不同预后尖锐湿疣组织中TLR3及TLR9的表达研究
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摘要
研究背景
尖锐湿疣(Condyloma Acuminatum, CA)是主要由感染人乳头瘤病毒(Human Papilloma Virus, HPV)引起人生殖器部位及附近表皮的一种良性乳头瘤样增生性疾病,典型病理改变是表皮中上层出现空泡细胞。CA治疗并不困难,但由于复发率很高,且发病率逐年上升而逐渐引起人们的重视。目前普遍认为,CA的发生、转归与机体免疫功能变化有关。CA患者机体免疫系统受抑制,尤其是细胞免疫功能低下是HPV进入机体后长期持续大量复制的主要原因。
Toll样受体(Toll-like receptor, TLR)是新近发现的一类模式识别受体,广泛分布于细胞表面参与病原微生物及其产物的识别,并通过诱导活性氧中间产物和活性氮中间产物的产生、前炎症因子的释放实现病原微生物的清除和机体免疫状态的调节。它们不仅在天然免疫中起重要作用,同时也被视为天然免疫与获得性免疫的连接点,影响获得性免疫。Toll样受体在CA发病机理中的作用已受到了越来越多的关注。在已发现的11种TLR家族成员中,TLR3和TLR9被认为是抗病毒免疫的重要受体之一。本研究通过观察不同预后CA患者皮损局部TLR3和TLR9的表达情况,试图从一个新的角度反映CA患者机体免疫状态,以期找到更好的治疗方式有效清除HPV,改善CA预后。
目的
通过观察不同预后CA患者皮损局部TLR3和TLR9的表达情况,探讨TLR3和TLR9在CA发病机制中的作用以及它们与CA发生、发展的关系。
方法
选择CA患者24例(其中无复发者14例,复发者10例)及正常对照者10例,应用免疫组化法及RT-PCR法分别检测各组CA组织和正常对照包皮组织中TLR3、TLR9的表达情况。所有数据以x±s表示,采用SPSS13.0统计软件进行数据分析,两组间比较采用独立样本t检验,P<0.05具有统计学意义。
结果
1、免疫组化定位分析：TLR3、TLR9蛋白定位于角质形成细胞的胞浆和(或)胞膜。对照组TLR3、TLR9于表皮全层呈中等强度或弱表达；无复发组TLR3、TLR9于表皮全层强阳性表达,以棘层、颗粒层为主；复发组TLR3、TLR9于表皮全层中等强度表达,以基底层、棘层为主。
2、RT-PCR半定量分析：无复发组TLR3、TLR9 mRNA与对照组相比表达升高(P<0.01；P<0.05),且无复发组TLR3的表达明显高于TLR9 (P<0.05);复发组TLR3、TLR9与对照组相比无明显差异(二者均P>0.05),与无复发组相比TLR3减少显著(P<0.05)。
结论
1、TLR3与TLR9在无复发组CA皮损局部表达上调；
2、TLR3与TLR9在复发组CA皮损局部的表达与对照组相比无显著性差异(P>0.05),较无复发组的表达有不同程度减少,其中TLR3减少有显著性差异(P<0.05)；
3、TLR3与TLR9的表达部位在无复发CA与复发CA组织中存在差异；
4、TLR3与TLR9的表达部位和表达量的改变可能与CA预后有关,且TLR3的影响可能更大。
Background
Condyloma acuminatum(CA) is a benign papillomatous hyperplasia caused by infecting human papilloma virus(HPV) to human genitals and the surrounding skin. The typical biopsy change is the vacuolated cell presenting in the upper epidermis. The therapies of the disease are not difficult, but the high recurrence rate and increasing incidence rate are attracting people's attention gradually. It widely recognized that change of organism immune function closely relates to the occurrence and turnover of CA. The suppression of patients'immune system especially cellular immune function is the main reason for HPV persistent infection.
Toll-like receptors (TLRs) are a kind of recently identified patterns recognition receptors. they widely distribute in the surface of cells and join the identification of pathogenic microorganism and their products. And they can clear the pathogenic microorganism and regulate immune status through inducing the production of reactive oxygen intermediates and reactive nitrogen intermediates and the release of proinflammatory factors. They play important roles in inherent immunity defense, and have always been considered as the joint between inherent immunity and adaptive immunity which can impact adaptive immunity further. The function of TLR has been paid more and more attention in CA. In the 11 TLR family members that have been found, TLR3 and TLR9 are considered as two important receptors in anti-virus immune response. In this research, we attempts to reflect the immune state of CA patients' organism from a new perspective so that we can find a better therapeutic way to clear HPV and improve CA patients'prognosis through observing the expression of TLR3 and TLR9 in CA patients'skin lesions with different prognosis.
Objective
To observe the expression of TLR3 and TLR9 so that to further explore their roles in pathogenesis of CA and the relationship with the occurrence and the development of CA.
Methods
Collect 24 CA patients (14 cases in non-recurrence,10 cases in recurrence) and 10 healthy controls. The expression of TLR3 and TLR9 in each group of CA and normal prepuce skins was detected by immunohistochemistry staining and RT-PCR method. All the datas are expressed by mean±standard. The software SPSS13.0 was applied for statistical analysis. T test analysis was used to compare cases and controls. The test results have statistical significance when P<0.05.
Results
1.Location analysis by immunohistochemistry staining:TLR3 and TLR9 proteins localized in the cytoplasm and (or) cell membrane of keratinocyte. In normal controls, the expression of TLR3 and TLR9 was mid-strong or weak positive throughout the epidermis; In non-recurrent group, the expression of TLR3 and TLR9 was strong positive throughout the epidermis, and mainly located in spinous layer and granular layer; In recurrent group, the expression of TLR3 and TLR9 was mid-strong positive throughout the epidermis, and mainly located in basal layer and spinous layer.
2.Semiquantitative analysis by RT-PCR:The expression of TLR3 and TLR9 mRNA in non-recurrent group was higher than that of normal controls(P<0.01; P< 0.05), and the expression of TLR3 mRNA was much higher than TLR9 mRNA (P< 0.05); The expression of TLR3 and TLR9 mRNA in recurrent group was similar with that of normal controls (P>0.05), but the expression of TLR3 mRNA in recurrent group was much lower than that of non-recurrent group (P<0.05).
Conclusion
1. The expression of TLR3 and TLR9 was up regulated in non-recurrent CA;
2. The expression of TLR3 and TLR9 in recurrent group was similar with that of normal controls (P> 0.05). Their expressions were reduced in different degree compared with non-recurrent group, and the decrease of TLR3 in recurrent group was significant (P<0.05);
3. There were differences between the recurrence CA and non-recurrent CA for TLR3 and TLR9's expression positions;
4. The changes of TLR3 and TLR9's expression position and level may be associated with the prognosis of CA, and TLR3 may exert greater impact on it.
尖锐湿疣(Condyloma Acuminatum, CA)是主要由感染人乳头瘤病毒(Human Papilloma Virus, HPV)引起人生殖器部位及附近表皮的一种良性乳头瘤样增生性疾病,典型病理改变是表皮中上层出现空泡细胞。CA治疗并不困难,但由于复发率很高,且发病率逐年上升而逐渐引起人们的重视。目前普遍认为,CA的发生、转归与机体免疫功能变化有关。CA患者机体免疫系统受抑制,尤其是细胞免疫功能低下是HPV进入机体后长期持续大量复制的主要原因。
Toll样受体(Toll-like receptor, TLR)是新近发现的一类模式识别受体,广泛分布于细胞表面参与病原微生物及其产物的识别,并通过诱导活性氧中间产物和活性氮中间产物的产生、前炎症因子的释放实现病原微生物的清除和机体免疫状态的调节。它们不仅在天然免疫中起重要作用,同时也被视为天然免疫与获得性免疫的连接点,影响获得性免疫。Toll样受体在CA发病机理中的作用已受到了越来越多的关注。在已发现的11种TLR家族成员中,TLR3和TLR9被认为是抗病毒免疫的重要受体之一。本研究通过观察不同预后CA患者皮损局部TLR3和TLR9的表达情况,试图从一个新的角度反映CA患者机体免疫状态,以期找到更好的治疗方式有效清除HPV,改善CA预后。
目的
通过观察不同预后CA患者皮损局部TLR3和TLR9的表达情况,探讨TLR3和TLR9在CA发病机制中的作用以及它们与CA发生、发展的关系。
方法
选择CA患者24例(其中无复发者14例,复发者10例)及正常对照者10例,应用免疫组化法及RT-PCR法分别检测各组CA组织和正常对照包皮组织中TLR3、TLR9的表达情况。所有数据以x±s表示,采用SPSS13.0统计软件进行数据分析,两组间比较采用独立样本t检验,P<0.05具有统计学意义。
结果
1、免疫组化定位分析：TLR3、TLR9蛋白定位于角质形成细胞的胞浆和(或)胞膜。对照组TLR3、TLR9于表皮全层呈中等强度或弱表达；无复发组TLR3、TLR9于表皮全层强阳性表达,以棘层、颗粒层为主；复发组TLR3、TLR9于表皮全层中等强度表达,以基底层、棘层为主。
2、RT-PCR半定量分析：无复发组TLR3、TLR9 mRNA与对照组相比表达升高(P<0.01；P<0.05),且无复发组TLR3的表达明显高于TLR9 (P<0.05);复发组TLR3、TLR9与对照组相比无明显差异(二者均P>0.05),与无复发组相比TLR3减少显著(P<0.05)。
结论
1、TLR3与TLR9在无复发组CA皮损局部表达上调；
2、TLR3与TLR9在复发组CA皮损局部的表达与对照组相比无显著性差异(P>0.05),较无复发组的表达有不同程度减少,其中TLR3减少有显著性差异(P<0.05)；
3、TLR3与TLR9的表达部位在无复发CA与复发CA组织中存在差异；
4、TLR3与TLR9的表达部位和表达量的改变可能与CA预后有关,且TLR3的影响可能更大。
Background
Condyloma acuminatum(CA) is a benign papillomatous hyperplasia caused by infecting human papilloma virus(HPV) to human genitals and the surrounding skin. The typical biopsy change is the vacuolated cell presenting in the upper epidermis. The therapies of the disease are not difficult, but the high recurrence rate and increasing incidence rate are attracting people's attention gradually. It widely recognized that change of organism immune function closely relates to the occurrence and turnover of CA. The suppression of patients'immune system especially cellular immune function is the main reason for HPV persistent infection.
Toll-like receptors (TLRs) are a kind of recently identified patterns recognition receptors. they widely distribute in the surface of cells and join the identification of pathogenic microorganism and their products. And they can clear the pathogenic microorganism and regulate immune status through inducing the production of reactive oxygen intermediates and reactive nitrogen intermediates and the release of proinflammatory factors. They play important roles in inherent immunity defense, and have always been considered as the joint between inherent immunity and adaptive immunity which can impact adaptive immunity further. The function of TLR has been paid more and more attention in CA. In the 11 TLR family members that have been found, TLR3 and TLR9 are considered as two important receptors in anti-virus immune response. In this research, we attempts to reflect the immune state of CA patients' organism from a new perspective so that we can find a better therapeutic way to clear HPV and improve CA patients'prognosis through observing the expression of TLR3 and TLR9 in CA patients'skin lesions with different prognosis.
Objective
To observe the expression of TLR3 and TLR9 so that to further explore their roles in pathogenesis of CA and the relationship with the occurrence and the development of CA.
Methods
Collect 24 CA patients (14 cases in non-recurrence,10 cases in recurrence) and 10 healthy controls. The expression of TLR3 and TLR9 in each group of CA and normal prepuce skins was detected by immunohistochemistry staining and RT-PCR method. All the datas are expressed by mean±standard. The software SPSS13.0 was applied for statistical analysis. T test analysis was used to compare cases and controls. The test results have statistical significance when P<0.05.
Results
1.Location analysis by immunohistochemistry staining:TLR3 and TLR9 proteins localized in the cytoplasm and (or) cell membrane of keratinocyte. In normal controls, the expression of TLR3 and TLR9 was mid-strong or weak positive throughout the epidermis; In non-recurrent group, the expression of TLR3 and TLR9 was strong positive throughout the epidermis, and mainly located in spinous layer and granular layer; In recurrent group, the expression of TLR3 and TLR9 was mid-strong positive throughout the epidermis, and mainly located in basal layer and spinous layer.
2.Semiquantitative analysis by RT-PCR:The expression of TLR3 and TLR9 mRNA in non-recurrent group was higher than that of normal controls(P<0.01; P< 0.05), and the expression of TLR3 mRNA was much higher than TLR9 mRNA (P< 0.05); The expression of TLR3 and TLR9 mRNA in recurrent group was similar with that of normal controls (P>0.05), but the expression of TLR3 mRNA in recurrent group was much lower than that of non-recurrent group (P<0.05).
Conclusion
1. The expression of TLR3 and TLR9 was up regulated in non-recurrent CA;
2. The expression of TLR3 and TLR9 in recurrent group was similar with that of normal controls (P> 0.05). Their expressions were reduced in different degree compared with non-recurrent group, and the decrease of TLR3 in recurrent group was significant (P<0.05);
3. There were differences between the recurrence CA and non-recurrent CA for TLR3 and TLR9's expression positions;
4. The changes of TLR3 and TLR9's expression position and level may be associated with the prognosis of CA, and TLR3 may exert greater impact on it.
引文
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3 Stem PL, Brown M, Staeey SN, et al. Natural HPV immunity and vaccination strategies. J ClinVirol,2000; 19(1-2):57-6.
4 Tjiong MY, Out TA, Ter SJ, et al. Epidermiologic and mucosa immunologic aspact of HPV infeetion and HPV-related servical neoplasia in the lower female genital tract:a eview. Int J Gynecol Cancer,2001; 11(1):9-17.
5 Lore K, Betts MR, Brenchley JM, et al. Toll-like receptor ligands modulate dendritic cells to augment cytomegalovirus and HIV-1-specific T cell responses. J Immunol,2003; 171:4320-8.
6 Rudd BD, Burstein E, Duckett CS, et al. Differential role for TLR3 in respiratory syncytial virus-induced chemokine expression. J Virol,2005; 79:3350-6.
7 Hengge UR, Ruzicka T. Topical immunomodulation in dermatology:potential of toll-like receptor agonists. Dermatol Surg,2004; 30:1101-12.
8 Chen XZ, Mao XH, Zhu KJ, et al. Toll like receptor agonists augment HPV11 E7-specific T cell responses by modulating monocyte-derived dendritic cells. Arch Dermatol Res.2010; 302 (1):57-65.
9 Ja KK, Hyun JK, Mi-Yeon K, et al. Expression of toll-like receptors in verruca and molluscum contagiosum. J Korean Med Sci.2008; 23:307-314.
10 ZhangJ, DingY, ZhouZ, et al. Expression of human papilloma virus16 E7 DNA in patients with colorectal adenocarcinoma. Sheng wu yi xue gong cheng xue za zhi.2005; 22(5):1024-6.
11 Janeway JCA, Medzhitov R. Innate immune recognition. Annu Rev Immunol.2002; 20: 197-216.
12 Doyle SE, O'Connell R, Vaidya SA, et al.. Toll-like reeeptor3 mediates a more potent antiviral response than toll-like reeeptor4. J Immunol.2003; 170(7):3565-3571.
13 Neill LAJ, Fitzgerald KA, Bowie AG. The Toll-IL-1 receptor adaptor family grows to five members. Trends in Immunology.2003; 24(6):286-289.
14 J Akira S, Sato S. Toll like receptors and their signaling mechanisms. Scand J Infect Dis.2003; 35(9):555-562.
15 Takeda K, Akira S. TLR signaling pathways. Semin Immunol.2004; 16(1):3-9.
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31 Vabulas RM, Braedel S, Hilf N, et al. The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Tolllike receptor2/4 pathway. J Biol Chem.2002; 277: 20847-53.
2 Man S, Fiander A. Inununology of human papillomavirus infection in lower genital tract neoPlasia. Best Pract Res Clin Obstet Gynaeeol,2001; 15(5):701-714.
3 Stem PL, Brown M, Staeey SN, et al. Natural HPV immunity and vaccination strategies. J ClinVirol,2000; 19(1-2):57-6.
4 Tjiong MY, Out TA, Ter SJ, et al. Epidermiologic and mucosa immunologic aspact of HPV infeetion and HPV-related servical neoplasia in the lower female genital tract:a eview. Int J Gynecol Cancer,2001; 11(1):9-17.
5 Lore K, Betts MR, Brenchley JM, et al. Toll-like receptor ligands modulate dendritic cells to augment cytomegalovirus and HIV-1-specific T cell responses. J Immunol,2003; 171:4320-8.
6 Rudd BD, Burstein E, Duckett CS, et al. Differential role for TLR3 in respiratory syncytial virus-induced chemokine expression. J Virol,2005; 79:3350-6.
7 Hengge UR, Ruzicka T. Topical immunomodulation in dermatology:potential of toll-like receptor agonists. Dermatol Surg,2004; 30:1101-12.
8 Chen XZ, Mao XH, Zhu KJ, et al. Toll like receptor agonists augment HPV11 E7-specific T cell responses by modulating monocyte-derived dendritic cells. Arch Dermatol Res.2010; 302 (1):57-65.
9 Ja KK, Hyun JK, Mi-Yeon K, et al. Expression of toll-like receptors in verruca and molluscum contagiosum. J Korean Med Sci.2008; 23:307-314.
10 ZhangJ, DingY, ZhouZ, et al. Expression of human papilloma virus16 E7 DNA in patients with colorectal adenocarcinoma. Sheng wu yi xue gong cheng xue za zhi.2005; 22(5):1024-6.
11 Janeway JCA, Medzhitov R. Innate immune recognition. Annu Rev Immunol.2002; 20: 197-216.
12 Doyle SE, O'Connell R, Vaidya SA, et al.. Toll-like reeeptor3 mediates a more potent antiviral response than toll-like reeeptor4. J Immunol.2003; 170(7):3565-3571.
13 Neill LAJ, Fitzgerald KA, Bowie AG. The Toll-IL-1 receptor adaptor family grows to five members. Trends in Immunology.2003; 24(6):286-289.
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