HLA-G and vertical mother-to-child transmission of human papillomavirus infection
Introduction
Human papillomavirus (HPV) infection is one of the most common sexually transmitted infection (STI) worldwide [1]. The prevalence is shown to be highest among women and men around their sexual debut, and nearly all sexually active women and male will be infected with HPV in their lifetime [1], [2]. However, HPV-infection can be transmitted in early life by vertical transmission from a mother to her child [3], [4], [5], [6]. This transmission could occur in fertilization, during pregnancy (prenatal), at delivery or during the perinatal period [3], [4]. Acquisition of HPV-infections in early life is most likely dependent on a combination of epigenetic, immune and genetic factors of the child acting in concert with endogenous and exogenous co-factors and viral load [7]. Most HPV-infections among adults are transient, whereas infections in early life may lead to long-term consequences such as HPV-related cancer [3], [8], [9]. If HPV-infections are acquired in early life, this will certainly impact the protective effect of prophylactic HPV vaccines (currently given to adolescent girls) which should be considered while designing the future policies of vaccination and screening programs.
Human Leukocyte Antigen (HLA)-G interferes with HPV-infection; its prevalence, persistence and progression to cervical cancer [10], [11], [12], [13]. HLA-polymorphism influences the innate and adaptive immune response by antigen presentation and are crucial to the cell-mediated immune (CMI) response by clearing the virus [14]. These different HLA-types are divided into classical and non-classical, where HLA-G alleles represent the non-classical class Ib [15]. HLA-G is highly tissue-specific and has a very low degree of polymorphism compared to the other HLA-molecules [16]. Recent studies have revealed HLA-G to play a significant role in female reproduction, including pregnancy complications like miscarriage, preterm birth, pre-eclampsia and recurrent spontaneous abortions [17]. On the other hand, HLA-G has also been associated with different cancers e.g. by facilitating their escape from immune surveillance [18].
With its preferential expression at the maternal-fetal interface and its immunosuppressive properties, HLA-G has proved to be important in the mother-to-child transmission of HIV-infection [19], [20], [21], [22]. These studies have reasoned that children have a natural protection against HIV-transmission provided by a HLA-G polymorphism, as suggested by the fact that a large proportion of children remain HIV-1 uninfected even if their mother had not been on any antiretroviral therapy. Interestingly enough, it was discovered that the vertical transmission of HIV-1 virus from a mother to her child increases when both are HLA concordant [19], [20], [22].
In our Finnish Family HPV (FFHPV)-cohort, we recently described a close mother-child concordance in HPV-genotype distribution at birth [23]. The most likely transmission route to the child was speculated to be via placenta or cord blood [23]. In the present study, we investigated the impact of HLA-G and its allele concordance in the mother-to-child transmission of HPV in the mother-child pairs of the FFHPV-cohort. Our hypothesis was that HLA-G allele concordance would predict the vertical transmission of HPV.
Section snippets
Finnish Family HPV-study
The FFHPV-study is a longitudinal cohort followed-up at University of Turku and Turku University Hospital, Turku(Finland) as described previously [24], [25]. At baseline (36-week of pregnancy), 329 families were enrolled, comprising 329 mothers, 131 fathers and 331 newborns, subsequently followed up (FU) for 6 years. All the families were Caucasian origin, have the same ethnic background and are representative of Finnish population. The study protocol and its amendment (#2/1998 and #2/2006)
Results
A total of nine different HLA-G alleles were identified among these 310 mother-child pairs, (Fig. 1b). The most common HLA-G alleles among the mothers and children was G*01:01:01; 83.9% (n = 260) and 84.8% (n = 263); followed by G*01:01:02; 39.7% (n = 124) and 37.0% (n = 115), respectively. The HLA-G genotype concordance and allele distribution among the 310 mother-child pairs are shown in Fig. 1. The most commonly shared allele was G*01:01:01, for which 76.5% (n = 237) of the pairs were at
Discussion
The role of host factors in mother-to-child transmission of HPV is unknown. The previous studies on vertical HPV-transmission have focused only on HPV-prevalence and/or HPV-concordance examined with different obstetrical or behavioral risk factors as covariates [3], [4]. However, several modes and phases exist during pregnancy and delivery when vertical HPV transmission could take place and those have not been adequately studied as yet. As an example, there are no previous studies on the
Acknowledgments
We thank Sophie Coutlée for HLA typing.
Funding
This study was supported by, Academy of Finland (#116438/2006, #130204/2008), Finnish Cancer Foundation, Solberg Foundation, Finnish Dental Society Apollonia, and the Government Special Foundation (EVO) to Turku University Hospital and University Hospital of Helsinki, and University of Helsinki post-doc funding. The authors do not declare any conflict of interest related to the topic of this article and the authors have no conflicts of interest to declare.
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