No abstract

BackgroundHuman papillomavirus (HPV) infection has traditionally been regarded as a sexually transmitted disease (STD), but recent evidence implicates that an infected mother can transmit HPV to her newborn during pregnancy, at delivery, perinatal period or later. Given the lack of any studies on HPV-specific immune responses in children, we conducted HPV16-specific cell-mediated immune (CMI) monitoring of the mother-child pairs with known oral and genital HPV follow-up (FU) data since the delivery. In the Finnish Family HPV Study, 10 out of 331 mothers developed incident cervical intraepithelial neoplasia (CIN) during their 14-year FU. Our hypothesis according to the common dogma is that there is no HPV16 specific immune response in offspring of the CIN mother as she/he has not started the sexual life yet.MethodsWe used overlapping 30–35 mer peptides covering the entire HPV16 E2, E6 and E7 protein sequences. Assays for lymphocyte proliferation capacity, cytokine production and HPV16-specific Foxp3 + CD25 + CD4+ regulatory T-cells were performed.ResultsHPV16-specific proliferative T-cell responses were broader in children than in their mothers. Nine of 10 children had responses against both E2 peptide pools compared to only 4 of the 10 mothers. Six of the 10 children and only 2 mothers displayed reactivity to E6 and/or E7. The cytokine levels of IL-2 (p = 0.023) and IL-5 (p = 0.028) induced by all peptide pools, were also higher among children than their mothers. The children of the mothers with incident CIN3 had significantly higher IFN-γ (p = 0.032) and TNF-α (p = 0.008) levels than other children.ConclusionsOur study is the first to show that also children could have HPV-specific immunity. These data indicate that the children have circulating HPV16-specific memory T-cells which might have been induced by previous HPV16 exposure or ongoing HPV 16 infection.

The purpose of this study was to evaluate if an early exposure to human papillomavirus (HPV) during the prenatal period or infancy could result in HPV16-specific T helper (Th) responses resembling those of adults with HPV-induced lesions. We tested HPV16-specific cell-mediated immunity (CMI) in children born with HPV-positive umbilical cord blood and/or placenta or having persistent oral HPV infection and in constantly oral HPV-negative controls. Peripheral blood mononuclear cells from 33 children from the Finnish HPV Family Study cohort (mean age 14.7 years) were stimulated with peptide pools covering the amino acid sequence of the HPV16 E2, E6, and E7 proteins. Lymphocyte proliferation, secretion of cytokines (IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-10, IL-17A), and the frequency of Foxp3+ regulatory T-cells were determined in relation to the HPV DNA status during a 14-year follow-up. 73.6% of cases and 85.7% of controls responded against HPV16 E2, while reactivity against E6 was found in 10.5 and 35.7%, respectively. The proliferative response against E6 and E7 was more frequent in controls than in cases (p = 0.047). No HPV16-specific CMI response or antibodies were detected in two children with persistent oral HPV16. The profiles of induced cytokines indicated higher levels of IL-5, IL-10, and IL-17A in children with HPV DNA in placenta and/or cord blood than in other children. HPV16-specific CMI is common in HPV DNA-negative children. The cytokine profile in children infected with HPV16 during early life suggests that the viral dose and/or specific environment created by the placenta may have significant impact on the type of HPV-specific immunity.

ObjectivesHPV infections are detected in sexually naive children. This has raised the question about the role of early HPV infections in either protecting or predisposing to further HPV infections. HPV16-specific cell-mediated immunity (CMI) was studied in 10 case-children born to mothers with an incident cervical intraepithelial neoplasia (CIN) diagnosed during their 14-year follow-up (FU), and in 21 children born to mothers, who remained constantly HPV-negative (controls). The mean age of children was 12.3 years.MethodsPeripheral blood mononuclear cells were isolated from blood and stimulated with peptide pools covering HPV16 E2, E6 and E7. Proliferation of lymphocytes, their secretion of cytokines, and the frequency of regulatory T-cells were determined. The results were correlated with the HPV status and analyzed in a nested case–control setting.ResultsAll children, except two controls, displayed CMI against HPV16 E2, E6 and/or E7 peptides associated with type 1 and 2 cytokine secretion. Only two statistically significant differences were found in the nested case–control setting; (1) case-children had a higher TNF-α response to HPV16 E2 (p = 0.004) than controls and (2) controls had no response to HPV16 E7.2 peptide pool while 3/10 case-children had (p = 0.013). Totally, 50 and 57 % of the cases and controls, respectively, had HPV positive oral samples at some FU-visit. In addition, the children without any HPV antibodies before the age of 6 months showed proliferative responses of PBMC after HPV16 exposure more frequently than other children (p = 0.045).ConclusionsHPV16-specific CMI is common in young, sexually inexperienced children. This suggests that oral HPV infections occur frequently in children. Our results might also explain the previous findings that half of healthy adults demonstrate HPV-specific CMI irrespective of their partner/sexual status.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0733-4) contains supplementary material, which is available to authorized users.

BackgroundVirus-specific cell-mediated immunity (CMI) plays a role in the outcome of genital HPV infections. To cast further light on the question why most women clear their HPV infection while others develop high-grade cervical intraepithelial neoplasia (CIN), we analyzed HPV16 E2-, E6- and E7 -specific CMI in women who developed CIN during a 10-year follow-up of the Finnish Family HPV cohort.MethodsOverlapping 30–35 mer peptides covering the entire HPV16 E2-, E6- and E7 protein sequences were used for defining the lymphocyte proliferation capacity, cytokine production (IL-2, IL-5, IL-10, IL-17A, IFN-γ and TNF-α) and numbers of HPV16 -specific CD4+ CD25+ Foxp3+ regulatory T-cells in 10 women who developed CIN, and in 22 control women who tested constantly HPV-negative during the follow-up. HPV-specific CMI was related to the demographic data including sexual behavior, smoking and alcohol consumption.ResultsWomen with CIN and their controls had similar T-cell mediated immunity against HPV16 E2, E6 and E7 peptide pools. However, nearly fourfold higher T-cell reactivity against common antigens was found in the CIN women than in the healthy donors (p = 0.001). HPV16 E6 stimulation resulted in higher IL-17A secretion in the controls than in the CIN women (p = 0.035). Smoking and use of alcohol affected the T-cell response to common antigens but not to HPV peptides (p = 0.032 and 0.045, respectively).ConclusionWhile both the CIN women and controls exhibited an HPV16-specific CMI, IL-17A might be of importance in HPV induced pathology. The hyper-responsiveness of the CIN patients to common antigens needs further studies. Smoking and alcohol had no effect on HPV-specific CMI.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0498-9) contains supplementary material, which is available to authorized users.