HPV L1蛋白及IL-2在宫颈组织中的表达及意义
摘要
目的：
探讨HPV L1蛋白及IL-2在慢性宫颈炎、不同级别宫颈上皮内瘤变及宫颈鳞癌中的表达及其对宫颈病变预后的指导意义。
方法：
采用免疫组化S-P法检测22例慢性宫颈炎、24例宫颈上皮内瘤变Ⅰ级(CINⅠ)、28例宫颈上皮内瘤变Ⅱ级(CINⅡ)、37例宫颈上皮内瘤变Ⅲ级(CINⅢ)及13例宫颈鳞癌(SCC)组织中HPV L1蛋白及IL-2的表达。
结果：
随着宫颈上皮内瘤变级别的递增,HPV L1蛋白的表达逐渐降低,其在CINⅠ、CINⅡ及CINⅢ中的阳性表达差异有显著性意义(P<0.05)；IL-2在慢性宫颈炎组织及CINⅠ的表达明显高于CINⅡ、CINⅢ及SCC组织中的表达,差异有显著性意义(P<0.05)；在宫颈上皮内瘤变组织中,HPV L1与IL-2的表达呈正相关(P<0.05)；IL-2(-)／HPV L1(-)在CINⅠ、CINⅡ、CINⅢ及SCC中所占比例分别为4.17%、28.57%、59.46%及92.31%,其表达与宫颈病变严重程度呈正相关；而IL-2(+)／HPV L1(+)在CINⅠ、CINⅡ、CINⅢ及SC中所占比例分别为62.5%、25.00%、8.11%及0%,其表达与宫颈病变严重程度呈负相关。
结论：
HPV L1蛋白及IL-2的表达均随着宫颈病变严重程度的增加而减少,两者在宫颈疾病的发生发展中具有重要意义；L1蛋白和IL-2的检测对宫颈疾病的预后具有指导意义,IL-2(-)／HPV L1(-)者其病变进展的可能性较大,而IL-2(+)／HPV L1(+)者其病变则趋向于维持或消退。
Objective:
To elucidate the relation between HPV L1 capsid protein and IL-2 expressions in different lesions of cervix, and to explore their prognostic significance in cervical lesions.
Methods:
The expression of HPV L1 capsid protein and IL-2 were measured by S-P immunohistochemistry, respectively, in 22 cases of chronic cervicitis,24 cases of CINⅠ, 28 cases of CINⅡ,37 cases of CINⅢand 13 cases of cervical squamous cell carcinoma(SCC).
Results:
The expression of HPV L1 protein decreased as the cervix lesions progressed, and there was notably difference in CINⅠ, CINⅡand CINⅢ(p<0.05). The expression of IL-2 in chronic cervicitis and CINⅠwas remarkably higher than that in CINⅡ, CINⅢand SCCs (p<0.05). The expression of IL-2 was positively correlated with the expression of HPV L1 protein in tissues of CIN (p<0.05). The relation between HPV L1 protein and IL-2, IL-2(-)/L1(-)cases represented 4.17% of CINⅠ,28.57% of CINⅡ, 59.46% of CINⅢ, and 92.31% of SCCs, it was positively correlated with the severity of cervical lesions; whereas IL-2(+)/L1(+)cases were negatively correlated with the severity of cervical lesions, it represented 62.5% of CINⅠ,25.00% of CINⅡ,8.11% of CINⅢ, and 0% of SCCs.
Conclusion:
Expression of HPV L1 capsid protein and IL-2 decreased with lesion progression from chronic cervicitis to CIN and SCCs, they play an important role in the development of cervical intraepithelial dysplasias. The correlation between L1 and IL-2 expressions suggests that IL-2(-)/L1(-)cases have the potential for progression, whereas IL-2(+)/L1(+)cases may be nonprogressive lesions or potentially in remission.
探讨HPV L1蛋白及IL-2在慢性宫颈炎、不同级别宫颈上皮内瘤变及宫颈鳞癌中的表达及其对宫颈病变预后的指导意义。
方法：
采用免疫组化S-P法检测22例慢性宫颈炎、24例宫颈上皮内瘤变Ⅰ级(CINⅠ)、28例宫颈上皮内瘤变Ⅱ级(CINⅡ)、37例宫颈上皮内瘤变Ⅲ级(CINⅢ)及13例宫颈鳞癌(SCC)组织中HPV L1蛋白及IL-2的表达。
结果：
随着宫颈上皮内瘤变级别的递增,HPV L1蛋白的表达逐渐降低,其在CINⅠ、CINⅡ及CINⅢ中的阳性表达差异有显著性意义(P<0.05)；IL-2在慢性宫颈炎组织及CINⅠ的表达明显高于CINⅡ、CINⅢ及SCC组织中的表达,差异有显著性意义(P<0.05)；在宫颈上皮内瘤变组织中,HPV L1与IL-2的表达呈正相关(P<0.05)；IL-2(-)／HPV L1(-)在CINⅠ、CINⅡ、CINⅢ及SCC中所占比例分别为4.17%、28.57%、59.46%及92.31%,其表达与宫颈病变严重程度呈正相关；而IL-2(+)／HPV L1(+)在CINⅠ、CINⅡ、CINⅢ及SC中所占比例分别为62.5%、25.00%、8.11%及0%,其表达与宫颈病变严重程度呈负相关。
结论：
HPV L1蛋白及IL-2的表达均随着宫颈病变严重程度的增加而减少,两者在宫颈疾病的发生发展中具有重要意义；L1蛋白和IL-2的检测对宫颈疾病的预后具有指导意义,IL-2(-)／HPV L1(-)者其病变进展的可能性较大,而IL-2(+)／HPV L1(+)者其病变则趋向于维持或消退。
Objective:
To elucidate the relation between HPV L1 capsid protein and IL-2 expressions in different lesions of cervix, and to explore their prognostic significance in cervical lesions.
Methods:
The expression of HPV L1 capsid protein and IL-2 were measured by S-P immunohistochemistry, respectively, in 22 cases of chronic cervicitis,24 cases of CINⅠ, 28 cases of CINⅡ,37 cases of CINⅢand 13 cases of cervical squamous cell carcinoma(SCC).
Results:
The expression of HPV L1 protein decreased as the cervix lesions progressed, and there was notably difference in CINⅠ, CINⅡand CINⅢ(p<0.05). The expression of IL-2 in chronic cervicitis and CINⅠwas remarkably higher than that in CINⅡ, CINⅢand SCCs (p<0.05). The expression of IL-2 was positively correlated with the expression of HPV L1 protein in tissues of CIN (p<0.05). The relation between HPV L1 protein and IL-2, IL-2(-)/L1(-)cases represented 4.17% of CINⅠ,28.57% of CINⅡ, 59.46% of CINⅢ, and 92.31% of SCCs, it was positively correlated with the severity of cervical lesions; whereas IL-2(+)/L1(+)cases were negatively correlated with the severity of cervical lesions, it represented 62.5% of CINⅠ,25.00% of CINⅡ,8.11% of CINⅢ, and 0% of SCCs.
Conclusion:
Expression of HPV L1 capsid protein and IL-2 decreased with lesion progression from chronic cervicitis to CIN and SCCs, they play an important role in the development of cervical intraepithelial dysplasias. The correlation between L1 and IL-2 expressions suggests that IL-2(-)/L1(-)cases have the potential for progression, whereas IL-2(+)/L1(+)cases may be nonprogressive lesions or potentially in remission.
引文
[1]Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associatedwith cervical cancer. N Engl J Med 2003;348:518-27.
[2]Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189:12-9.
[3]Baseman JG, Koutsky LA. The epidemiology of human papillomavirus infections. J Clin Virol,2005,32:16-24.
[4]Canadas MP, Bosch FX, Junquera ML, et al. Concordance of prevalence of human papillomavirus DNA in anogenital and oral infections in a high-risk population. J Clin Microbiol,2004,42:1330-1332.
[5]Griesser H, Sander H, Hilfrich R, Moser B, Schenck U. Correlation of immunochemical detection of HPV L1 capsid protein in pap smears with regression of high-risk HPV positive mild/moderate dysplasia. Anal Quant Cytol Histol.2004;26:241-245.
[6]D. Rauber, G. Mehlhorn, P.A. Fasching, et al. Prognostic signficance of the detection of human papilloma virus L1 protein in smears of mild to moderate cervical intraepithelial lesions. European Journal of Obstetrics & Gynecology and Reproductive Biology 2008,140:258-262.
[7]Young Sam Choi, Woo Dae Kang, et al. Human Papillomavirus L1 Capsid Protein and Human Papillomavirus Type 16 as Prognostic Markers in Cervical Intraepithelial Neoplasia 1. International Journal of Gynecological Cancer, 2010,20 (2):288-293.
[8]Pardo-Govea T, Callejas D, et al. Gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha) and interleukins 2,4 and 6 (IL-2, IL-4, IL-6)
in cervical-uterine cells of intraepithelial neoplasia:a preliminary report. Invest Clin,2005,46(1):5-13.
[9]A Sharma, M Rajappa, A Saxena, et al. Cytokine profile in Indian women with cervical intraepithelial neoplasia and cancer cervix. Int J Gynecol Cancer,2007, 17:879-885.
[10]Mario Clerici, Marina Merola, et al. Cytokine Production Patterns in Cervical Intraepithelial Neoplasia:Association With Human Papillomavirus Infection. Journal of the National Cancer Institute,1997,89(3):245-250.
[11]欧阳永娥,明德松,庄建良,陈一峰.食管癌上皮细胞及其浸润淋巴细胞白介素2和白介素10的表达.中国现代医学杂志,2005,15(5)：699-703.
[12]Middleton K, Peh W, Southern S A, et al. Organization of the human papillomavirus productive cycle during neoplastic progression provides a basis for the selection of diagnostic markers. J Virol,2003,77(19):10186-10201.
[13]Melsheimer P, Kaul S, Dobeck S, Bastert G. Immunocytochemical detection of HPV high-risk type L1 capsid proteins in LSIL and HSIL as compared with detection of HPV L1 DNA. Acta Cytol.2003;47:124-128.
[14]Tomomi Yoshida, Takaaki Sano, Tatsuya Kanuma, et al. Immunochemical Analysis of HPV L1 Capsid Protein and p16 Protein in Liquid-based Cytology Samples From Uterine Cervical Lesions. Cancer,2008,114(2):83-88.
[15]Heejeong Lee, Kyung-Ji Lee, Chan-Kwon Jung, et al. Expression of HPV L1 Capsid Protein in Cervical Specimens With HPV Infection. Diagnostic Cytopathology,2008,36(12):864-7.
[16]Hagensee ME, Koutsky LA, Lee SK, et al. Detection of cervical antibodies to human papillomavirus type 16 (HPV-16) capsid antigens in relation to detection of HPV-16 DNA and cervical lesions.J Infect Dis 2000; 181:1234-1239.
[17]Aagje G Bais, Ilse Beckmann, Patricia C Ewing, et al. Cytokine Release in
HR-HPV(+)Women without and with Cervical Dysplasia (CIN II and III) or Carcinoma, Compared with HR-HPV(-) Controls. Mediators of Inflammation, 2007,24147:1-8.
[18]Tsukui T, Hildesheim A, Schiffman MH et al. Interleukin-2 production in vitro by peripheral lymphocytes in response to human papillomavirus-derived peptides:correlation with cervical pathology. Cancer Res 1996;56:3967-74.
[19]武燕.宫颈癌患者Th1／Th2细胞因子表达水平的研究.肿瘤研究与临床,2006,18(5)：310-316.
[20]B. Spellberg and J. E. Edwards Jr.. Type 1/type 2 immunity in infectious diseases. Clinical Infectious Diseases,2001,32(1):76-102.
[21]M. Clerici, G. M. Shearer, and E. Clerici. Cytokine dysregulation in invasive cervical carcinoma and other human neoplasias:time to consider the TH1/TH2 paradigm. Journal of the National Cancer Institute,1998,90(4):261-263.
[22]Catherine Dupuy, Dominique Buzoni-Gatel, et al. Cell mediated immunity induced in mice by HPV 16 L1 virus-like particles. Microbial Pathogenesis, 1997,22:219-225.
[23]Alfonso Garcia-Pineres, Allan Hildesheim, Lori Dodd, et al. Cytokine and Chemokine Profiles following Vaccination with Human Papillomavirus Type 16 L1 Virus-Like Particles. Clinical and Vaccine Immunology,2007,14 (8): 984-989.
[24]Sanchez AE, Aquino G, Ostoa Saloma P, et al. Cholera toxin B-subunit gene inhances mucosal immunoglobulin A, Th1-type, and CD8+cytotoxic responses when coadministered intradermally with a DNA vaccine[J]. Clin Diagn Lab Immunol,2004,11 (4):711-719.
[1]Ho GY, Bieman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women[J]. N Engl Med,1998, 338 (7):423-8.
[2]Schiffman M, Castle PE. Human papillomavirus:epidemiology and public health. Arch Pathol Lab Med,2003,127(8):930-4.
[3]Carter JJ, Koutsky LA, Hughes JP, et al. Comparison of human papillomavirus types 16,18, and 6 capsid antibody responses following incident[J]. Infect Dis, 2000,181 (6):1911-1919.
[4]Dillner J. The serological response to papillomaviruses. Semin Cancer Biol, 1999,9:423-30.
[5]Viscidi RP, Schiffman M, Hildesheim A, Herrero R, Castle PE, Bratti MC, et al. Seroreactivity to human papillomavirus (HPV) types 16,18, or 31 and risk of subsequent HPV infection:results from a population-based study in Costa
Rica. Cancer Epidemiol Biomarkers Prev,2004,13:324-7.
[6]Passmore JA, Marais DJ, Sampson C, et al. Cervicovaginal, oral, and serum IgG and IgA responses to human papillomavirus type 16 in women with cervical intraepithelial neoplasia[J]. Med Virol,2007,79(9):1375-1380.
[7]Nguyen HH, Broker TR, Chow LT, et al. Immune responses to human papillomavirus in genital tract of women with cervical cancer. Gynecol Oncol, 2005,96(2):452-61.
[8]Rocha-Zavaleta L, Pereira-Suarez AL, Yescas G, et al. Mucosal IgG and Ig A responses to human papillomavirus type 16 capsid proteins in HPV16-infected women with out visible pathology[J]. Viral Immunol,2003,16(2):159-168.
[9]Burg SH, Palefsky JM. Human Immunodeficiency Virus and Human Papilloma Virus-why HPV-induced lesions do not spontaneously resolve and why therapeutic vaccination can be successful[J]. Transl Med,2009,18(7):108.
[10]Ma C, Zhang WY, Wang JD. Expressions of Th, DC, NK cells in cervical tissue and the relationship with immune function. Zhonghua Yi Xue Za Zhi,2009, 89(23):1650-3.
[11]Welters MJP, van der Logt P, van den Eeden SJF, et al. Detection of human papillomavirus type 18 E6 and E7-specifc CD4+ T-helper immunity in relation to health versus disease[J]. Int Cancer,2006,118:950-6.
[12]Bottley G, Watherston OG, Hiew YL, et al. High-risk human papillomavirus E7 expression reduces cell-surface MHC class I molecules and increases susceptibility to natural killer cells. Oncogene,2008,27(12):1794-9.
[13]Garcia-Iglesias T, Del Toro-Arreola A, et al. Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions. BMC Cancer,2009,9:186.
[14]Fausch SC, Da Silva DM, Rudolf MP, Kast WM. Human papillomavirus virus-like particles do not activate Langerhans cells:a possible immune escape mechanism used by human papillomaviruses.[J]. Immunol,2002,169:3242-9.
[15]Da Silva DM, Fausch SC, Verbeek JS, Kast WM. Uptake of human papillomavirus virus-like particles by dendritic cellsis mediated by Fc{gamma} receptors and contributes to acquisition of T cell immunity[J]. Immunol,2007, 178:7587-97
[16]De Jong A, V PM, Vander Hulst JM, et al. Human papillomavirus type 16 positive cervical cancer is associated with impaired CD4+T cell immunity against early antigens E2 and E6[J]. Cancer Res,2004,64(15):5449-5455.
[17]Fahey LM, Raff AB, Da Silva DM, Kast WM. A major role for the minor capsid protein of human papillomavirus type 16 in immune escape[J]. Immunol,2009, 183(10):6151-6.
[18]Lee KA, Cho KJ, Kim SH, et al. IL-18 E42A mutant is resistant to the inhibitory effects of HPV-16 E6 and E7 oncogenes on the IL-18-mediated immune response. Cancer Lett,2005,229(2):261-70.
[19]Tindle RW. Immune evasion in human papillomavirus associated cervical cancer. Nat Rev Cancer,2002,2:59-65.
[20]Palefsky JM, Gillison ML, Strickler HD. Chapter 16:HPV vaccines in immunocompromised women and men. Vaccine,2006,24 (Suppl 3):S140-6.
[21]Fausch SC, Fahey LM, Da Silva DM, et al. Human papillomavirus can phosphoinositide 3-kinase activation[J]. Immunol,2005,174:7172-7178.
[2]Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189:12-9.
[3]Baseman JG, Koutsky LA. The epidemiology of human papillomavirus infections. J Clin Virol,2005,32:16-24.
[4]Canadas MP, Bosch FX, Junquera ML, et al. Concordance of prevalence of human papillomavirus DNA in anogenital and oral infections in a high-risk population. J Clin Microbiol,2004,42:1330-1332.
[5]Griesser H, Sander H, Hilfrich R, Moser B, Schenck U. Correlation of immunochemical detection of HPV L1 capsid protein in pap smears with regression of high-risk HPV positive mild/moderate dysplasia. Anal Quant Cytol Histol.2004;26:241-245.
[6]D. Rauber, G. Mehlhorn, P.A. Fasching, et al. Prognostic signficance of the detection of human papilloma virus L1 protein in smears of mild to moderate cervical intraepithelial lesions. European Journal of Obstetrics & Gynecology and Reproductive Biology 2008,140:258-262.
[7]Young Sam Choi, Woo Dae Kang, et al. Human Papillomavirus L1 Capsid Protein and Human Papillomavirus Type 16 as Prognostic Markers in Cervical Intraepithelial Neoplasia 1. International Journal of Gynecological Cancer, 2010,20 (2):288-293.
[8]Pardo-Govea T, Callejas D, et al. Gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha) and interleukins 2,4 and 6 (IL-2, IL-4, IL-6)
in cervical-uterine cells of intraepithelial neoplasia:a preliminary report. Invest Clin,2005,46(1):5-13.
[9]A Sharma, M Rajappa, A Saxena, et al. Cytokine profile in Indian women with cervical intraepithelial neoplasia and cancer cervix. Int J Gynecol Cancer,2007, 17:879-885.
[10]Mario Clerici, Marina Merola, et al. Cytokine Production Patterns in Cervical Intraepithelial Neoplasia:Association With Human Papillomavirus Infection. Journal of the National Cancer Institute,1997,89(3):245-250.
[11]欧阳永娥,明德松,庄建良,陈一峰.食管癌上皮细胞及其浸润淋巴细胞白介素2和白介素10的表达.中国现代医学杂志,2005,15(5)：699-703.
[12]Middleton K, Peh W, Southern S A, et al. Organization of the human papillomavirus productive cycle during neoplastic progression provides a basis for the selection of diagnostic markers. J Virol,2003,77(19):10186-10201.
[13]Melsheimer P, Kaul S, Dobeck S, Bastert G. Immunocytochemical detection of HPV high-risk type L1 capsid proteins in LSIL and HSIL as compared with detection of HPV L1 DNA. Acta Cytol.2003;47:124-128.
[14]Tomomi Yoshida, Takaaki Sano, Tatsuya Kanuma, et al. Immunochemical Analysis of HPV L1 Capsid Protein and p16 Protein in Liquid-based Cytology Samples From Uterine Cervical Lesions. Cancer,2008,114(2):83-88.
[15]Heejeong Lee, Kyung-Ji Lee, Chan-Kwon Jung, et al. Expression of HPV L1 Capsid Protein in Cervical Specimens With HPV Infection. Diagnostic Cytopathology,2008,36(12):864-7.
[16]Hagensee ME, Koutsky LA, Lee SK, et al. Detection of cervical antibodies to human papillomavirus type 16 (HPV-16) capsid antigens in relation to detection of HPV-16 DNA and cervical lesions.J Infect Dis 2000; 181:1234-1239.
[17]Aagje G Bais, Ilse Beckmann, Patricia C Ewing, et al. Cytokine Release in
HR-HPV(+)Women without and with Cervical Dysplasia (CIN II and III) or Carcinoma, Compared with HR-HPV(-) Controls. Mediators of Inflammation, 2007,24147:1-8.
[18]Tsukui T, Hildesheim A, Schiffman MH et al. Interleukin-2 production in vitro by peripheral lymphocytes in response to human papillomavirus-derived peptides:correlation with cervical pathology. Cancer Res 1996;56:3967-74.
[19]武燕.宫颈癌患者Th1／Th2细胞因子表达水平的研究.肿瘤研究与临床,2006,18(5)：310-316.
[20]B. Spellberg and J. E. Edwards Jr.. Type 1/type 2 immunity in infectious diseases. Clinical Infectious Diseases,2001,32(1):76-102.
[21]M. Clerici, G. M. Shearer, and E. Clerici. Cytokine dysregulation in invasive cervical carcinoma and other human neoplasias:time to consider the TH1/TH2 paradigm. Journal of the National Cancer Institute,1998,90(4):261-263.
[22]Catherine Dupuy, Dominique Buzoni-Gatel, et al. Cell mediated immunity induced in mice by HPV 16 L1 virus-like particles. Microbial Pathogenesis, 1997,22:219-225.
[23]Alfonso Garcia-Pineres, Allan Hildesheim, Lori Dodd, et al. Cytokine and Chemokine Profiles following Vaccination with Human Papillomavirus Type 16 L1 Virus-Like Particles. Clinical and Vaccine Immunology,2007,14 (8): 984-989.
[24]Sanchez AE, Aquino G, Ostoa Saloma P, et al. Cholera toxin B-subunit gene inhances mucosal immunoglobulin A, Th1-type, and CD8+cytotoxic responses when coadministered intradermally with a DNA vaccine[J]. Clin Diagn Lab Immunol,2004,11 (4):711-719.
[1]Ho GY, Bieman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women[J]. N Engl Med,1998, 338 (7):423-8.
[2]Schiffman M, Castle PE. Human papillomavirus:epidemiology and public health. Arch Pathol Lab Med,2003,127(8):930-4.
[3]Carter JJ, Koutsky LA, Hughes JP, et al. Comparison of human papillomavirus types 16,18, and 6 capsid antibody responses following incident[J]. Infect Dis, 2000,181 (6):1911-1919.
[4]Dillner J. The serological response to papillomaviruses. Semin Cancer Biol, 1999,9:423-30.
[5]Viscidi RP, Schiffman M, Hildesheim A, Herrero R, Castle PE, Bratti MC, et al. Seroreactivity to human papillomavirus (HPV) types 16,18, or 31 and risk of subsequent HPV infection:results from a population-based study in Costa
Rica. Cancer Epidemiol Biomarkers Prev,2004,13:324-7.
[6]Passmore JA, Marais DJ, Sampson C, et al. Cervicovaginal, oral, and serum IgG and IgA responses to human papillomavirus type 16 in women with cervical intraepithelial neoplasia[J]. Med Virol,2007,79(9):1375-1380.
[7]Nguyen HH, Broker TR, Chow LT, et al. Immune responses to human papillomavirus in genital tract of women with cervical cancer. Gynecol Oncol, 2005,96(2):452-61.
[8]Rocha-Zavaleta L, Pereira-Suarez AL, Yescas G, et al. Mucosal IgG and Ig A responses to human papillomavirus type 16 capsid proteins in HPV16-infected women with out visible pathology[J]. Viral Immunol,2003,16(2):159-168.
[9]Burg SH, Palefsky JM. Human Immunodeficiency Virus and Human Papilloma Virus-why HPV-induced lesions do not spontaneously resolve and why therapeutic vaccination can be successful[J]. Transl Med,2009,18(7):108.
[10]Ma C, Zhang WY, Wang JD. Expressions of Th, DC, NK cells in cervical tissue and the relationship with immune function. Zhonghua Yi Xue Za Zhi,2009, 89(23):1650-3.
[11]Welters MJP, van der Logt P, van den Eeden SJF, et al. Detection of human papillomavirus type 18 E6 and E7-specifc CD4+ T-helper immunity in relation to health versus disease[J]. Int Cancer,2006,118:950-6.
[12]Bottley G, Watherston OG, Hiew YL, et al. High-risk human papillomavirus E7 expression reduces cell-surface MHC class I molecules and increases susceptibility to natural killer cells. Oncogene,2008,27(12):1794-9.
[13]Garcia-Iglesias T, Del Toro-Arreola A, et al. Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions. BMC Cancer,2009,9:186.
[14]Fausch SC, Da Silva DM, Rudolf MP, Kast WM. Human papillomavirus virus-like particles do not activate Langerhans cells:a possible immune escape mechanism used by human papillomaviruses.[J]. Immunol,2002,169:3242-9.
[15]Da Silva DM, Fausch SC, Verbeek JS, Kast WM. Uptake of human papillomavirus virus-like particles by dendritic cellsis mediated by Fc{gamma} receptors and contributes to acquisition of T cell immunity[J]. Immunol,2007, 178:7587-97
[16]De Jong A, V PM, Vander Hulst JM, et al. Human papillomavirus type 16 positive cervical cancer is associated with impaired CD4+T cell immunity against early antigens E2 and E6[J]. Cancer Res,2004,64(15):5449-5455.
[17]Fahey LM, Raff AB, Da Silva DM, Kast WM. A major role for the minor capsid protein of human papillomavirus type 16 in immune escape[J]. Immunol,2009, 183(10):6151-6.
[18]Lee KA, Cho KJ, Kim SH, et al. IL-18 E42A mutant is resistant to the inhibitory effects of HPV-16 E6 and E7 oncogenes on the IL-18-mediated immune response. Cancer Lett,2005,229(2):261-70.
[19]Tindle RW. Immune evasion in human papillomavirus associated cervical cancer. Nat Rev Cancer,2002,2:59-65.
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