Primary biliary cirrhosis(PBC) is a chronic,progressive,cholestatic,organ-specific autoimmune disease of unknown etiology.It predominantly affects middle-aged women,and is characterized by autoimmune-mediated destruct...Primary biliary cirrhosis(PBC) is a chronic,progressive,cholestatic,organ-specific autoimmune disease of unknown etiology.It predominantly affects middle-aged women,and is characterized by autoimmune-mediated destruction of small-and medium-size intrahepatic bile ducts,portal inflammation and progressive scarring,which without proper treatment can ultimately lead to fibrosis and hepatic failure.Serum autoantibodies are crucial tools for differential diagnosis of PBC.While it is currently accepted that antimitochondrial antibodies are the most important serological markers of PBC,during the last five decades more than sixty autoantibodies have been explored in these patients,some of which had previously been thought to be specific for other autoimmune diseases.展开更多
AIM:To examine the clinical features and analyze prognostic factors in a prospective study of primary biliary cirrhosis(PBC) patients.METHODS:From 1995 to 2010,PBC patients without hepatic decompensation seen at the P...AIM:To examine the clinical features and analyze prognostic factors in a prospective study of primary biliary cirrhosis(PBC) patients.METHODS:From 1995 to 2010,PBC patients without hepatic decompensation seen at the Peking Union Medical College Hospital were enrolled.Clinical signs and manifestations(pruritus,persistent fatigue,jaundice and pain in the right hypochondrium),laboratory parameters(auto-antibodies for autoimmune hepatic disease,biliary and hepatic enzymes,immunoglobulin,bilirubin,and albumin) and imaging findings were recorded at entry and at specific time points during follow-up.Cox regression and Kaplan-Meier analyses,respectively,assessed the risk factors for hepatic decompensation and survival.RESULTS:Two hundred and sixty-two PBC patients were enrolled with a median follow-up of 75.2 mo(range,21-201 mo).The 240 patients were aged 51.5 ± 10.2 years at diagnosis and 91.6% were female.Two hundred and forty-five(93.5%) were seropositive for anti-mitochondrial antibodies.At presentation,170 patients(64.9%) were symptomatic,while 96 patients(36.6%) had extra-hepatic autoimmune disease.During the follow-up period,62(23.7%) patients developed hepatic decompensation of whom four underwent liver transplantation and 17 died.The cumulative survival rate and median survival time were 83.9% and 181.7 mo,respectively.Cox regression analysis revealed that an incomplete ursodeoxycholic acid(UDCA) response or inconsistent treatment [P < 0.001;hazard risk(HR) 95%CI = 2.423-7.541],anti-centromere antibodies(ACA) positivity(P < 0.001;HR 95%CI = 2.516-7.137),alanine aminotransferase ratio(AAR) elevations(P < 0.001;HR 95%CI = 1.357-2.678),and histological advanced liver disease(P = 0.006;HR 95%CI = 1.481-10.847) were predictors of hepatic decompensation.The clinical features and survival of PBC in China are consistent with those described in Western countries.CONCLUSION:Incomplete UDCA response or inconsistent treatment,ACA positivity,AAR elevations,and advanced histological stage are predictors of decompensation.展开更多
目的检测中国系统性硬化症（SSc）患者血清中硬皮病相关自身抗体一抗Sel-70抗体、抗着丝点抗体（ACA）和抗RNA多聚酶Ⅲ抗体（ARA），分析其与各种临床表现之间的关系。方法序贯纳入人选欧洲抗风湿病联盟硬皮病实验研究组（EULAR Sclerod...目的检测中国系统性硬化症（SSc）患者血清中硬皮病相关自身抗体一抗Sel-70抗体、抗着丝点抗体（ACA）和抗RNA多聚酶Ⅲ抗体（ARA），分析其与各种临床表现之间的关系。方法序贯纳入人选欧洲抗风湿病联盟硬皮病实验研究组（EULAR Scleroderma Trial and Research Group，EUSTAR）的135例中国SSc患者，分别用线性免疫印迹法、免疫双扩散法和间接免疫荧光法检测ARA、抗Scl-70抗体、ACA在患者血清中表达水平，并进一步分析自身抗体与患者各种临床表现之间的相关性。结果在135例SSc患者中抗Sel-70、ACA、ARA的阳性率分别为49．6％、13．3％和8．9％。抗Scl-70抗体阳性组患者的病程显著短于阴性组[（71±59）个月VS（90±103）个月，P=0．041]，肺间质病变的患炳率亦显著高于阴性组（P=0．031），但阳性组肺动脉高压的患病率显著低于阴性组（P=0．042），修订的Rodnan皮肤硬化评分（P=0．008）、面颈部皮肤硬化（P=0．002）、肘／膝关节远端皮肤硬化（P=0．004）以及指端凹陷性瘢痕／指垫消失的发生率（P=0．01）均显著高于阴性组；ACA阳性组患者的病程长于阴性组，差异具有统计学意义[（90±107）个月VS（69±64）个月，P=0．036]，肺间质病变的患病率显著低于阴性组（P＝0．045），IgM水平亦显著低于阴性组（P=0．045）；ARA阳性组和阴性组患者的病程等各项临床指标差异均无统计学意义，但阳性组血清肌酐和尿素氮水平显著高于阴性组（P〈0．001）。ACA和ARA患者各项皮肤硬化指标在阳性组和阴性组差异均无统计学意义。结论硬皮病特异相关的自身抗体与不同的临床表现紧密相关，检测此类抗体可能有助于SSc的诊断、脏器受累和预后评估。这些自身抗体在中国SSc患者的临床相关性可能不同于其他地区的SSc患者。展开更多
Uncontrolled fibrosis of skin and internal organs is the main characteristic of scleroderma, and collagen is a major extracellular matrix protein that deposits in the fibrotic organs. As the chaperone of collagen, hea...Uncontrolled fibrosis of skin and internal organs is the main characteristic of scleroderma, and collagen is a major extracellular matrix protein that deposits in the fibrotic organs. As the chaperone of collagen, heat shock protein 47 （HSP47） is closely related with the development of fbrosis. To explore the potential func- tion of HSP47 in the pathogenesis of scleroderma, the clinical, in vivo and in vitro studies were performed. In clinical, the increased mRNA level of HSP47 was observed in the skin fibroblasts and PBMC from scle- roderma patients, and the enhanced protein level of HSP47 was also detected in the skin biopsy and plasma of the above patients. Unexpectedly, the enhanced levels of HSP47 were positively correlated with the presence of anti-centromere antibody in scleroderma patients. Moreover, a high expression of HSP47 was found in the skin lesion of BLM-induced scleroderma mouse model. Further in vitro studies demonstrated that HSP47 knockdown could block the intracellular and extracellular collagen over-productions induced by exogenous TGF-13. Therefore, the results in this study provide direct evidence that HSP47 is involved in the pathogenesis of scleroderma. The high expression of HSP47 can be detected in the circulatory system of scleroderma patients, indicating that HSP47 maybecome a pathological marker to assess the progres- sion of scleroderma, and also explain the systemic fibrosis of scleroderma. Meanwhile, collagen over-ex- pression is blocked by HSP47 knockdown, suggesting the possibility that HSP47 can be a potential therapeutic target for scleroderma.展开更多
文摘Primary biliary cirrhosis(PBC) is a chronic,progressive,cholestatic,organ-specific autoimmune disease of unknown etiology.It predominantly affects middle-aged women,and is characterized by autoimmune-mediated destruction of small-and medium-size intrahepatic bile ducts,portal inflammation and progressive scarring,which without proper treatment can ultimately lead to fibrosis and hepatic failure.Serum autoantibodies are crucial tools for differential diagnosis of PBC.While it is currently accepted that antimitochondrial antibodies are the most important serological markers of PBC,during the last five decades more than sixty autoantibodies have been explored in these patients,some of which had previously been thought to be specific for other autoimmune diseases.
基金Supported by National Science Technology Pillar Program in the 11th Five-Year Plan,No. 2008BAI59B03Research Special Fund for the Public Welfare Industry of Health,No.201202004
文摘AIM:To examine the clinical features and analyze prognostic factors in a prospective study of primary biliary cirrhosis(PBC) patients.METHODS:From 1995 to 2010,PBC patients without hepatic decompensation seen at the Peking Union Medical College Hospital were enrolled.Clinical signs and manifestations(pruritus,persistent fatigue,jaundice and pain in the right hypochondrium),laboratory parameters(auto-antibodies for autoimmune hepatic disease,biliary and hepatic enzymes,immunoglobulin,bilirubin,and albumin) and imaging findings were recorded at entry and at specific time points during follow-up.Cox regression and Kaplan-Meier analyses,respectively,assessed the risk factors for hepatic decompensation and survival.RESULTS:Two hundred and sixty-two PBC patients were enrolled with a median follow-up of 75.2 mo(range,21-201 mo).The 240 patients were aged 51.5 ± 10.2 years at diagnosis and 91.6% were female.Two hundred and forty-five(93.5%) were seropositive for anti-mitochondrial antibodies.At presentation,170 patients(64.9%) were symptomatic,while 96 patients(36.6%) had extra-hepatic autoimmune disease.During the follow-up period,62(23.7%) patients developed hepatic decompensation of whom four underwent liver transplantation and 17 died.The cumulative survival rate and median survival time were 83.9% and 181.7 mo,respectively.Cox regression analysis revealed that an incomplete ursodeoxycholic acid(UDCA) response or inconsistent treatment [P < 0.001;hazard risk(HR) 95%CI = 2.423-7.541],anti-centromere antibodies(ACA) positivity(P < 0.001;HR 95%CI = 2.516-7.137),alanine aminotransferase ratio(AAR) elevations(P < 0.001;HR 95%CI = 1.357-2.678),and histological advanced liver disease(P = 0.006;HR 95%CI = 1.481-10.847) were predictors of hepatic decompensation.The clinical features and survival of PBC in China are consistent with those described in Western countries.CONCLUSION:Incomplete UDCA response or inconsistent treatment,ACA positivity,AAR elevations,and advanced histological stage are predictors of decompensation.
文摘目的检测中国系统性硬化症（SSc）患者血清中硬皮病相关自身抗体一抗Sel-70抗体、抗着丝点抗体（ACA）和抗RNA多聚酶Ⅲ抗体（ARA），分析其与各种临床表现之间的关系。方法序贯纳入人选欧洲抗风湿病联盟硬皮病实验研究组（EULAR Scleroderma Trial and Research Group，EUSTAR）的135例中国SSc患者，分别用线性免疫印迹法、免疫双扩散法和间接免疫荧光法检测ARA、抗Scl-70抗体、ACA在患者血清中表达水平，并进一步分析自身抗体与患者各种临床表现之间的相关性。结果在135例SSc患者中抗Sel-70、ACA、ARA的阳性率分别为49．6％、13．3％和8．9％。抗Scl-70抗体阳性组患者的病程显著短于阴性组[（71±59）个月VS（90±103）个月，P=0．041]，肺间质病变的患炳率亦显著高于阴性组（P=0．031），但阳性组肺动脉高压的患病率显著低于阴性组（P=0．042），修订的Rodnan皮肤硬化评分（P=0．008）、面颈部皮肤硬化（P=0．002）、肘／膝关节远端皮肤硬化（P=0．004）以及指端凹陷性瘢痕／指垫消失的发生率（P=0．01）均显著高于阴性组；ACA阳性组患者的病程长于阴性组，差异具有统计学意义[（90±107）个月VS（69±64）个月，P=0．036]，肺间质病变的患病率显著低于阴性组（P＝0．045），IgM水平亦显著低于阴性组（P=0．045）；ARA阳性组和阴性组患者的病程等各项临床指标差异均无统计学意义，但阳性组血清肌酐和尿素氮水平显著高于阴性组（P〈0．001）。ACA和ARA患者各项皮肤硬化指标在阳性组和阴性组差异均无统计学意义。结论硬皮病特异相关的自身抗体与不同的临床表现紧密相关，检测此类抗体可能有助于SSc的诊断、脏器受累和预后评估。这些自身抗体在中国SSc患者的临床相关性可能不同于其他地区的SSc患者。
基金This study was partially supported by the grants from the National Science Foundation of China （81270120, 81470254）, International S ＆ T Cooperation Program of China （2013DFA30870）, the 111 Project （B13016）, the Science and Technology Committee of Shanghai Municipality （10JC1402100）, and US NIH NIAID U01 （1U01AI090909）. The computations involved in this study were supported by Fudan University High-End Computing Center.
文摘Uncontrolled fibrosis of skin and internal organs is the main characteristic of scleroderma, and collagen is a major extracellular matrix protein that deposits in the fibrotic organs. As the chaperone of collagen, heat shock protein 47 （HSP47） is closely related with the development of fbrosis. To explore the potential func- tion of HSP47 in the pathogenesis of scleroderma, the clinical, in vivo and in vitro studies were performed. In clinical, the increased mRNA level of HSP47 was observed in the skin fibroblasts and PBMC from scle- roderma patients, and the enhanced protein level of HSP47 was also detected in the skin biopsy and plasma of the above patients. Unexpectedly, the enhanced levels of HSP47 were positively correlated with the presence of anti-centromere antibody in scleroderma patients. Moreover, a high expression of HSP47 was found in the skin lesion of BLM-induced scleroderma mouse model. Further in vitro studies demonstrated that HSP47 knockdown could block the intracellular and extracellular collagen over-productions induced by exogenous TGF-13. Therefore, the results in this study provide direct evidence that HSP47 is involved in the pathogenesis of scleroderma. The high expression of HSP47 can be detected in the circulatory system of scleroderma patients, indicating that HSP47 maybecome a pathological marker to assess the progres- sion of scleroderma, and also explain the systemic fibrosis of scleroderma. Meanwhile, collagen over-ex- pression is blocked by HSP47 knockdown, suggesting the possibility that HSP47 can be a potential therapeutic target for scleroderma.
