HLA-Ⅰ、CD8和CD4在宫颈不同病变组织中的表达及意义
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摘要
目的:宫颈癌是全球妇女最常见的恶性肿瘤之一,尽管开展了早期筛查,但每年的新发病例及死亡病例数仍较高,特别是在经济欠发达地区,一旦发现,往往处于宫颈癌的晚期,致使五年生存率降低。机体的全身及局部免疫状态在清除肿瘤细胞方面的作用已经得到研究者的公认。免疫逃逸在恶性肿瘤的发生发展中起着重要的作用,其机制之一是通过下调人类白细胞抗原Ⅰ(human leukocyte antigen classⅠ,HLA-Ⅰ)的表达,减少CD~8+T淋巴细胞的活化,以降低机体对肿瘤细胞的杀伤作用,使肿瘤细胞得以继续生长。本研究通过检测宫颈癌、宫颈上皮内瘤变(cervical intraepithelial neoplasia,CIN)及慢性宫颈炎组织和癌旁组织石蜡切片中HLA-I类抗原和CD8、CD4分子的表达情况,以了解宫颈的局部免疫状态,并探讨其与宫颈癌的相关性及提示可能的免疫治疗。
方法:采用免疫组织化学SP法检测宫颈癌、CIN、慢性宫颈炎和癌旁组织中HLA-Ⅰ类抗原、CD8和CD4分子的表达情况。将经临床病理确诊的宫颈癌、CIN、慢性宫颈炎组织各20例(与宫颈癌相同病理号的癌旁组织亦20例),切片后分别应用HLA-Ⅰ、CD8和CD4单克隆抗体,按照免疫组织化学试剂盒(福州迈新生物技术开发公司)中的步骤进行SP法实验,DAB染色,以PBS代替一抗做空白对照,以扁桃体组织做阳性对照。
结果:以细胞膜和细胞浆内出现棕黄色或棕褐色颗粒为染色阳性细胞,根据细胞着色的程度及着色细胞百分率进行综合评分。免疫组织化学结果显示,在宫颈癌、CIN、慢性宫颈炎和癌旁组织中:HLA-Ⅰ类抗原的阳性表达率分别为40%、95%、100%和100%,宫颈癌组的表达率明显降低(P<0.01);CD8分子的阳性表达率分别为35%、95%、100%和100%,宫颈癌组的表达率明显降低(P<0.01);CD4分子的阳性表达率分别为45%、80%、100%和100%,宫颈癌组的表达率亦明显降低(P<0.01)。CD8分子和HLA-I类抗原之间的表达存在正相关关系(Spearman秩相关系数r =0.913,P<0.001)。在宫颈癌组中,HLA-Ⅰ类抗原、CD8和CD4分子在不同临床分期、不同分化组、有无淋巴结转移组表达均无统计学差异,在CINⅠ组与CINⅡ～Ⅲ组表达亦无统计学差异(P均>0.05)。
结论:HLA-Ⅰ类抗原、CD8和CD4分子在宫颈上皮内瘤变和宫颈癌组织中表达减少及无表达,提示宫颈的局部免疫状态与宫颈病变的发生发展具有密切的相关性。
Objective: Cervical cancer is the second leading cause of cancer related death among women worldwide. In spite of early screening,new cases and deaths are still at a high level each year. Especially in economically underdeveloped areas, women were often in the advanced stage and five-year survival rate decreased once they were diagnosed with cervical cancer. It has been acknowledged that the systemic and local immune status play important roles in clearance of tumor cells. The mechanism of escape from immune-surveillance is responsible for the growth of malignant tumor, one of which is down-regulating the expression of human leukocyte antigen classⅠ( HLA-I), inducing the decrease of CD8+ T lymphocytes for activation, then reducing the killing effect for tumor cells and leading to the progression and metastasis. In this research, we examined the expression of HLA-I, CD8 and CD4 in cervical cancer, cervical intraepithelial neoplasia(CIN), chronic cervicitis and peri-cancer tissues using SP immunohistochemistry, to understand local immune state of cervix and investigate their association with cervical cancer.
Methods: The SP immunohistochemistry was used to detect the expression of HLA-I, CD8 and CD4 in patients with cervical cancer, cervical intraepithelial neoplasia(CIN), chronic cervicitis and peri-cancer tissues, who were diagnosed by clinical pathology. Each of these four tissues was chosen 20 cases, sliced and HLA-I, CD8, CD4 monoclonal antibodies were applied to them according to the steps of immunohistochemical kit (Maixin Bio. Fuzhou), then staining by DAB. PBS instead of primary antibody was used as blank control and tonsillar tissue as positive control.
Results: Flaxen to brown particles on cell membranes or in cytoplasm were recognized as staining positive cells and comprehensive assessment was given according to the ImmunoReactive Score that evaluated the proportion of the cells expressing such molecules and the intensity of the staining. The percentage of positive tissue staining of HLA class I antigen in cervical cancer, CIN, chronic cervicitis and peri-cancer tissues were 40%, 95%, 100.0% and 100.0%, respectively. And the percentage of CD8 in various tissues was 35%, 95%, 100% and 100.0%, respectively. The positive tissue staining percentage of CD4 in the tissues above was 45%, 80%, 100% and 100%, respectively. The percentage of positive tissue staining of HLA-I, CD8 and CD4 were signifi cantly lower in tissues of cervical cancer when compared with other tissues (P < 0.01). No correlation between positive tissue staining of HLA-I, CD8, and CD4 and clinicopathologic profiles was observed (P > 0.05). A positive correlation was found between HLA-I and CD8 expression (Spearman’s correlation r =0.913,P<0.001).
Conclusion: The expression of HLA-I, CD8 and CD4 are down-regulated or deleted in CIN and cervical cancer, which suggest the local immune status of cervix is closely related to the development and progression of CIN and cervical cancer.
方法:采用免疫组织化学SP法检测宫颈癌、CIN、慢性宫颈炎和癌旁组织中HLA-Ⅰ类抗原、CD8和CD4分子的表达情况。将经临床病理确诊的宫颈癌、CIN、慢性宫颈炎组织各20例(与宫颈癌相同病理号的癌旁组织亦20例),切片后分别应用HLA-Ⅰ、CD8和CD4单克隆抗体,按照免疫组织化学试剂盒(福州迈新生物技术开发公司)中的步骤进行SP法实验,DAB染色,以PBS代替一抗做空白对照,以扁桃体组织做阳性对照。
结果:以细胞膜和细胞浆内出现棕黄色或棕褐色颗粒为染色阳性细胞,根据细胞着色的程度及着色细胞百分率进行综合评分。免疫组织化学结果显示,在宫颈癌、CIN、慢性宫颈炎和癌旁组织中:HLA-Ⅰ类抗原的阳性表达率分别为40%、95%、100%和100%,宫颈癌组的表达率明显降低(P<0.01);CD8分子的阳性表达率分别为35%、95%、100%和100%,宫颈癌组的表达率明显降低(P<0.01);CD4分子的阳性表达率分别为45%、80%、100%和100%,宫颈癌组的表达率亦明显降低(P<0.01)。CD8分子和HLA-I类抗原之间的表达存在正相关关系(Spearman秩相关系数r =0.913,P<0.001)。在宫颈癌组中,HLA-Ⅰ类抗原、CD8和CD4分子在不同临床分期、不同分化组、有无淋巴结转移组表达均无统计学差异,在CINⅠ组与CINⅡ～Ⅲ组表达亦无统计学差异(P均>0.05)。
结论:HLA-Ⅰ类抗原、CD8和CD4分子在宫颈上皮内瘤变和宫颈癌组织中表达减少及无表达,提示宫颈的局部免疫状态与宫颈病变的发生发展具有密切的相关性。
Objective: Cervical cancer is the second leading cause of cancer related death among women worldwide. In spite of early screening,new cases and deaths are still at a high level each year. Especially in economically underdeveloped areas, women were often in the advanced stage and five-year survival rate decreased once they were diagnosed with cervical cancer. It has been acknowledged that the systemic and local immune status play important roles in clearance of tumor cells. The mechanism of escape from immune-surveillance is responsible for the growth of malignant tumor, one of which is down-regulating the expression of human leukocyte antigen classⅠ( HLA-I), inducing the decrease of CD8+ T lymphocytes for activation, then reducing the killing effect for tumor cells and leading to the progression and metastasis. In this research, we examined the expression of HLA-I, CD8 and CD4 in cervical cancer, cervical intraepithelial neoplasia(CIN), chronic cervicitis and peri-cancer tissues using SP immunohistochemistry, to understand local immune state of cervix and investigate their association with cervical cancer.
Methods: The SP immunohistochemistry was used to detect the expression of HLA-I, CD8 and CD4 in patients with cervical cancer, cervical intraepithelial neoplasia(CIN), chronic cervicitis and peri-cancer tissues, who were diagnosed by clinical pathology. Each of these four tissues was chosen 20 cases, sliced and HLA-I, CD8, CD4 monoclonal antibodies were applied to them according to the steps of immunohistochemical kit (Maixin Bio. Fuzhou), then staining by DAB. PBS instead of primary antibody was used as blank control and tonsillar tissue as positive control.
Results: Flaxen to brown particles on cell membranes or in cytoplasm were recognized as staining positive cells and comprehensive assessment was given according to the ImmunoReactive Score that evaluated the proportion of the cells expressing such molecules and the intensity of the staining. The percentage of positive tissue staining of HLA class I antigen in cervical cancer, CIN, chronic cervicitis and peri-cancer tissues were 40%, 95%, 100.0% and 100.0%, respectively. And the percentage of CD8 in various tissues was 35%, 95%, 100% and 100.0%, respectively. The positive tissue staining percentage of CD4 in the tissues above was 45%, 80%, 100% and 100%, respectively. The percentage of positive tissue staining of HLA-I, CD8 and CD4 were signifi cantly lower in tissues of cervical cancer when compared with other tissues (P < 0.01). No correlation between positive tissue staining of HLA-I, CD8, and CD4 and clinicopathologic profiles was observed (P > 0.05). A positive correlation was found between HLA-I and CD8 expression (Spearman’s correlation r =0.913,P<0.001).
Conclusion: The expression of HLA-I, CD8 and CD4 are down-regulated or deleted in CIN and cervical cancer, which suggest the local immune status of cervix is closely related to the development and progression of CIN and cervical cancer.
引文
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