人乳头瘤病毒相关皮肤病发病机制研究
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摘要
【背景】人乳头瘤病毒是一广泛存在的病毒,可以引起良性(低风险型)和恶性的(高风险型)皮肤或粘膜的皮损,但关于人乳头瘤病毒的致病机制还不清楚。人乳头瘤病毒感染可能和朗格汉斯细胞,T淋巴细胞,病毒本身等因素有关,此外,还可能与部分患者的某些基因出现甲基化和细胞因子的变化有关。疣状表皮发育不良患者出现人乳头瘤病毒易感可能与EVER1/2基因的突变有关。
【目的】本论文通过研究尖锐湿疣患者DNA甲基化和疣状表皮发育不良中朗格汉斯细胞和细胞因子的变化,探讨人乳头瘤病毒相关性皮肤病的发病机制。
【方法】
从基因角度研究尖锐湿疣的发病和DNA甲基化之间的关系,采用甲基化特异性聚合酶链式反应,对51例尖锐湿疣患者及47例正常对照进行实验,观察对人乳头瘤病毒易感的EVER1基因甲基化的阳性率,对尖锐湿疣和EVER1基因甲基化之间的关系进行研究,以探讨尖锐湿疣的发病机制。
采用免疫组化方法检测疣状表皮发育不良病人中朗格汉斯细胞和细胞因子的表达情况,以研究细胞因子在其发病中的作用。选取10例疣状表皮发育不良病人的皮损,对其表皮中朗格汉斯细胞的表面标记分子CD1a和CD83,及与免疫反应相关的IL-10,IL-23和CD86三种细胞因子进行免疫组化染色并观察其表达,同时以10例正常人的眼皮标本作对照。
【结果】
尖锐湿疣组中甲基化阳性率为13.73%(7／51),部分甲基化率为17.65%(9／51),非甲基化率为68.62%(35／51),总的甲基化阳性率为31.38%。正常对照组的甲基化阳性率8.51%(4／47),部分甲基化率为2.13%(1／47),非甲基化率为89.36%(42／47),总的甲基化阳性率为10.64%。两组比较有显著性差异(p<0.05)。
在疣状表皮发育不良的所有组织中均可见到CD1a阳性表达的朗格汉斯细胞,未见CD83阳性表达的朗格汉斯细胞,且CD1a阳性的朗格汉斯细胞的计数在EV组较正常组相比明显降低且分布不均匀。疣状表皮发育不良组中IL-10,IL-23和CD86三种细胞因子的表达为阳性,而正常组有1例IL-10阳性,其余均为阴性；病例组中三种细胞因子的评分为3-6分,而正常组除了IL-10中的1例为3分,其余均为0分；病例组中三种细胞因子的阳性率为(++)-(+++),而正常组中除了IL-10中的1例为(++),其余均为(-),疣状表皮发育不良组三种细胞因子表达阳性率明显高于正常组。
【结论】
本研究结果显示尖锐湿疣患者甲基化发生率为31.38%,高于正常对照组(p<0.05),表明尖锐湿疣的发生可能和EVER1基因启动子区的甲基化相关。
在疣状表皮发育不良组中CD1a阳性的朗格汉斯细胞的变化和CD83的不表达说明朗格汉斯细胞的功能可能受到抑制,使其不能转变为成熟状态并刺激T细胞发生免疫反应,从而造成了人乳头瘤病毒的感染。而IL-10,IL-23和CD86的阳性表达说明疣状表皮发育不良的发病还可能和角质形成细胞分泌的细胞因子有关。
The pathogenesis of human papilomavirus related dermatosis
[Objective]
To investigate the pathogenesis of human papilomavirus infected dermatosis, we focused on two human papilomavirus related skin diseases-condyloma acuminatum and epidermodysplasia verruciformis.
[Methods]
To investigate the relationship between condyloma acuminatum and DNA methylation, methylation-specific PCR was performed to study 51 cases of condyloma acuminatum patients and 47 cases of normal controls, and to calculate the positive rate of methylation on EVER1 gene which was the predisposing gene of human papilomavirus.
To study the role of langerhans cells and cytokines in pathogenesis of human papilomavirus related disease epidermodysplasia verruciformis. The expression of CDla and CD83 were measured by immunohistochemistry in 10 cases of EV lesions and 10 cases of normal human skin. The form, quantity and distribution of LCs were observed under the light microscope. Furthermore, Immunohistochemical stain was also utilized to measure the expressions of IL-10, IL-23 and CD86 in 10 patients with epidermodysplasia verruciformis and in 10 healthy human controls
[Results]
The positive rate of DNA methylation in condyloma acuminatum patients was 13.73%(7/51).partly positive rate 17.65%(9/51).negative rate 68.62% (35/51),total positive rate 31.38%, while in normal controls that was 8.51%(4/47),2.13%(1/47),89.36%, and 10.64%, respectively.
There were CD1a+LCs in all cases of epidermodysplasia verruciformis patients and normal controls, but CD83+LC could not be found in all cases. The quantity of CD1a+LCs in the lesions of epidermodysplasia verruciformis was statistically significant lower(P<0.01)than that in the normal skin. We could also observe the distribution of LCs in epidermodysplasia verruciformis lesions was uneven. And the expressions of IL-10、IL-23 and CD86 could be found in 10 lesional epidermodysplasia verruciformis skin while only IL-10 could be found in the epidermal keratinacytes from one normal control human skin;the score of epidermodysplasia verruciformis group was between three and six, while in normal control group only one case of IL-10 was three, and others were zero; the positive rate of epidermodysplasia verruciformis group were (++) and (+++), while in normal control group only one case of IL-10 was (++),and others were negative.
[Conclusion]
The positive rate of methylation in condyloma acuminatum patients was higher than than in the normal controls(p<0.05), demonstrating that the pathogenesis of condyloma acuminatum may be related to the methylation of EVER1 gene promoter region.
The results indicate that the density of LCs is decreased and the function of LCs is inhibited in EV patients. LCs can not be transformed into the mature status, as a result, immunologic reaction can not be started by antigen presenting and stimulating T lymphocytes. This may account for the HPV infection in EV patients. And the pathogenesis of epidermodysplasia verruciformis may also be correlated with IL-10, IL-23 and CD86 which were secreted by lesional keratinocytes.
【目的】本论文通过研究尖锐湿疣患者DNA甲基化和疣状表皮发育不良中朗格汉斯细胞和细胞因子的变化,探讨人乳头瘤病毒相关性皮肤病的发病机制。
【方法】
从基因角度研究尖锐湿疣的发病和DNA甲基化之间的关系,采用甲基化特异性聚合酶链式反应,对51例尖锐湿疣患者及47例正常对照进行实验,观察对人乳头瘤病毒易感的EVER1基因甲基化的阳性率,对尖锐湿疣和EVER1基因甲基化之间的关系进行研究,以探讨尖锐湿疣的发病机制。
采用免疫组化方法检测疣状表皮发育不良病人中朗格汉斯细胞和细胞因子的表达情况,以研究细胞因子在其发病中的作用。选取10例疣状表皮发育不良病人的皮损,对其表皮中朗格汉斯细胞的表面标记分子CD1a和CD83,及与免疫反应相关的IL-10,IL-23和CD86三种细胞因子进行免疫组化染色并观察其表达,同时以10例正常人的眼皮标本作对照。
【结果】
尖锐湿疣组中甲基化阳性率为13.73%(7／51),部分甲基化率为17.65%(9／51),非甲基化率为68.62%(35／51),总的甲基化阳性率为31.38%。正常对照组的甲基化阳性率8.51%(4／47),部分甲基化率为2.13%(1／47),非甲基化率为89.36%(42／47),总的甲基化阳性率为10.64%。两组比较有显著性差异(p<0.05)。
在疣状表皮发育不良的所有组织中均可见到CD1a阳性表达的朗格汉斯细胞,未见CD83阳性表达的朗格汉斯细胞,且CD1a阳性的朗格汉斯细胞的计数在EV组较正常组相比明显降低且分布不均匀。疣状表皮发育不良组中IL-10,IL-23和CD86三种细胞因子的表达为阳性,而正常组有1例IL-10阳性,其余均为阴性；病例组中三种细胞因子的评分为3-6分,而正常组除了IL-10中的1例为3分,其余均为0分；病例组中三种细胞因子的阳性率为(++)-(+++),而正常组中除了IL-10中的1例为(++),其余均为(-),疣状表皮发育不良组三种细胞因子表达阳性率明显高于正常组。
【结论】
本研究结果显示尖锐湿疣患者甲基化发生率为31.38%,高于正常对照组(p<0.05),表明尖锐湿疣的发生可能和EVER1基因启动子区的甲基化相关。
在疣状表皮发育不良组中CD1a阳性的朗格汉斯细胞的变化和CD83的不表达说明朗格汉斯细胞的功能可能受到抑制,使其不能转变为成熟状态并刺激T细胞发生免疫反应,从而造成了人乳头瘤病毒的感染。而IL-10,IL-23和CD86的阳性表达说明疣状表皮发育不良的发病还可能和角质形成细胞分泌的细胞因子有关。
The pathogenesis of human papilomavirus related dermatosis
[Objective]
To investigate the pathogenesis of human papilomavirus infected dermatosis, we focused on two human papilomavirus related skin diseases-condyloma acuminatum and epidermodysplasia verruciformis.
[Methods]
To investigate the relationship between condyloma acuminatum and DNA methylation, methylation-specific PCR was performed to study 51 cases of condyloma acuminatum patients and 47 cases of normal controls, and to calculate the positive rate of methylation on EVER1 gene which was the predisposing gene of human papilomavirus.
To study the role of langerhans cells and cytokines in pathogenesis of human papilomavirus related disease epidermodysplasia verruciformis. The expression of CDla and CD83 were measured by immunohistochemistry in 10 cases of EV lesions and 10 cases of normal human skin. The form, quantity and distribution of LCs were observed under the light microscope. Furthermore, Immunohistochemical stain was also utilized to measure the expressions of IL-10, IL-23 and CD86 in 10 patients with epidermodysplasia verruciformis and in 10 healthy human controls
[Results]
The positive rate of DNA methylation in condyloma acuminatum patients was 13.73%(7/51).partly positive rate 17.65%(9/51).negative rate 68.62% (35/51),total positive rate 31.38%, while in normal controls that was 8.51%(4/47),2.13%(1/47),89.36%, and 10.64%, respectively.
There were CD1a+LCs in all cases of epidermodysplasia verruciformis patients and normal controls, but CD83+LC could not be found in all cases. The quantity of CD1a+LCs in the lesions of epidermodysplasia verruciformis was statistically significant lower(P<0.01)than that in the normal skin. We could also observe the distribution of LCs in epidermodysplasia verruciformis lesions was uneven. And the expressions of IL-10、IL-23 and CD86 could be found in 10 lesional epidermodysplasia verruciformis skin while only IL-10 could be found in the epidermal keratinacytes from one normal control human skin;the score of epidermodysplasia verruciformis group was between three and six, while in normal control group only one case of IL-10 was three, and others were zero; the positive rate of epidermodysplasia verruciformis group were (++) and (+++), while in normal control group only one case of IL-10 was (++),and others were negative.
[Conclusion]
The positive rate of methylation in condyloma acuminatum patients was higher than than in the normal controls(p<0.05), demonstrating that the pathogenesis of condyloma acuminatum may be related to the methylation of EVER1 gene promoter region.
The results indicate that the density of LCs is decreased and the function of LCs is inhibited in EV patients. LCs can not be transformed into the mature status, as a result, immunologic reaction can not be started by antigen presenting and stimulating T lymphocytes. This may account for the HPV infection in EV patients. And the pathogenesis of epidermodysplasia verruciformis may also be correlated with IL-10, IL-23 and CD86 which were secreted by lesional keratinocytes.
引文
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[1]Pretet JL, Charlot JF, Mougin C. Virological and carcinogenic aspects of HPV[J].Bull Acad Natl Med.2007 Mar;191(3):611-23; discussion 623.
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