宫颈高危型HPV感染对宿主细胞因子IL-18影响的实验研究

目的 检测高危型HPV感染宫颈上皮瘤样病变及宫颈癌患者外周血IL-18的水平变化，分析Th1细胞的细胞因子免疫活动，为肿瘤的免疫治疗提供实验依据。方法 在细胞因子中加入荧光标记的特异性抗细胞因子单克隆抗体，特异性抗原抗体结合，以流式细胞仪分析特异性细胞因子IL-18表达水平。结果 高危型HPV感染宫颈上皮瘤样病变及宫颈癌患者IL—18表达水平较正常对照组降低，差异有统计学意义。结论 高危型HPV感染宫颈上皮瘤样病变及宫颈癌宫颈癌患者IL-18表达降低，这可能是肿瘤细胞发生免疫逃逸，从而导致肿瘤的发生或者转移的原因之一。     

γδT细胞在人乳头瘤病毒感染及宫颈癌发生中的作用

宫颈癌是严重威胁女性健康的疾病之一,几乎所有的流行病学调查均显示人乳头瘤病毒（HPV）感染是宫颈癌及癌前病变发病的主要条件.γδT细胞属于固有免疫细胞,是女性生殖器官上皮内淋巴细胞的主要成分.γδT细胞具有抗感染、抗肿瘤、免疫监视和免疫调节等作用,是固有免疫及适应性免疫间的桥梁.但某些肿瘤研究中也发现,γδT细胞同时具有免疫抑制作用,促进肿瘤的生长.文献报道宫颈癌患者肿瘤组织中存在着明显的γδT细胞浸润,且γδT细胞对宫颈癌细胞系有杀伤作用,这充分预示着γδT细胞在宫颈癌的发生中具有潜在的调节作用.因而研究γδT细胞抗HPV感染及其在宫颈癌及癌前病变中的作用具有重要意义.     

人类乳头瘤病毒(H1PV)病毒样颗粒的研究进展

人乳头瘤病毒(human papillomavirus,HPV)是一类具有严格宿主范围和组织特异性的DNA病毒,主要感染人的皮肤或粘膜上皮细胞,引起感染部位发生良性和恶性病变.根据DNA序列的同源性组织特异性等,HPV可分为许多型别.目前发现的人乳头瘤病毒已超过100型[1],其中感染人生殖道的人乳头瘤病毒有35个型别[1],根据其致瘤性不同分为低危型和高危型两大类.高危HPV的感染与宫颈癌的发生有十分密切的关系.约80%的宫颈癌与四个型别的HPV感染有关,分别是HPV16、18、31和45型,其中50%的宫颈癌与HPV16感染有关[1].因此,使用疫苗阻断病毒的感染能有效的减少宫颈癌的发病率.同时还能减少其它一些和HPV相关的肿瘤如:肛门、外阴及扁桃体的肿瘤等.     

人类宫颈癌遗传学研究进展

宫颈癌是严重危害妇女健康的疾病。目前的研究结果表明,宫颈癌在发生、发展过程中显示出与许多内外因素的变化有关。这些变化包括癌基因的激活、肿瘤抑制基因的失活以及人类乳头状瘤病毒(HPV)的感染等。本文从宫颈癌与原癌基因、肿瘤抑制基因、细胞染色体变化以及等位基因丢失和HPV感染等几个方面概述了宫颈癌目前的研究进展。     

持续性人乳头瘤病毒感染与宫颈癌的研究进展

宫颈癌是一种常见的妇科肿瘤, 严重威胁广大女性的生命和健康.虽然引起宫颈癌的原因很多,但目前认为,人乳头瘤病毒(human papillomavirus,HPV)感染是宫颈癌的根本致病因素.HPV通常在感染后能自行消失,只有持续的高危型人乳头瘤病毒感染才是导致宫颈癌的根本原因.本文就HPV持续性感染与子宫颈癌研究进展进行了概述,并对其研究前景作一展望.     

女性下生殖道HPV感染和HPV相关的宫颈肿瘤

子宫颈病变是女性最常见的疾患之一.在女性癌瘤中,宫颈癌的发病率仅次于乳腺癌.人乳头状瘤病毒(HPV)感染在宫颈肿瘤的发病机制中起着重要的作用,许多学者关注HPV疫苗的预防和治疗.在女性生殖道HPV传播及继发性感染是局部性的,因此,针对这种局部性传播疫苗的有效性最好能用局部免疫的参数来评价.     

HPV逃避宫颈癌宿主免疫应答的机制

人乳头瘤病毒(HPV)使用不同的方法逃避宿主的免疫识别。近期研究发现宫颈上皮为HPV病毒摧毁宿主免疫应答提供了一个保护的微环境,例如子宫颈缺乏炎性环境使宫颈部位的树突状细胞(DCs)和朗格罕式细胞(LC)对HPV抗原产生耐受;CD4+T细胞在上皮内瘤变的退行中起关键作用,而CD8+T细胞在浸润性癌中其关键作用;CD8+T淋巴细胞中的信号分子TCRzeta链表达减少;宫颈癌和宫颈上皮内瘤变患者表达NKG2D的NK细胞和T细胞数量减少;宫颈癌患者CD4+CD25+FoxP3+调节性T细胞频率增加;Nrp-1+Treg表现出较强的抑制活性;肿瘤细胞中的Treg网络和吲哚胺2,3-双加氧酶使肿瘤细胞易于产生免疫逃逸等。此篇综述阐述了宿主免疫系统在清除HPV感染中的作用及HPV摧毁宿主免疫应答所采取的策略。了解HPV的逃逸机制将有助于分析宫颈癌免疫治疗中的困难并设计出更好的治疗策略。     

人乳头瘤病毒16型L1基因真核表达质粒的构建及鉴定

研究表明 ,高危型人乳头瘤病毒 1 6型 (Humanpapillo mavirustype 1 6 ,HPV1 6 )的感染与宫颈癌及人类许多肿瘤的发生密切相关。HPV1 6晚期基因L1 (Latergene ,L)编码病毒主要衣壳蛋白 ,能刺激机体产生抗体[1 ] ,保护机体不受同型别HPV的感染 ,体外实验也证明L1蛋白上存在有T细胞和B细胞免疫识别表位 ,是研制HPV预防性疫苗的重要靶抗原之一。自然感染的HPV1 6免疫原性低下 ,不能有效激发机体产生特异性抗肿瘤免疫效应。通过DNA疫苗介导的免疫可望达到增强免疫、防治HPV相关肿瘤的目的 ,具有良好的应用前景[2 ] 。本实验拟构建并…     

地方株HPV16 L1基因免疫保护性研究

人乳头状瘤病毒（human papillomavims，HPV）至今已鉴定的HPV型超过200个，约40个型能感染生殖道，以性接触方式传播。分子流行病学证据显示HPV是引起浸润性宫颈癌和宫颈上皮内癌的主要原因，其中HPV16型在宫颈癌中检出率最高，约50％的宫颈癌患者肿瘤组织能被检测到，HPV16也是我国妇女宫颈癌的主要型别。因为HPV感染性疾病的难治性、复发性和潜在致癌性，研制开发安全、有效的HPV疫苗有一定的实用意义。     

HPV感染各类宫颈疾病肿瘤标志物检测的临床价值

研究表明，人类乳头状瘤病毒（humanpapiUomavirus，HPV）感染为宫颈癌前病变和浸润性宫颈癌发生的必要条件。故及时监测HPV是预防、诊断和治疗宫颈病变和宫颈癌的必要检查项目。而肿瘤标志物在临床上主要应用于肿瘤的筛查、辅助诊断和预后判断。本文拟对HPV感染各类宫颈疾病患者肿瘤标志物进行测定和比较分析，探讨其与疾病变化的关系。     

HLA-DRB1*1602 allele is positively associated with HPV cervical infection in Bolivian Andean women

Incidence of cervical cancer is high among Bolivian Andean women. Human papillomavirus (HPV) infection is known as the major risk factor of cervical cancer. The host immune system plays an important role in the outcome of HPV infection and associated malignancies. In order to study the immunogenetic background of Bolivian Andean women with regard to HPV infection status, we compared HLA class I and class II allele frequencies between 37 HPV positive and 68 HPV negative Bolivian women. Demographic variables, including distribution of Andean ethnicities, were similar in both groups. Comparison of HLA class I allele frequencies between both groups indicated no significant difference. In contrast, HLA class II DRB1*1602 allele, an Amerindian allele, was significantly higher in the HPV positive women compared with HPV negative controls (chi(2) = 5.2, p < 0.05, odds ratio = 3.17; 95% confidence interval = 1.4-8.8). HPV types present in the HPV positive group were HPV-18, -16, -31, -33, and -58. These results suggest that HLA class II DRB1*1602 may confer susceptibility to infection with genetically related HPV types. This is the first report of an HLA class II association with HPV infection in an Andean population.     

喉癌发生中人乳头瘤病毒感染与Langerhans细胞、p53表达的关系

目的：探讨喉癌的发生机理。方法：应用免疫组化ＬＳＡＢ法对３０例喉鳞状细胞癌人乳头瘤病毒（ＨＰＶ）感染、Ｌａｎｇｅｒｈａｎｓ细胞（ＬＣ）及ｐ５３蛋白表达进行了研究。结果：２６．７％的病例可以检测到ＨＰＶ抗原成分。ＨＰＶ感染的癌旁粘膜内ＬＣ数量明显少于无感染者，且形态也发生改变。ｐ５３蛋白表达阳性率在ＨＰＶ感染组（３７．５％）明显低于ＨＰＶ检测阴性组（８３．３３％）。结论：提示ＨＰＶ、ＬＣ、ｐ５３在喉癌发生发展过程中起一定作用，且相互影响，ＨＰＶ感染引起ＬＣ数量减少，局部免疫功能降低，ＨＰＶ感染还可能通过表达的肿瘤蛋白或其他机制使抑癌基因ｐ５３失活，进而导致肿瘤的发生。     

Association between human papillomavirus 16 E6 variants and human leukocyte antigen class I polymorphism in cervical cancer of Swedish women

Persistent infection with human papillomavirus (HPV), particularly HPV16, represents the prime risk factor in cervical carcinogenesis. HPV variants (e.g., within the E6 gene) together with immunogenetic factors of the host may be responsible either for effective viral clearance, or alternatively, for viral persistence. Peripheral blood from 27 HPV16 positive Swedish women with cervical carcinoma, who had previously been tested for HPV16 E6 variants, was used for human leukocyte antigen (HLA) class I typing. Women with HLA-B*44, HLA-B*51, or HLA-B*57 who were infected with the HPV16 E6 variant L83V had an approximately four- to fivefold increased risk for cancer compared with controls (odds ratio [OR] = 3.5, 95% CI = 1.1-11.1, OR = 4.2, 95% CI = 1.19-14.69, or OR = 4.67, 95% CI = 1.2-18.6, respectively). Epitope predictive algorithm with SYFPEITHI revealed that the variant at amino acid 83 affects the binding affinity in association with HLA-B*44. Interestingly, the HLA-B*15 allele seems protective because it was absent in HPV16 positive cancer. It is concluded that specific HLA class I alleles, combined with certain HPV16 E6 variants, may be crucial for immune surveillance in cervical carcinogenesis. The evaluation of associations of HLA alleles with HPV variants may be helpful in defining prognostic markers and in designing vaccines capable of mediating immune protection against HPV infection.     

Tumor necrosis factor A and MHC class I chain related gene A (MIC-A) polymorphisms in Swedish patients with cervical cancer

Human papillomaviruses type 16 and 18 are the major cause of cervical cancer. However, genetic factors contribute to the propensity of persistent HPV infection and cervical carcinoma. Allelic variants of the human leukocyte genes have shown to be associated with cervical neoplasia. The strongest associations have been found with the genes in the HLA class II region. The aim of this study was to analyze the association of two non-HLA class II markers with invasive cervical cancer. Microsatellite polymorphism of the TNFA gene located in the class III region and a short tandem repeat polymorphism of the MICA gene located in the centromeric end of the HLA class I region were analyzed. Eighty-five patients and 120 matched control individuals from a population-based cohort from Northern Sweden participated in this nested case-control study. MICA was not associated with cervical carcinoma. TNFa-11 frequency was increased in the HPV18 DNA positive patients (OR = 2.84, p = 0.0481, CI = 1.04-7.78, pc = NS). TNFa-11 was not associated with susceptibility to HPV16 infection, but it increased the risk for cervical cancer with the HLA DQ6 (DQA 1*0102-DQB 1*0602) haplotype. Our findings indicate that the association of TNFA with cervical cancer is different with CIN. The extended HLA DQ6-TNFa-11 haplotype is increasing the risk for development of cervical cancer significantly (OR = 3.08, p = 0.0104, CI = 1.30-7.31).     

Detection of EBV and HPV in nasopharyngeal carcinoma by in situ hybridization

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a common cancer in Southeast Asia and is frequently associated with Epstein-Barr virus (EBV). Human papilloma virus (HPV) is an epitheliotrophic oncogenic virus that has been detected in a variety of head and neck tumors including NPC. This retrospective study was undertaken to investigate the prevalence of EBV and HPV infection subtypes 6/11 and 16/18 in 20 patients with NPC. METHODS: In situ hybridization for EBV-encoded RNA (EBER) and tyramid signal amplification of ISH for HPV DNA subtypes 6/11 and 16/18 was performed to evaluate the prevalence of EBV and HPV latency infection among Iranian Patients with NPC. RESULTS: 16 cases were classified as WHO type III (undifferentiated carcinoma) and 4 as WHO type II (non-keratinizing SCC). EBER-ISH was positive in 19 (95%) of NPCs evaluated and in one metastases from cervical primary, included in this series. Two of 20 NPC (10%) contained HPV 6/11 sequences and two of 20 NPC (10%) contained HPV 16/18 sequences, and combined EBV and HPV infection was detected in 3 of the 20 (15%) patients. CONCLUSION: Our data indicated that EBV is closely associated with NPC in Iran. In addition, a low percentage of EBV positive NPC contained HPV sequences. The significance of coexistence of EBV and HPV in NPC requires further study.     

Human leukocyte antigen (HLA)-E and HLA-G polymorphisms in human papillomavirus infection susceptibility and persistence

Human leukocyte antigen (HLA)-E and HLA-G molecules act as powerful modulators of innate and adaptive immune responses. The study examined whether HLA-E and/or HLA-G polymorphisms are associated with human papillomavirus (HPV) infection susceptibility and persistence in 636 female university students in Montreal. HLA-G*01:01:02 and HLA-G*01:01:08 alleles were associated with increased risk of HPV-16 (odds ratio (OR) = 2.10, 95% confidence interval (CI), 1.11-3.96) and any infections with HPV types from α species 1, 8, 10, and 13 (OR = 2.72, 95% CI, 1.11-6.68). HLA-G*01:01:02 and HLA-G*01:03 alleles were associated with persistent HPV-16 (OR = 2.07, 95% CI, 1.16-3.68) and persistent infections with HPV types from α species 2, 3, 4, and 15 (OR = 2.99, 95% CI, 1.12-8.00). HLA-E polymorphism was not associated with risk of acquisition or persistence of HPV infection. These results suggest that HLA-G molecules may play a role in mediating HPV infection risk.     

Different methods of identifying new antigenic epitopes of human papillomavirus type 16 E6 and E7 proteins

Human papillomavirus (HPV) infection is the most common cause of sexually transmitted viral infection and is the main cause of cervical cancer. Identification of HPV T-cell epitopes would be instrumental not only in our understanding of the protective immune response but also in the development of vaccines and immunotherapies. In contrast to viruses which cause systemic infection, identification of HPV epitopes is technically challenging because HPV causes a localized mucosal infection and the frequency of pathogen-specific T lymphocytes in peripheral blood is expected to be low. Here we describe three new antigenic epitopes (E7 7-15 [TLHEYMLDL], E6 52-61 [FAFRDLCIVY], and E7 79-87 [LEDLLMGTL]) of HPV 16 E6 and E7 proteins which have oncogenic activities. E7 7-15 was identified among peptides previously shown to bind to human leukocyte antigen (HLA)-A2.1 molecule, but it was found likely to be restricted by the HLA-B48 molecule. E6 52-61 (likely to be restricted by HLA-B57) and E7 79-87 (likely to be restricted by HLA-B60) were detected, based on the magnitude of the T-cell immune responses, in another individual. In particular, T-cell clones specific for the E6 52-61 epitope were isolated effectively by magnetically selecting them based on gamma interferon secretion. This is an efficient method of identifying new epitopes of antigens for which the number of specific T lymphocytes in the circulation is expected to be small, and it should be widely applicable in identifying new T-cell epitopes.     

Different Methods of Identifying New Antigenic Epitopes of Human Papillomavirus Type 16 E6 and E7 Proteins

Human papillomavirus (HPV) infection is the most common cause of sexually transmitted viral infection and is the main cause of cervical cancer. Identification of HPV T-cell epitopes would be instrumental not only in our understanding of the protective immune response but also in the development of vaccines and immunotherapies. In contrast to viruses which cause systemic infection, identification of HPV epitopes is technically challenging because HPV causes a localized mucosal infection and the frequency of pathogen-specific T lymphocytes in peripheral blood is expected to be low. Here we describe three new antigenic epitopes (E7 7-15 [TLHEYMLDL], E6 52-61 [FAFRDLCIVY], and E7 79-87 [LEDLLMGTL]) of HPV 16 E6 and E7 proteins which have oncogenic activities. E7 7-15 was identified among peptides previously shown to bind to human leukocyte antigen (HLA)-A2.1 molecule, but it was found likely to be restricted by the HLA-B48 molecule. E6 52-61 (likely to be restricted by HLA-B57) and E7 79-87 (likely to be restricted by HLA-B60) were detected, based on the magnitude of the T-cell immune responses, in another individual. In particular, T-cell clones specific for the E6 52-61 epitope were isolated effectively by magnetically selecting them based on gamma interferon secretion. This is an efficient method of identifying new epitopes of antigens for which the number of specific T lymphocytes in the circulation is expected to be small, and it should be widely applicable in identifying new T-cell epitopes.     

Detection of human papillomavirus in esophageal carcinoma

The aim of the study was to assess the prevalence of human papillomavirus (HPV) in the esophagus in the coastal region of Eastern Guangdong, Southern China, an area with a high incidence of esophageal carcinoma. Fresh surgical resection esophageal specimens were obtained from 176 esophageal carcinoma patients admitted to the Tumor Hospital of Shantou University Medical College. The samples were subjected to polymerase chain reaction (PCR) to detect HPV infection using consensus and type-specific primers for HPV type 6, 11, 16, and 18. The incidence rate was 65.5%, 69.1%, and 60% in tissues of cancerous, paracancerous and normal mucosa, respectively. Further analysis of the distribution of HPV types in the three sections of tissues showed that the high-risk HPV types 16 and 18 were found mainly in the cancer cells (43.2%), whereas the low-risk HPV types 6 and 11 were seen mainly in the normal mucosa (52.3%). The total infection rate of the high-risk HPV types 16 and HPV 18 was the highest in cancerous tissues (54.5%), followed by paracancerous tissues (19.5%), and the lowest in normal mucosa (11.7%). There was high incidence of HPV infection in the esophageal epithelium in Eastern Guangdong, Southern China, where esophageal carcinoma is prevalent. HPV was seen in the normal, paracancerous and cancerous tissues, with the high-risk HPV type 16 and 18 more common in cancerous tissues. The results indicate that the high incidence of esophageal carcinoma in this area is associated with HPV infection.     

Extremely high Langerhans cell infiltration contributes to the favourable prognosis of HPV-infected squamous cell carcinoma and adenocarcinoma of the lung

AIMS: The infiltration of Langerhans cells in adenocarcinomas and squamous cell carcinomas of the lung was examined in relation to prognostic implications and human papillomavirus (HPV) infection. METHODS AND RESULTS: Samples from 62 adenocarcinoma and 59 squamous cell carcinoma patients in 1995-97, the prognosis of which had been followed up, were used. The Langerhans cells were demonstrated immunohistochemically using anti S100a and CD1 antibodies. Human papillomavirus (HPV) infection was examined by polymerase chain reaction (PCR) and nonisotopic in-situ hybridization (NISH) methods. Statistical analysis was carried out using the Kaplan-Meier method (Wilcoxon analysis) and multiple regression analysis. HPV infection was demonstrated in 12 cases (19.4%) of adenocarcinoma. The HPV-infected adenocarcinomas had abundant faintly eosinophilic cytoplasm, and were immunohistochemically positive for the surfactant apoprotein A. In the 59 cases of squamous cell carcinomas 19 were of the well differentiated form, and 29 and 11 were moderately and poorly differentiated cases, respectively. HPV was detected in 29 cases (49.2%) (13 well and 16 moderately differentiated cases). In all HPV-infected adenocarcinoma and squamous cell carcinoma cases, extremely large numbers of Langerhans cells (more than 100 per high-power field) were demonstrated in the tumour nests. In contrast, in the non-HPV-infected adenocarcinomas and squamous cell carcinomas, only a few (less than about 10 per high-power field) Langerhans cells were observed. The squamous cell carcinoma cases with high Langerhans cell infiltration, which were also infected with HPV, showed a significantly good prognosis (P = 0.007). The adenocarcinoma cases with high Langerhans cell infiltration tended to have a better prognosis than the cases with low Langerhans cell infiltration, but the difference was not statistically significant. The low number of highly infiltrated cases was insufficient for an adequate statistical analysis. Furthermore, there was no significant correlation between either Langerhans cell infiltration and smoking, or HPV infection and smoking, in either squamous cell carcinoma or adenocarcinoma cases. CONCLUSIONS: It was considered that the extremely high Langerhans cell infiltration in the tumours was caused by HPV infection. The extremely large number of Langerhans cells in the tumours contributes to the favourable prognosis for HPV-infected lung cancer.