述各项表现的SLE患者相比,其CD147表达更高、RECK蛋白的表达更低、分泌MMP-9的能力更强,更容易出现血管炎而引起严重的器官损伤,临床上应予以充分重视;
(四)SLE患者PBMCs CD147的表达与病情活动正相关,可用于判断SLE病情及治疗效果;
(五)SLE患者PBMCs RECK蛋白表达与疾病损伤负相关,可用于判断疾病损伤程度及预后,指导治疗;
(六)SLE患者PBMCs MMP-9 mRNA表达与病情活动正相关,与疾病损伤正相关,可用于判断病情及预后;
(七)SLE患者PBMCs分泌MMP-9能力与病情活动正相关,可用于协助判断SLE病情及治疗效果;
(八)SLE患者血清MMP-9浓度与健康对照无区别,此浓度与病情活动及预后均无明显相关,不能用于判断病情活动及预后;
(九)SLE患者PBMCs表面高表达的CD147对RECK蛋白的表达有抑制作用,可刺激MMP-9的分泌增多,在SLE血管炎所致损伤中起到重要作用;
(一○)SLE患者PBMCs RECK蛋白表达受抑与分泌MMP-9的增多有关,增加其表达可防止SLE中血管损伤的发生发展;
(一一)抗CD147单抗可抑制SLE患者PBMCs分泌MMP-9,此抑制作用与增加RECK蛋白的表达相关,有望用于SLE的治疗。
Background
Systemic lupus erythematosus(SLE)is the most representative autoimmune disease in humans.It is characterized by the presence of activated T cells and B cells in conjunction with the development of many different auto antibodies,and chronic inflammation that can affect various parts of the body including skin and kidney,resulting in significant morbility and mortality.Despite a large number of studies,the etiology and pathogenesis of SLE are not completely understood yet.An extremely complicated and multifactorial interaction among various genetic,hormone and environmental factors is probably involved.
As a basic pathology change happened in SLE,vasculitis appears in about fifty percents of SLE patients with various clinical manifestations.It could appear at any stage of SLE and has been estimated as the most effective index of disease activity.It is most commonly recognized in the skin but may be responsible for symptoms and findings in a number of organs and its presence is associated with increased mortality.For example, pulmonary hypertension will happen if vasculitis appears in lung;acute pancreatitis or haemorrhage,perforation or necrosis of esophagus,stomach,intestine or colon will happen if vasculitis appears in digestive system;crisis of lupus encephalopathy including anepia,hemiparalysis or major epilepsy caused by cerebral infarction or cerebral haemorrhage will happen ifvasculitis appears in central nervous system.
The prognosis of patients with SLE has improved substantially over the past two decades,with a ten-year survival of more than ninety percents in some centers.The prognosis heterogeneity associated with SLE can be attributed to gender,age,genetic clinical factors and treatment.Education,earlier intervention,better disease damage control and improved general management of hypertension,co-morbid infections and other clinical risks have contributed to reduced end-organ damage and less morbidity and mortality.Nonetheless,the serious organ damage caused by vasculitis remains a challenge for physicians.Further study of the pathology and controlling methods of vasculitis in SLE helps to find new strategies to improve long-term prognostic and life quality of the SLE patients.
Members of matrix metalloproteinases(MMPs)family can degenerate components of extracellular cell matrix(ECM)and thus play an important role in vasculitis.As a member of matrix metalloproteinases family,matrix metalloprteinases-9(MMP-9)has been associated with SLE for several years since 2002.It cleaves denatured collagens and type IV collagen,the major component of the basement membranes,and thus be involved in many physical and pathological progresses such as embryonic development,repair in trauma,vasculogenesis,inflammation,infiltration and metastasis of tumor and connective tissue diseases.MMP-9 triggers inflammation directly,by tissue destruction,or indirectly, by generation of an inflammatory signal or recruitment of inflammatory cells.Thus, overproduced MMP-9 may induce microvascular damage and leakage of substances that further augment endothelial cell damage and facilitate the movement of inflammatory cells across the basement membrane,ultimately leading to various vasculities of SLE. Inhibition of MMP-9 might be beneficial to preventing organ damage in SLE caused by vasculitis.
However,studies on changes of serum concentration of MMP-9 in SLE and the correlation between serum concentration of MMP-9 and disease activity showed different results.Because recta-analysis is an efficient tool to systematically review those published articles in associated articles with different results which could lead to powerful evidence and right direction for further research,we collected the published articles and make meta-analysis of the serum MMP-9 concentration changed in SLE patients and the differences between patietns with different disease activity.
In recent years,some MMPs inhibitors such as KR-31813 and BB-1101 were studied in therapy of certain human cancer and autoimmune diseases but no clinical efficacy was demonstrated.The non-specificity of inhibition or serious skeletal muscle damage of articular damage of these inhibitors calls for a new inhibition of MMPs.A new therapy targeted on MMP-9 which can improve long-term prognostic and life quality of patients with SLE is expected.
CD147,also known as tumor cell-derived collagenase stimulatory factor(TCSF), extracellular matrix metalloproteinase inducer(EMMPIN),human leukocyte activated antigen M6,and basic immunoglobulin(Basigin),is a member of immunoglobulin superfamily(IgSF).It is capable of inducing the expression and activation of several MMPs of different cells and involves in intercellular action and interaction between cells and matrix thus play an important role in infiltration and metastasis of tumor and development of some autoimmune diseases by an as yet unknown mechanism.CD147 is highly expressed on activated T lymphocytes and was identified as an activation associated antigen on phytohemagglutinine(PHA)activated T cells.
Reversion-inducing cysteine-rich protein with Kazal motifs(RECK),a novel MMPs inhibitor,is a membrane-anchored glycoprtein of approximately 110kD that contains multiple epidermal growth factor-like repeats and serine protease inhibitor-like domains. It inhibits MMP-2,MMP-9 and membrane type-1 secretion and activity.As a new MMPs inhibitor,RECK has been shown to be a prognostic marker in several kind of human tumor and plays an important role in angiogenesis.The expression of RECK in inflamed synovial membranes of patients with rheumatoid arthritis was decreased compared to those of patients with osculoarthritis or traumatic arthritis.Downregulation of RECK has been complicated with angiogenesis and infiltration of tumor.Apart of these studies,little was known on what role it plays in SLE.
Objective
To evaluate changes of serum concentration of MMP-9 in SLE patients and the correlation between serum concentration of MMP-9 with disease activity;determine the expression of CD147,RECK protein,RECK mRNA,MMP-9 mRNA and MMP-9 secretion of PBMCs in SLE patients;analyze correlation between these factors and clinical characters of SLE patients;study the roles of CD147 and RECK played in SLE and evaluate their value in SLE therapy.
Objects and methods
1.Objects
(1)Reported articles about serum concentrations of MMP-9 and correlation between serum concentration of MMP-9 and disease activity in SLE;
(2)Sixty nine SLE patients;
(3)Twenty three healthy donors.
2.Methods
(1)Articles searched out were selected critically according to the criteria of Lichtenstein;
(2)Peripheral blood mononuclear cells(PBMCs)were isolated by Ficoll gradient centrifugation;
(3)Flow cytometry analysis(FCAS)was used to determine the expression of CD147 on PBMCs;
(4)Semi-quantitative reverse transcription-polymerase chain reaction(RT-PCR)was used to determine the expression of RECK mRNA and MMP-9 mRNA;
(5)Western blotting was used to determine the expression of RECK protein;
(6)Enzyme linked immunosorbent assay(ELISA)was used to detect the concentrations of MMP-9 in serum and culture supernatants;
(7)Statistical analysis
①Meta analysis was used to evaluate the changes of serum concentration of MMP-9 in SLE patients and correlation between serum concentration of MMP-9 with disease activity;
②Student's t test was used to analysis the differences between between variables in SLE patients and healthy donors;
③Pearson r correlation test was used to evaluate the relationship between variables;
④A 2×2 factorial experiment was designed to study the effects of anti-CD147 monoantibody on the expression of RECK,the expression of MMP-9 and secretion of MMP-9;
⑤P values of less than 0.05 were considered significant.
Results
1.Meta analysis
(1)There is no difference between serum concentrations of MMP-9 in SLE patients and healthy controls;
(2)There is no difference between serum concentrations of MMP-9 in SLE patients with different disease activity.
2.Changes of expression of CD147,RECK and MMP-9,MMP-9 secretion of PBMCs and serum concentration of MMP-9 in patients with SLE and their clinical significance
(1)CD147 expression of PBMCs from SLE patients and its relationship with clinical features
CD147 was highly expressed on PBMCs from SLE patients than on PBMCs from healthy donors.PBMCs from SLE patients with oral ulcers,renal damage,or those with abnormal serum concentration of anticardiolipin antibody were more likely to have higher expression of CD147 than those from SLE patients without such manifestation.A positive correlation between CD147 expression and SLEDAI was observed,but no correlation between CD147 expression and SDI was found.
(2)RECK expression of PBMCs from SLE patients and its relationship with clinical features
PBMCs from SLE patients expressed lower RECK protein compared with those from healthy donors.PBMCs from SLE patients with malar rash,oral ulcers,renal damage or those with abnormal serum concentration of anti-Smith antibody or anticardiolipin antibody were more likely to have much lower expression of RECK protein than those from SLE patients without such manifestation.A negative correlation between RECK protein expression and SDI was observed,but no correlation between RECK expression and SLEDAI was found.
PBMCs from SLE patients expressed lower RECK mRNA compared with those from healthy donors.PBMCs from SLE patients with discoid rash were more likely to have much lower expression of RECK mRNA than those from SLE patients without discoid rash.No correlation was found between RECK mRNA and SDI.No correlation was found between RECK mRNA and SLEDAI.
(3)MMP-9 mRNA expression of PBMCs from SLE patients and its relationship with clinical features
PBMCs from SLE patients expressed higher MMP-9 mRNA compared with those from healthy donors.PBMCs from SLE patients with oral ulcer or those with abnormal serum concentration of antinuclear antibodies were more likely to have much higher expression of MMP-9 mRNA than those from SLE patients without such manifestation. MMP-9 mRNA expression was positively correlated with SLEDAI.MMP-9 mRNA expression was positively correlated with SDI,too.
(4)MMP-9 secretion of PBMCs from SLE patients and its relationship with clinical features
PBMCs from SLE patients secreted more MMP-9 compared with those from healthy donors.PBMCs from SLE patients with malar rash,oral ulcer,renal damage or those with abnormal serum concentration of anti-Smith antibody or anticardiolipin antibody were more likely to secreted much more MMP-9 than those from SLE patients without such manifestation.MMP-9 secretion was positively correlated with SLEDAI.MMP-9 secretion was positively correlated with SDI,too.
(5)Serum concentration of MMP-9 in SLE patients and its relationship with clinical features
There is no difference between the MMP-9 serum concentrations of SLE patients and healthy donors.The concentration of MMP-9 in serum of SLE patients with renal damage was lower than those of SLE patients without renal damage.No correlation between serum concentrations of MMP-9 with SLEDAI was found.No correlation between serum concentrations of MMP-9 with SDI was found.
3.Correlation between expression of CD 147,RECK,MMP-9,secretion of MMP-9 and serum concentration of MMP-9 in patiens with SLE
(1)Correlation between CD 147 expression and MMP-9 expression
CD147 expression was positively correlated with MMP-9 mRNA expression;
(2)Correlation between CD147 expression and MMP-9 secretion
CD147 expression was positively correlated with MMP-9 secretion;
(3)Correlation between CD147 expression and serum concentration of MMP-9
No correlation was found between CD147expression and serum concentation of MMP-9;
(4)Correlation between RECK expression and MMP-9 expression
The expression of RECK protein was negatively correlated with MMP-9 mRNA expression,but no correlation was found between the expression of RECK mRNA and MMP-9 mRNA expression;
(5)Correlation between RECK expression and MMP-9 secretion
The expression of RECK protein was negatively correlated with MMP-9 secretion, but no correlation was found between the expression of RECK mRNA and MMP-9 secretion;
(6)Correlation between RECK expression and serum concentration of MMP-9
Neither of RECK protein expression nor RECK mRNA expression was correlated with serum concentration of MMP-9;
(7)Correlation between CD 147 expression and RECK expression
The expression of CD147 was negatively correlated with RECK protein expression, but no correlation was found between the expression of CD147 and RECK mRNA;
4.Effects of anti-CD147 monoantibody on expression of RECK,MMP-9 and secretion of MMP-9
(1)As to PBMCs from SLE patients,anti-CD147 monoantibody could increase RECK protein expression,decrease MMP-9 mRNA expression and decrease MMP-9 secretion;
(2)As to PBMCs from healthy donors,anti-CD147 monoantibody had no effect on expression of RECK protein,RECK mRNA,MMP-9 mRNA and secretion of MMP-9;
(3)Anti-CD147 monoantibody could decrease the effects of PHA(MMP-9 secretion increased,MMP-9 mRNA expression increased,RECK protein expression decresed)on PBMCs from SLE patients and healthy donors.
Conclusion
1.The serum concentration of MMP-9 should not be used in SLE diagnosis,neither should it be used in judgement of disease activity;
2.Compared with PBMCs from healthy donors,PBMCs from SLE patients expressed higher CD147,lower RECK protein,lower RECK mRNA,higher MMP-9 mRNA and secreted more MMP-9;
3.PBMCs from SLE patients with oral ulcers,renal damage or those with abnormal serum concentration of anticardiolipin antibody were more likely to express much higher CD147,lower RECK protein,lower RECK mRNA,lower MMP-9 mRNA and secret more MMP-9 than those from SLE patients without such manifestation.Physicians should pay more attention to those patients because serious organ damage caused by vasculitis are more likely to appear;
4.CD147 expression on PBMCs from SLE patients was positively correlated with disease activity and could be used to assess disease status and estimate the therapeutic effects;
5.RECK protein expression on PBMCs from SLE patients was negatively correlated with damage accrual and might be regarded as an indicator of the disease course allowing clinicians to anticipate the intermediate and long-term outcomes of the disease;
6.MMP-9 mRNA expression was positively correlated with disease activity and damage accrual of SLE patients and could be used to assess disease status and anticipate the prognostics of SLE patients;
7.MMP-9 secretion ability of PBMCs in SLE patients was positively correlated with disease activity and could be used to assess disease status and estimate the therapeutic effects;
8.There is no difference between serum concentrations of MMP-9 in SLE patients and healthy donors;serum concentration was correlated with neither disease activity nor damage accrual;
9.Over expression of CD147 inhibited the expression of RECK protein and this inhibition increased the secretion of MMP-9 which plays important role in SLE pathology;
10.The decreased expression of RECK was correlated with overproduction of MMP-9.Vascular damage could be prevented by increasing the expression of RECK protein.This will be benefit for development of new therapy.
11.Anti-CD147 monoantibody could inhibit MMP-9 secretion of PBMCs in SLE patients.This effect might be correlated with upregulation of RECK protein.Anti-CD147 monoantibody might be prospective in SLE treatment.
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