特发性眼眶炎性假瘤发病分子机理研究
摘要
特发性眼眶炎性假瘤(Idiopathic Orbital Inflammatory Pseudotumor, IOIP)为常见眼眶疾病,占眼眶病变的7.1%-12.3%。IOIP是指无全身与局部原因的特发性眼眶组织内慢性炎症细胞浸润,形成眶内占位性病变,纤维化是IOIP重要的病理变化。一般IOIP病人需要做手术切除病变组织,进行免疫组织化学检测才能确诊,而且容易复发。由于该病的病因和发病机制不明,诊断与治疗相当困难与棘手,是眼科领域研究的难点之一,所以对IOIP发病机理的研究显得特别迫切。
本研究对进行炎性假瘤手术患者病理组织11例和非患者的正常组织4例,提取总RNA后,进行芯片检测,芯片结果用Real time RT-PCR进一步法验证。按照表达差异变化大于21.5倍或小于2-1.5和P<0.005的标准,筛选出表达差异基因744个,其中在IOIP组包括552个下调基因和192个表达上调基因。用主成分分析法和聚类法分析,IOIP组和正常对照组显著的分为两组。结果显示,IOIP组与正常对照组相比较,T细胞的标志分子(CD_3和CD_(45))和B细胞的标志分子(CD_(20)和CD_(79))及大量与T和B淋巴细胞扩增和激活相关的基因(SYK, CD20, LAT, SPIB, LCK, HCST和CD_(72))显著表达上调,证实眼眶炎性假瘤是以T或B细胞增殖为主的多克隆性病变。同时,发现PI_3K和NF-κB通路的激活及炎性相关因子的高表达。
EB病毒的感染会引起淋巴细胞的浸润,但EBV的感染是否和IOIP的发病相关还未被证明。在聚类分析中,受EBV感染激活的EBI2基因在IOIP组中显著表达上调(最大表达差异倍数11.7,P=0.00029),被认为是在EBV感染细胞里最过表达的基因(>200倍)。EBV-DNA检测显示,IOIP病理组织中有90%(9/10)阳性,而在正常对照组(0/4)中未检测到阳性结果。
纤维化是IOIP重要的病理改变,造成纤维化的主要原因就是细胞外基质在组织中过多堆积。ECM的代谢主要由基质金属蛋白酶(matrix metalloproteinase,MMPs)及其抑制因子(tissue inhibitors of metalloproteinase,TIMPs)所调节,MMPs促进ECM的降解,而TIMPs通过抑制MMPs,阻止ECM的降解,从而形成或促进纤维化,其中起主要作用的是TIMP-1。本研究发现部分样品(5/11)中TIMP-1在芯片检测中表达上调,提示其可能参与了IOIP的纤维化过程。本研究成功构建TIMP1-shRNA载体,通过RNAi方法,有效的抑制TIMP-1基因的表达,在纤维化相关蛋白(透明质酸和纤维连接蛋白)中检测到抑制效果。
综上所述,本研究证明EBV感染与IOIP的发病相关,EBI2基因是IOIP的分子标志,IOIP可能是由EBV感染引起的自身免疫疾病,这些发现表明应重新审视IOIP现有的临床诊断和治疗方案。由于EBV是鼻咽癌的主要致病因素,有研究发现伴眼征的鼻咽癌发生率为13.1～29.0%,而IOIP作为一种由EBV引起的眼部常见病,有可能是EBV早期激活的标志,对其进行进一步深入研究将对EBV致癌机理的研究提供重要的线索。
Idiopathic Orbital Inflammatory Pseudotumor (IOIP) is an inflammatory pseudotumor (IPT) in the orbit of unknown etiology. It is a common eye disease, accounting for 7.1%-12.3%. Fibrosis is the important pathological changes of IOIP. IOIPs are not formally diagnosed until the excised mass is examined by histological and immunohistochemical staining. Due to the lack of well-defined pathogenic mechanism and diagnostic markers, diagnosis and treatment of the disease remain a big challenge.
In this study, eleven IOIP tissue samples were obtained from patients at surgical resection, and four normal tissues were collected as controls. Total RNA was extracted and gene expression profiles of both diseased and normal tissues were analyzed with human oligonucleotide microarrays representing 32,050 well-characterized human genes. The expression patterns of selected genes were further confirmed by Real Time RT-PCR. Microarray analysis identified 744 genes differentially expressed in IOIP and non-IOIP samples with at least 21.5-fold changes and P value < 0.005, including 512 down-regulated and 192 up-regulated genes in IOIPs. Principal component analysis (PCA) and hierarchical clustering of microarray data successfully distinguished the IOIP group and the non-IOIP control group. Compared to the non-IOIP, T cell marker (CD_3 and CD_(45)), B cell marker (CD_(20) and CD_(79)) and a great deal of genes related to T and B cell proliferation and activation (SYK, CD_(20), LAT, SPIB, LCK, HCST和CD_(72)) were up-regulated in IOIPs. It is suggested that IOIP is a polyclonal disease mainly of T and B cell proliferation and the pathway of PI_3K and NF-κB and inflammation factors were activated in IOIPs.
Epstein-Barr virus infection, which causes plenty of lymphocytes infiltration, has also been proposed to be the etiology of IOIPs, however, the relationship between EBV infection and the development of IOIP has not been validated. Hierarchical clustering of microarray data successfully distinguished the IOIP group and the non-IOIP control group. The EBI2 gene, usually activated by EBV, was significantly up-regulated in IOIP group (max=11.7 folds in the microarray data, P=0.00029). EBV-DNA was detected in 9/10 (90%) of the IOIP tissue, 0/4 of the non-IOIP group. It is indicated that EBV infection is the primary reason of IOIP pathogensis.
Fibrosis is one of the important pathological changes in IOIPs, the main reason of fibrosis is the accumulation of ECM (Extracellular Matrix). The metabolism of ECM is regulated by MMPs (Matrix Metalloproteinase) and their inhibitors (Tissue Inhibitors of Metalloproteinase). MMPs promote ECM degradation while TIMPs induce the fibrosis by inhibiting MMPs function. TIMP1 is the major factor in TIMPs. In this study, TIMP1 was activated in 5/11 tissue samples in microarray, indicating that TIMP1 is related to the fibrosis in IOIP. TIMP1-shRNA vector was successfully constructed and the gene expression of TIMP1 was suppressed efficiently using RNAi, the protein related to fibrosis was also detected reduced.
In conclusion, EBV is a primary etiological factor and the EBI2 gene may serve as a molecular marker for IOIP. These results show that the present clinical diagnosis and therapeutic schedule need modified. Considering EBV is the main pathogenic factor of NPC and about 13.1～29.0% of NPC patients accompany with eye symptoms. As a common disease in eye is associated with EBV, IOIP may be the early stage of the NPC. The research on IOIP may give a clue on the mechanism of carcinogenesis of EBV.
本研究对进行炎性假瘤手术患者病理组织11例和非患者的正常组织4例,提取总RNA后,进行芯片检测,芯片结果用Real time RT-PCR进一步法验证。按照表达差异变化大于21.5倍或小于2-1.5和P<0.005的标准,筛选出表达差异基因744个,其中在IOIP组包括552个下调基因和192个表达上调基因。用主成分分析法和聚类法分析,IOIP组和正常对照组显著的分为两组。结果显示,IOIP组与正常对照组相比较,T细胞的标志分子(CD_3和CD_(45))和B细胞的标志分子(CD_(20)和CD_(79))及大量与T和B淋巴细胞扩增和激活相关的基因(SYK, CD20, LAT, SPIB, LCK, HCST和CD_(72))显著表达上调,证实眼眶炎性假瘤是以T或B细胞增殖为主的多克隆性病变。同时,发现PI_3K和NF-κB通路的激活及炎性相关因子的高表达。
EB病毒的感染会引起淋巴细胞的浸润,但EBV的感染是否和IOIP的发病相关还未被证明。在聚类分析中,受EBV感染激活的EBI2基因在IOIP组中显著表达上调(最大表达差异倍数11.7,P=0.00029),被认为是在EBV感染细胞里最过表达的基因(>200倍)。EBV-DNA检测显示,IOIP病理组织中有90%(9/10)阳性,而在正常对照组(0/4)中未检测到阳性结果。
纤维化是IOIP重要的病理改变,造成纤维化的主要原因就是细胞外基质在组织中过多堆积。ECM的代谢主要由基质金属蛋白酶(matrix metalloproteinase,MMPs)及其抑制因子(tissue inhibitors of metalloproteinase,TIMPs)所调节,MMPs促进ECM的降解,而TIMPs通过抑制MMPs,阻止ECM的降解,从而形成或促进纤维化,其中起主要作用的是TIMP-1。本研究发现部分样品(5/11)中TIMP-1在芯片检测中表达上调,提示其可能参与了IOIP的纤维化过程。本研究成功构建TIMP1-shRNA载体,通过RNAi方法,有效的抑制TIMP-1基因的表达,在纤维化相关蛋白(透明质酸和纤维连接蛋白)中检测到抑制效果。
综上所述,本研究证明EBV感染与IOIP的发病相关,EBI2基因是IOIP的分子标志,IOIP可能是由EBV感染引起的自身免疫疾病,这些发现表明应重新审视IOIP现有的临床诊断和治疗方案。由于EBV是鼻咽癌的主要致病因素,有研究发现伴眼征的鼻咽癌发生率为13.1～29.0%,而IOIP作为一种由EBV引起的眼部常见病,有可能是EBV早期激活的标志,对其进行进一步深入研究将对EBV致癌机理的研究提供重要的线索。
Idiopathic Orbital Inflammatory Pseudotumor (IOIP) is an inflammatory pseudotumor (IPT) in the orbit of unknown etiology. It is a common eye disease, accounting for 7.1%-12.3%. Fibrosis is the important pathological changes of IOIP. IOIPs are not formally diagnosed until the excised mass is examined by histological and immunohistochemical staining. Due to the lack of well-defined pathogenic mechanism and diagnostic markers, diagnosis and treatment of the disease remain a big challenge.
In this study, eleven IOIP tissue samples were obtained from patients at surgical resection, and four normal tissues were collected as controls. Total RNA was extracted and gene expression profiles of both diseased and normal tissues were analyzed with human oligonucleotide microarrays representing 32,050 well-characterized human genes. The expression patterns of selected genes were further confirmed by Real Time RT-PCR. Microarray analysis identified 744 genes differentially expressed in IOIP and non-IOIP samples with at least 21.5-fold changes and P value < 0.005, including 512 down-regulated and 192 up-regulated genes in IOIPs. Principal component analysis (PCA) and hierarchical clustering of microarray data successfully distinguished the IOIP group and the non-IOIP control group. Compared to the non-IOIP, T cell marker (CD_3 and CD_(45)), B cell marker (CD_(20) and CD_(79)) and a great deal of genes related to T and B cell proliferation and activation (SYK, CD_(20), LAT, SPIB, LCK, HCST和CD_(72)) were up-regulated in IOIPs. It is suggested that IOIP is a polyclonal disease mainly of T and B cell proliferation and the pathway of PI_3K and NF-κB and inflammation factors were activated in IOIPs.
Epstein-Barr virus infection, which causes plenty of lymphocytes infiltration, has also been proposed to be the etiology of IOIPs, however, the relationship between EBV infection and the development of IOIP has not been validated. Hierarchical clustering of microarray data successfully distinguished the IOIP group and the non-IOIP control group. The EBI2 gene, usually activated by EBV, was significantly up-regulated in IOIP group (max=11.7 folds in the microarray data, P=0.00029). EBV-DNA was detected in 9/10 (90%) of the IOIP tissue, 0/4 of the non-IOIP group. It is indicated that EBV infection is the primary reason of IOIP pathogensis.
Fibrosis is one of the important pathological changes in IOIPs, the main reason of fibrosis is the accumulation of ECM (Extracellular Matrix). The metabolism of ECM is regulated by MMPs (Matrix Metalloproteinase) and their inhibitors (Tissue Inhibitors of Metalloproteinase). MMPs promote ECM degradation while TIMPs induce the fibrosis by inhibiting MMPs function. TIMP1 is the major factor in TIMPs. In this study, TIMP1 was activated in 5/11 tissue samples in microarray, indicating that TIMP1 is related to the fibrosis in IOIP. TIMP1-shRNA vector was successfully constructed and the gene expression of TIMP1 was suppressed efficiently using RNAi, the protein related to fibrosis was also detected reduced.
In conclusion, EBV is a primary etiological factor and the EBI2 gene may serve as a molecular marker for IOIP. These results show that the present clinical diagnosis and therapeutic schedule need modified. Considering EBV is the main pathogenic factor of NPC and about 13.1～29.0% of NPC patients accompany with eye symptoms. As a common disease in eye is associated with EBV, IOIP may be the early stage of the NPC. The research on IOIP may give a clue on the mechanism of carcinogenesis of EBV.
引文
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