抗膜突蛋白抗体在弥漫性结缔组织病中的研究
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摘要
背景
弥漫性结缔组织病(CTD),作为非器官特异性自身免疫性疾病往往具有如下如下特点：患者血液中常常出现高滴度的自身抗体和(或)与自身组织成分起反应的致敏淋巴细胞；而患者体内产生的自身抗体或致敏淋巴细胞,与相应的自身组织抗原结合,通过不同的方式造成组织器官的免疫损伤和功能障碍而致病。因而,结缔组织病自身抗体反应的特异性和致病性显示其在对该疾病的诊断分类、病情评估、以及判断预后中的价值。
肺脏受累是CTD常见并发症之一,多起病隐袭,早期诊断困难,并且往往治疗效果不佳,是导致CTD患者死亡的重要原因之一。其中以肺动脉高压(pulmonary arterial hypertension, PAH)和间质性肺病(interstitial lung disease, ILD)为甚,目前已经成为风湿免疫科和呼吸内科医师面临的一大难题。我科既往研究应用免疫印迹法检测发现CTD-PAH患者的外周血中存在特异性抗78-kDa抗体,并且与患者雷诺现象,较长病程和PAH严重程度相关。经过蛋白组学方法分离鉴定所得特异性抗78-kDa抗体的靶抗原成分为膜突蛋白。并且在细胞水平证实人肺血管内皮细胞有膜突蛋白表达,抗膜突蛋白抗体可能通过诱导肺微血管内皮细胞早期凋亡和改变细胞骨架结构而引起细胞损伤。
本项研究首次应用重组膜突蛋白作为抗原,建立检测患者外周血中抗膜突蛋白抗体的酶联免疫分析法和免疫印迹方法,并在大样本量患者群体中进行筛查,结合患者临床信息,以期探讨抗膜突蛋白抗体检测在CTD中的临床意义。
目的
1.应用原核系统重组、纯化、表达膜突蛋白,并利用该蛋白建立患者外周血抗膜突蛋白抗体检测方法。
2.应用酶联免疫分析法和免疫印迹法检测不同CTD患者外周血中抗膜突蛋白抗体,结合临床信息,分析抗膜突蛋白抗体检测的临床意义。
3.应用酶联免疫分析法检测SSc患者外周血中抗膜突蛋白抗体,结合胸部HRCT和肺功能评估,分析抗膜突蛋白抗体与CTD相关肺脏受累之间的关系。
4.应用酶联免疫分析法检测pSS患者外周血中抗膜突蛋白抗体,结合唾液腺和泪腺功能评估,分析抗膜突蛋白抗体检测在pSS中的临床意义。
方法
1.应用Access软件分别建立CTD-PAH, SSc患者临床观察数据库,录入患者临床资料,同时收集患者外周血标本。
2.根据膜突蛋白的cDNA进行基因重组,在大肠杆菌进行蛋白表达和纯化,并以此为抗原,建立酶联免疫吸附法和免疫印迹法检测患者血清,同时对400例健康受试者群体进行筛查,确定本检测方法的cut-off值。
3.应用酶联免疫吸附法和免疫印迹法对于SSc, MCTD, SLE, pSS, SV患者外周血进行抗膜突蛋白抗体筛查,结合临床资料,分析其临床意义。
4.应用间接免疫荧光技术在形态学上观察pSS患者唇腺组织中膜突蛋白表达,探索患者外周血中抗膜突蛋白抗体的自身靶抗原。
结果
1.应用基因重组技术,在大肠杆菌进行膜突蛋白表达和纯化,获得重组人膜突蛋白,应用该抗原建立外周血抗膜突蛋白抗体ELISA检测方法,通过对400例健康受试者进行检查,确定本方法的参考临界值为0.158。
2.应用抗膜突蛋白抗体ELISA检测方法对于295例CTD患者进行抗体筛查结果示：SSc患者抗膜突蛋白抗体阳性率为52.5%,MCTD为39.5%,SLE为51.8%,pSS为69.2%,SV为22.5%,均显著高于非CTD患者阳性率(12.5%)(p<0.001%)。针对不同脏器受累分析提示：CTD相关肺脏受累(主要为PAH和ILD)组抗膜突蛋白抗体阳性率(57.0%)高于无肺脏受累组(40.8%)(P=0.018)。比较无脏器受累CTD组(33),CTD-ILD组(32),CTD-PAH组(14)和CTD-ILD&PAH组(14)患者抗膜突蛋白抗体检测OD均值提示：CTD-ILD&PAH组(0.231±0.141)显著高于其他组(0.120±0.347,0.164±0.064,0.158±0.048,p=0.001)。
3.抗膜突蛋白抗体检测结果与临床表现的相关性分析显示：有雷诺现象的CTD患者抗膜突蛋白抗体的阳性率(48.6%)高于无雷诺现象的患者(22.7%)(p=0.025),抗体检测OD均值比较：CTD病程大于五年患者组(0.182±0.109)明显高于病程小于五年的患者组(0.157±0.069,p=0.050),CTD合并重度PAH患者组(0.200±0.079)高于轻中度患者(0.158±0.057,p=0.057)。与患者的炎性指标及抗U1RNP、抗SSA抗体之间无明显相关性。
4.对于入组EUSTAR的62例SSc患者进行抗膜突蛋白抗体检测结果显示：整体阳性率为37.7%,根据胸部HRCT诊断是否合并ILD提示：SSc-ILD患者的阳性率为45.2%,明显高于non-ILD SSc组(9.1%)(P=0.037)。结合PFT评估：肺功能受累组抗体OD均值显著高于无肺功能受累组。
5.对于入组SICCA的83例pSS患者进行抗膜突蛋白抗体检测结果显示：唾液腺和泪腺功能受损组患者的抗膜突蛋白抗体阳性率[24(47.1%)和20(44.4%)]明显高于功能正常组患者[5(22.7%)和5(18.5%)](p=0.050和0.025),并且抗膜突蛋白抗体与唇腺病理评分之间显著相关。
6.应用单克隆抗体证实正常人唇腺上皮细胞中有膜突蛋白表达,并且pSS患者受累唇腺中膜突蛋白表达上调。同时应用患者外周血作为一抗证实抗膜突蛋白抗体的自身靶抗原为该蛋白。
结论
1.外周血ELISA方法检测CTD患者抗膜突蛋白抗体阳性率显著高于非CTD患者。
2.CTD不同靶器官受累的患者抗体膜突蛋白抗体阳性率不同,合并肺脏受累(主要为PAH和ILD)患者的阳性率明显增高,
3.抗膜突蛋白抗体与CTD合并PAH相关,并可能预测PAH病情轻重。
4.抗膜突蛋白抗体并与CTD合并ILD相关,并可能预测ILD病情轻重。
5.pSS患者外周血中抗膜突蛋白抗体阳性率较高,并可能提示患者唾液腺、泪腺功能受损程度。
6.膜突蛋白在正常人唇腺上皮细胞有表达,并在pSS患者唇腺上皮细胞中表达上调。pSS患者外周血中抗膜突蛋白抗体识别的自身靶抗原为该蛋白。
Background
Generally, connective tissue diseases (CTDs) represent a heterogeneous group of immunologically mediated inflammatory disorders. As a result of the inflammatory reaction a large variety of organs may be affected. Pulmonary involvement is frequent in the course of rheumatologic diseases, and may be due to various causes including infection and specific manifestations of the immune process. Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the most common features, and the leading causes of mortality in patients with CTD. In our previous research, immunoblotting revealed the presence of specific antibodies to a78-kDa membrane protein (78-kDa AECA) derived from EA.hy926in patients with CTD&PAH, which was correlated with Raynaud's phenomenon, longer course and severity of PAH. This78-kDa protein was recognized as moesin with MALDI-TOF MS. Anti-moesin antibodies could be frequently detected in patients with CTD&PAH, which might play a role in the pathogenesis of PAH associated with CTD.
Objectives
1. To express, purify recombinant moesin, and establish ELISA and immunoblotting methods for detecting anti-moesin antibodies in sera of patients with CTD.
2. To detect the anti-moesin antibody in patients with CTD-PAH, and to analyze the connection between the characteristics of CTD and the level of anti-moesin antibodies.
3. To detect the positive rate of anti-moesin antibody in patients with pulmonary arterial hypertension(PAH) associated with Connective Tissue diseases (CTD), and analyze their clinical significance.
3. To detect the positive rate of anti-moesin antibody in patients with Systemic sclerosis (SSc), which might be clinical significance.
4. To detect the positive rate of anti-moesin antibody in patients with primary Sjogren's syndrome (pSS), which might be clinical significance.
5. To localize moesin in human salivary glands, detect the target antigens of anti-moesin antibodies in patients with pSS.
Methods
1. With ACCESS software, established the clinical information databases for the patients with CTD-PAH and SSc separately.
2. Expressed, purified recombinant moesin, and established ELISA and immunoblotting methods for detecting anti-moesin antibodies in sera of patients with CTD.
3. With ELISA and western blotting, detected the positive rates of anti-moesin antibodies in patients with SSc, MCTD, SLE, pSS, SV, analyzed the correlation between anti-moesin antibodies and clinical characters.
4. Immunofluorescence labeling with anti-moesin mAb in human salivary glands.
Results
1. The recombinant moesin was highly purified, the cut-off value of ELISA assay was Determined (0.158).
2. The prevalence of anti-moesin antibodies by ELISA was52.5%in SSc,39.5%in MCTD,51.8%in SLE,69.2%in pSS, and22.5%in SV, significantly higher than those patients without CTD (5%)(p<0.010). The mean OD values of anti-moesin antibodies level in CTD without pulmonary involvement group, CTD-ILD group, CTD-PAH group, CTD-PAH&ILD group are as follows respectively:0.120±0.347,0.164±0.064,0.158±0.048,0.231±0.141.
3. A higher positive rates of anti-moesin antibodies were related to Raynaud's phenomenon, long course with more than5-year duration and severity of PAH. While AECA-78KD positive rate has no correlation to patients' anti-U1RNP antibody, anti-SSA antibody and inflammation index including erythrocyte sedimentation rate, CRP, and complement.
4. Serum anti-moesin Antibodies were present in34(37.7%) of the patients with SSc who were enrolled in EUSTAR:Compared with non-ILD group (9.1%), the positive rats of anti-moesin antibodies in SSc-ILD group is significant higher (45.2%)(p=0.037). Radiological patterns including diffuse patchy ground-glass opacities, basal irregular lines and consolidation on HRCT scan is correlation with the level of anti-moesin antibodies.
5. Serum anti-moesin Antibodies were present in28(37.8%) of the patients with pSS who were enrolled in SICCA. Compared with anti-moesin Abs negative group, the unstimulated flow rates were significantly decreased in anti-moesin Abs positive group. In addition, the levels of anti-moesin antibodies are correlated with several features of disease, including hyperglobulinemia, lacrimal and salivary dysfunctions, as well as salivary gland infiltrates.
6. Moesin can be detected by IIF on the epithelial cell of labial glands. Immunofluorescence labeling with anti-moesin mAb was found in both serous acini and mucous acini in labial glands. Labeling was found at the luminal side of duct cell.
Conclusions
1. Anti-moesin antibodies could be found more frequently in patients with CTD than those without CTD by ELISA. CTD patients with different target organ involved has different positive rate of anti-moesin antibodies.
2. Anti-moesin antibodies could be found more frequently in CTD patients with pulmonary involvement (mainly PAH and ILD).
3. Serum anti-moesin Antibodies were present in the patients with SSc-ILD. The presence of anti-moesin Antibodies in serum appeared to be connected with more severe pulmonary function damage in SSc-ILD.
4. Serum anti-moesin Antibodies were present in the patients with pSS. The presence of anti-moesin Antibodies in serum appeared to be connected with more severe lacrimal gland function and salivary gland function damage, as measured by Schirmer test and unstimulated flow rate separately.
5. Moesin is one of the auto-antigen recognized by anti-moesin antibodies in labial glands of patient with pSS.
弥漫性结缔组织病(CTD),作为非器官特异性自身免疫性疾病往往具有如下如下特点：患者血液中常常出现高滴度的自身抗体和(或)与自身组织成分起反应的致敏淋巴细胞；而患者体内产生的自身抗体或致敏淋巴细胞,与相应的自身组织抗原结合,通过不同的方式造成组织器官的免疫损伤和功能障碍而致病。因而,结缔组织病自身抗体反应的特异性和致病性显示其在对该疾病的诊断分类、病情评估、以及判断预后中的价值。
肺脏受累是CTD常见并发症之一,多起病隐袭,早期诊断困难,并且往往治疗效果不佳,是导致CTD患者死亡的重要原因之一。其中以肺动脉高压(pulmonary arterial hypertension, PAH)和间质性肺病(interstitial lung disease, ILD)为甚,目前已经成为风湿免疫科和呼吸内科医师面临的一大难题。我科既往研究应用免疫印迹法检测发现CTD-PAH患者的外周血中存在特异性抗78-kDa抗体,并且与患者雷诺现象,较长病程和PAH严重程度相关。经过蛋白组学方法分离鉴定所得特异性抗78-kDa抗体的靶抗原成分为膜突蛋白。并且在细胞水平证实人肺血管内皮细胞有膜突蛋白表达,抗膜突蛋白抗体可能通过诱导肺微血管内皮细胞早期凋亡和改变细胞骨架结构而引起细胞损伤。
本项研究首次应用重组膜突蛋白作为抗原,建立检测患者外周血中抗膜突蛋白抗体的酶联免疫分析法和免疫印迹方法,并在大样本量患者群体中进行筛查,结合患者临床信息,以期探讨抗膜突蛋白抗体检测在CTD中的临床意义。
目的
1.应用原核系统重组、纯化、表达膜突蛋白,并利用该蛋白建立患者外周血抗膜突蛋白抗体检测方法。
2.应用酶联免疫分析法和免疫印迹法检测不同CTD患者外周血中抗膜突蛋白抗体,结合临床信息,分析抗膜突蛋白抗体检测的临床意义。
3.应用酶联免疫分析法检测SSc患者外周血中抗膜突蛋白抗体,结合胸部HRCT和肺功能评估,分析抗膜突蛋白抗体与CTD相关肺脏受累之间的关系。
4.应用酶联免疫分析法检测pSS患者外周血中抗膜突蛋白抗体,结合唾液腺和泪腺功能评估,分析抗膜突蛋白抗体检测在pSS中的临床意义。
方法
1.应用Access软件分别建立CTD-PAH, SSc患者临床观察数据库,录入患者临床资料,同时收集患者外周血标本。
2.根据膜突蛋白的cDNA进行基因重组,在大肠杆菌进行蛋白表达和纯化,并以此为抗原,建立酶联免疫吸附法和免疫印迹法检测患者血清,同时对400例健康受试者群体进行筛查,确定本检测方法的cut-off值。
3.应用酶联免疫吸附法和免疫印迹法对于SSc, MCTD, SLE, pSS, SV患者外周血进行抗膜突蛋白抗体筛查,结合临床资料,分析其临床意义。
4.应用间接免疫荧光技术在形态学上观察pSS患者唇腺组织中膜突蛋白表达,探索患者外周血中抗膜突蛋白抗体的自身靶抗原。
结果
1.应用基因重组技术,在大肠杆菌进行膜突蛋白表达和纯化,获得重组人膜突蛋白,应用该抗原建立外周血抗膜突蛋白抗体ELISA检测方法,通过对400例健康受试者进行检查,确定本方法的参考临界值为0.158。
2.应用抗膜突蛋白抗体ELISA检测方法对于295例CTD患者进行抗体筛查结果示：SSc患者抗膜突蛋白抗体阳性率为52.5%,MCTD为39.5%,SLE为51.8%,pSS为69.2%,SV为22.5%,均显著高于非CTD患者阳性率(12.5%)(p<0.001%)。针对不同脏器受累分析提示：CTD相关肺脏受累(主要为PAH和ILD)组抗膜突蛋白抗体阳性率(57.0%)高于无肺脏受累组(40.8%)(P=0.018)。比较无脏器受累CTD组(33),CTD-ILD组(32),CTD-PAH组(14)和CTD-ILD&PAH组(14)患者抗膜突蛋白抗体检测OD均值提示：CTD-ILD&PAH组(0.231±0.141)显著高于其他组(0.120±0.347,0.164±0.064,0.158±0.048,p=0.001)。
3.抗膜突蛋白抗体检测结果与临床表现的相关性分析显示：有雷诺现象的CTD患者抗膜突蛋白抗体的阳性率(48.6%)高于无雷诺现象的患者(22.7%)(p=0.025),抗体检测OD均值比较：CTD病程大于五年患者组(0.182±0.109)明显高于病程小于五年的患者组(0.157±0.069,p=0.050),CTD合并重度PAH患者组(0.200±0.079)高于轻中度患者(0.158±0.057,p=0.057)。与患者的炎性指标及抗U1RNP、抗SSA抗体之间无明显相关性。
4.对于入组EUSTAR的62例SSc患者进行抗膜突蛋白抗体检测结果显示：整体阳性率为37.7%,根据胸部HRCT诊断是否合并ILD提示：SSc-ILD患者的阳性率为45.2%,明显高于non-ILD SSc组(9.1%)(P=0.037)。结合PFT评估：肺功能受累组抗体OD均值显著高于无肺功能受累组。
5.对于入组SICCA的83例pSS患者进行抗膜突蛋白抗体检测结果显示：唾液腺和泪腺功能受损组患者的抗膜突蛋白抗体阳性率[24(47.1%)和20(44.4%)]明显高于功能正常组患者[5(22.7%)和5(18.5%)](p=0.050和0.025),并且抗膜突蛋白抗体与唇腺病理评分之间显著相关。
6.应用单克隆抗体证实正常人唇腺上皮细胞中有膜突蛋白表达,并且pSS患者受累唇腺中膜突蛋白表达上调。同时应用患者外周血作为一抗证实抗膜突蛋白抗体的自身靶抗原为该蛋白。
结论
1.外周血ELISA方法检测CTD患者抗膜突蛋白抗体阳性率显著高于非CTD患者。
2.CTD不同靶器官受累的患者抗体膜突蛋白抗体阳性率不同,合并肺脏受累(主要为PAH和ILD)患者的阳性率明显增高,
3.抗膜突蛋白抗体与CTD合并PAH相关,并可能预测PAH病情轻重。
4.抗膜突蛋白抗体并与CTD合并ILD相关,并可能预测ILD病情轻重。
5.pSS患者外周血中抗膜突蛋白抗体阳性率较高,并可能提示患者唾液腺、泪腺功能受损程度。
6.膜突蛋白在正常人唇腺上皮细胞有表达,并在pSS患者唇腺上皮细胞中表达上调。pSS患者外周血中抗膜突蛋白抗体识别的自身靶抗原为该蛋白。
Background
Generally, connective tissue diseases (CTDs) represent a heterogeneous group of immunologically mediated inflammatory disorders. As a result of the inflammatory reaction a large variety of organs may be affected. Pulmonary involvement is frequent in the course of rheumatologic diseases, and may be due to various causes including infection and specific manifestations of the immune process. Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the most common features, and the leading causes of mortality in patients with CTD. In our previous research, immunoblotting revealed the presence of specific antibodies to a78-kDa membrane protein (78-kDa AECA) derived from EA.hy926in patients with CTD&PAH, which was correlated with Raynaud's phenomenon, longer course and severity of PAH. This78-kDa protein was recognized as moesin with MALDI-TOF MS. Anti-moesin antibodies could be frequently detected in patients with CTD&PAH, which might play a role in the pathogenesis of PAH associated with CTD.
Objectives
1. To express, purify recombinant moesin, and establish ELISA and immunoblotting methods for detecting anti-moesin antibodies in sera of patients with CTD.
2. To detect the anti-moesin antibody in patients with CTD-PAH, and to analyze the connection between the characteristics of CTD and the level of anti-moesin antibodies.
3. To detect the positive rate of anti-moesin antibody in patients with pulmonary arterial hypertension(PAH) associated with Connective Tissue diseases (CTD), and analyze their clinical significance.
3. To detect the positive rate of anti-moesin antibody in patients with Systemic sclerosis (SSc), which might be clinical significance.
4. To detect the positive rate of anti-moesin antibody in patients with primary Sjogren's syndrome (pSS), which might be clinical significance.
5. To localize moesin in human salivary glands, detect the target antigens of anti-moesin antibodies in patients with pSS.
Methods
1. With ACCESS software, established the clinical information databases for the patients with CTD-PAH and SSc separately.
2. Expressed, purified recombinant moesin, and established ELISA and immunoblotting methods for detecting anti-moesin antibodies in sera of patients with CTD.
3. With ELISA and western blotting, detected the positive rates of anti-moesin antibodies in patients with SSc, MCTD, SLE, pSS, SV, analyzed the correlation between anti-moesin antibodies and clinical characters.
4. Immunofluorescence labeling with anti-moesin mAb in human salivary glands.
Results
1. The recombinant moesin was highly purified, the cut-off value of ELISA assay was Determined (0.158).
2. The prevalence of anti-moesin antibodies by ELISA was52.5%in SSc,39.5%in MCTD,51.8%in SLE,69.2%in pSS, and22.5%in SV, significantly higher than those patients without CTD (5%)(p<0.010). The mean OD values of anti-moesin antibodies level in CTD without pulmonary involvement group, CTD-ILD group, CTD-PAH group, CTD-PAH&ILD group are as follows respectively:0.120±0.347,0.164±0.064,0.158±0.048,0.231±0.141.
3. A higher positive rates of anti-moesin antibodies were related to Raynaud's phenomenon, long course with more than5-year duration and severity of PAH. While AECA-78KD positive rate has no correlation to patients' anti-U1RNP antibody, anti-SSA antibody and inflammation index including erythrocyte sedimentation rate, CRP, and complement.
4. Serum anti-moesin Antibodies were present in34(37.7%) of the patients with SSc who were enrolled in EUSTAR:Compared with non-ILD group (9.1%), the positive rats of anti-moesin antibodies in SSc-ILD group is significant higher (45.2%)(p=0.037). Radiological patterns including diffuse patchy ground-glass opacities, basal irregular lines and consolidation on HRCT scan is correlation with the level of anti-moesin antibodies.
5. Serum anti-moesin Antibodies were present in28(37.8%) of the patients with pSS who were enrolled in SICCA. Compared with anti-moesin Abs negative group, the unstimulated flow rates were significantly decreased in anti-moesin Abs positive group. In addition, the levels of anti-moesin antibodies are correlated with several features of disease, including hyperglobulinemia, lacrimal and salivary dysfunctions, as well as salivary gland infiltrates.
6. Moesin can be detected by IIF on the epithelial cell of labial glands. Immunofluorescence labeling with anti-moesin mAb was found in both serous acini and mucous acini in labial glands. Labeling was found at the luminal side of duct cell.
Conclusions
1. Anti-moesin antibodies could be found more frequently in patients with CTD than those without CTD by ELISA. CTD patients with different target organ involved has different positive rate of anti-moesin antibodies.
2. Anti-moesin antibodies could be found more frequently in CTD patients with pulmonary involvement (mainly PAH and ILD).
3. Serum anti-moesin Antibodies were present in the patients with SSc-ILD. The presence of anti-moesin Antibodies in serum appeared to be connected with more severe pulmonary function damage in SSc-ILD.
4. Serum anti-moesin Antibodies were present in the patients with pSS. The presence of anti-moesin Antibodies in serum appeared to be connected with more severe lacrimal gland function and salivary gland function damage, as measured by Schirmer test and unstimulated flow rate separately.
5. Moesin is one of the auto-antigen recognized by anti-moesin antibodies in labial glands of patient with pSS.
引文
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[2]Lankes WT, Furthmayr H. Moesin:a member of the protein 4.1-talin-ezrin family of proteins. Proc Natl Acad Sci U S A.1991,88 (19):8297-301.
[3]Polesello C, Payre F. Small is beautiful:what flies tell us about ERM protein function in development. Trends Cell Biol,2004,14:294-302.
[4]Wagatsuma M, Kimura M, Suzuki R, et al. Ezrin, radixin and moesin are possible auto-immune antigens in rheumatoid arthritis. Mol Immunol.1996,33 (15):1171-1176.
[5]Takamatsu H, Feng X, Chuhjo T, et al. Specific antibodies to moesin, a membrane-cytoskeleton linker protein, are frequently detected in patients with acquired aplastic anemia. Blood,2007,109:2514-2520.
[6]Graham A, Ford I, Morrison R, et al. Anti-endothelial antibodies interfere in apoptotic cell clearance and promote thrombosis in patients with antiphospholipid syndrome. J Immuno,2009, 182:1756-1762.
[7]Fries JF, Hochberg MC, Medsger TA Jr, Hunder GG, Bombardier C, and the American College of Rheumatology Diagnostic and Therapeutic Criteria Committee. Criteria for rheumatic disease: different types and different functions. Arthritis Rheum 1994;37:454-62.
[8]Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581-90.
[9]Manthorpe R, Asmussen K, Oxholm P. Primary Sjo"gren's syndrome:diagnostic criteria, clinical features, and disease activity. VIth International Symposium on Sjo"gren's syndrome:Avon Connecticut, USA. J Rheumatol 1997;24 (Suppl 50):8-11.
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[11]Hiroichi Kobayashi, junji Sagara, Junya Masumoto shifts in cellular localization of moesin in normal oral epithelium, oral epithelial dysplasia, verrucous carcinoma and oral squamous cell carcinoma.J Oral Pathol Med 2003:32:344-9.
[12]Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581-90.
[13]Webb WR, Muller NL, Naidich DP. High-resolution computed tomography findings of lung disease. High-resolution CT of the lung.3rd ed. Lippincott Williams & Wilkins, Philadelphia,2001: 71-192.
[14]Austin JH, Miiller NL, Friedman PJ, et al. Glossary of terms for CT of the lungs: recommendations of the Nomenclature Committee of the Fleischner Society. Radiology 200: 327-331,1996.
[15]Webb WR, Miiller NL, Naidich DP. High-resolution computed tomography findings of lung disease. High-resolution CT of the lung.3rd ed. Lippincott Williams & Wilkins, Philadelphia,2001: 71-192.
[16]Austin JH, Miiller NL, Friedman PJ, et al. Glossary of terms for CT of the lungs: recommendations of the Nomenclature Committee of the Fleischner Society. Radiology 200: 327-331,1996.
[17]American Thoracic Society. Standardisation of spirometry,1994 update. Am J Respir Crit Care Med 1994; 152:1107-36.
[18]American Thoracic Society. Single-breath carbon monoxide diffusing capacity (transfer factor). Recommendations for a standard technique-1995 update. Am J Respir Crit Care Med 1995;152:2185-98.
[19]Tzelepis GE, Toya SP, Moutsopoulos HM. Occult connective tissue diseases mimicking idiopathic interstitial pneumonias. Eur Respir J 2008;31:11-20.
[20]Steen VD, Conte C, Owens GR, Medsger TA Jr. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum 1994;37:1283-9.
[21]Masi AT, Rodnan GP, Medsger TA, Altman R,'D'Angelo W, Fries J, et al. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthr Rheum 1980; 23:581-90.
[22]Wells AU, Cullinan P, Hansell DM, Rubens MB, Black CM, Newman-Taylor AJ, et al. Fibrosing alveolitis associated with systemic sclerosis has a better prognosis than lone cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 1994; 149:1583-90.
[23]Steen VD, Medsger TA, Jr. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 2000; 43:2437-44.
[24]Strange C, Highland KB. Interstitial lung disease in the patient who has connective tissue disease. Clin Chest Med 2004;25:549-59, viii.
[25]Minai OA, Dweik RA, Arroliga AC. Manifestations of scleroderma pulmonary disease. Clin Chest Med 1998; 19:713-731.
[26]Lahdensuo A, Korpela M. Pulmonary findings in patients with primary Sjogren's syndrome. Chest 1995;108:316-9.
[27]Collard HR, King TE Jr, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003;168:538-42.
[28]Jegal Y, Kim D, Shim T et al. Physiology is a stronger predictor of survival than pathology in fibrotic interstitial pneumonia. Am J Respir Crit Care Med 2005; 171:639-44.
[29]Latsi PI, du Bois RM, Nicholson AG et al. Fibrotic idiopathic interstitial pneumonia:the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med 2003;168:531-7.
[30]American Thoracic Society. ATS statement:guidelines for the six-minute walk test Am J Respir Crit Care Med 2002;166:111-17.
[31]Soshi Hashimoto, Fumimasa Amaya, Hiroki Matsuyama, et al. Dysregulation of lung injury and repair in moesin-deficient mice treated with intratracheal bleomycin.
[32]Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al, and the European Study Group on Classification Criteria for Sjogren's Syndrome. Classification criteria for Sjogren's syndrome:a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61:554-8.
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[34]Manthorpe R, Asmussen K, Oxholm P. Primary Sjogren's syndrome:diagnostic criteria, clinical features, and disease activity. Ⅵth International Symposium on Sjogren's syndrome:Avon Connecticut, USA. J Rheumatol 1997;24 (Suppl 50):8-11.
[35]Moutsopoulos HM. Sjogren's syndrome autoimmune epithelitis. Clin Immunol Immunopathol 1994;72:162-5.
[36]Shern RJ, Fox PC, Cain JL, Li SH (1990). A method for measuring the flow of saliva from the minor salivary glands. J Dent Res 69:1146-1149.
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