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Journal ArticleDOI

Persistent Oral Human Papillomavirus (HPV) Infection is Associated with Low Salivary Levels of Matrix Metalloproteinase 8 (MMP-8).

TL;DR: Persistent oral HPV infection was associated with a low salivary MMP-8 concentration indicating eventually a failure in oral anti-inflammatory defence, according to a 6-year follow-up study.
About: This article is published in Journal of Clinical Virology.The article was published on 2017-12-01 and is currently open access. It has received 11 citations till now. The article focuses on the topics: HPV infection & Oral mucosa.

Summary (3 min read)

Introduction

  • The difference was more pronounced in non-smoking women, in this group also the salivary MMP8 levels differed (p = 0.047).
  • Persistent oral HPV infection was associated with a low salivary MMP-8 concentration indicating eventually a failure in oral anti-inflammatory defence, also known as Conclusions.

1. Background

  • Approximately 24% of oral cavity squamous cell carcinomas (SCC) are human papillomavirus (HPV) DNA positive [1].
  • Oral HPV persistence may be associated with behavioural factors such as smoking or sexual behaviour [9], but both innate and adaptive immunity are important in HPV clearance [10].
  • The main part of salivary MMP-8 and MMP-9 originates from polymorphonuclear neutrophils (PMN) via gingival crevicular fluid, but they are secreted also by other non PMN-lineage cell types, including e.g. MMP-8 secretion by oral fibroblasts [15] and MMP-9 secretion by gingival keratinocytes and acinar cells [16].
  • Specifically, MMP-9 is overexpressed both in epithelial cells E-mail address: anna.haukioja@utu.fi (A. Haukioja).

3.1. Study population

  • The participants were selected among the study population of the Finnish Family HPV Study (University of Turku and Turku University Hospital, Turku, Finland); see [38,39].
  • The original study protocol and its amendments (#3/1998 and #2/2006) have been approved by the Research Ethics Committee of Turku University Hospital, Turku, Finland.
  • The original study population consisted of 331 mothers, 131 fathers and 324 infants, and for this study a nested case-control setting was used with a subgroup of 57 women with a persistent oral HPV infection and of 102 women who were always HPV DNA-negative during the six-year follow-up.
  • For this study, the authors considered women who had given a breast milk sample as lactating.

3.2. Collection of salivary and serum samples

  • The salivary and serum samples used in this study were collected two months post-delivery.
  • Paraffin stimulated whole saliva was collected on ice, centrifuged (1500 x g), refrigerated and stored at −70° C. Blood samples were centrifuged at 2400 r.p.m. for 10 min (Sorvall GLC2; DuPont Instruments) divided into 1 ml aliquots and stored first at −20 ° C for one week maximum and then at −70 ° C until analysed.

3.3. Collection of oral scrapings and HPV DNA detection

  • The collection of oral scrapings from the buccal mucosa, as well as the extraction of HPV-DNA and HPV-testing and genotyping were performed as described earlier [3,5,42].
  • Multimetrix kit® (Multimetrix, Progen Biotechnik GmbH, Heidelberg, Germany) detecting altogether 24 low and high risk HPV-genotypes was used for HPV genotyping.

3.4. Detection of MMP-8, MMP-9, TIMP-1 and MPO in saliva and serum samples

  • Salivary and serum MMP-8 levels were measured by using timeresolved immunofluorometric assay (IFMA) and monoclonal MMP-8 specific antibodies obtained from Medix Biochemica, Espoo, Finland as described earlier [15,41].
  • Salivary MMP-9, MPO and TIMP-1 levels were measured by using commercial enzyme-linked immunosorbent assay -kits as described earlier: MMP-9 Quantikine (R &D Systems, Minneapolis, MN, USA) [43], MPO (Immundiagnostik AG, Bensheim, Germany) [41] and TIMP-1 Amersham (Human, Biotrak, system, GE Healthcare, Amersham, Buckinghamshire, UK) [41].

3.5. Statistics

  • The differences between salivary concentrations of MMP-8, MMP-9, TIMP-1 as well as their molar ratios, and between the salivary and serum concentrations of MPO in HPV DNA-positive and HPV DNA-negative groups or with regards to smoking, lactation or alcohol use were compared with Mann-Whitney U-test.
  • A non-parametric test was chosen since a part of the data was not normally distributed (quantile-quantile plots and Shapiro-Wilk test), not even after a logarithmic transformation.
  • In the first one, the concentrations of all measured markers were in line with other samples, but the other sample had a high MPO level, indicating possible contamination by blood.
  • All analyses were done also by leaving this sample out, but this did not influence the interpretation of the results.
  • Pearson correlation coefficients were calculated for the relationships between salivary and serum MPO, and salivary MPO and MMP-8 after logarithmic transformation of the data.

4. Results

  • The salivary concentrations of MMP-8, MMP-9, TIMP-1 and MPO, and the salivary MMP-8/TIMP-1 and MMP-9/TIMP-1 ratios and the serum concentration of MMP-8 in HPV DNA-positive and HPV DNAnegative women are presented in Table 1.
  • Similar trend was seen in the MMP-8 levels, although this lacked statistical significance (p = 0.057).
  • In contrast, among smokers there was no difference.
  • The salivary MMP-9 or MPO concentrations, salivary MMP-9/ TIMP-1 molar ratio or serum MMP-8 concentrations did not differ between HPV DNA-positive and negative women even if the smoking status was taken into account.
  • There were no differences between smokers and non-smokers with regards to their salivary MMP-8, TIMP-1 or MPO concentrations, or the MMP-8/TIMP-1 molar ratio, but the MMP-9 concentration and the MMP-9/TIMP-1 molar ratio were significantly lower in smokers than in non-smokers (p = 0.020 and p = 0.003, respectively).

5. Discussion

  • To their knowledge, this is the first time when low salivary MMP-8 levels, indicating a lowered anti-inflammatory defence in the oral cavity, have been connected with an asymptomatic, persistent viral infection in the oral cavity.
  • Based on this study, however, it cannot be concluded whether a low salivary MMP-8 concentration indicates a condition with an increased risk for chronic HPV infection or if the infection itself lowers MMP-8 expression.
  • Part of salivary MMP-8 originates from other cell types than PMN, and a considerable proportion of salivary MMP-8 can be of fibroblast-type [15,43].
  • This study included only women who had been pregnant, whereas the control group in the other study included nonpregnant, healthy age-match controls suggesting that the observed differences in [41] may be related to the pregnancy, not lactation per se.
  • This work was supported by the Academy of Finland (SS), the Cancer Society of Finland (SS), the Sohlberg foundation (SS) and the Helsinki Univerity Central Hospital Research Foundation (TS).

Acknowledgments

  • The authors are grateful to the women who participated in the Finnish Family HPV Study.
  • Dr. Marjut Rintala and professor Seija Grenman gratefully acknowledged for organizing the follow-up visits during the first two years.
  • Technician Tatjana Peskova is highly appreciated for conducting the HPV testing of the collected samples.

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Citations
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Journal ArticleDOI
24 Dec 2004-Science

1,949 citations

Journal ArticleDOI
TL;DR: Genetic editing of the HPV-18 E7 CKII recognition site in C4-1 cervical tumour-derived cells is performed, and it is found that phosphorylation of E7 plays a direct role in the ability of E6 to activate AKT signaling, which in turn is required for optimal levels of MMP secretion.
Abstract: The Human Papillomavirus E7 oncoprotein plays an essential role in the development and maintenance of malignancy, which it achieves through targeting a number of critical cell control pathways. An important element in the ability of E7 to contribute towards cell transformation is the presence of a Casein Kinase II phospho-acceptor site within the CR2 domain of the protein. Phosphorylation is believed to enhance E7 interaction with a number of different cellular target proteins, and thereby increase the ability of E7 to enhance cell proliferation and induce malignancy. However, there is little information on how important this site in E7 is, once the tumour cells have become fully transformed. In this study, we have performed genome editing of the HPV-18 E7 CKII recognition site in C4-1 cervical tumour-derived cells. We first show that mutation of HPV18 E7 S32/S34 to A32/A34 abolishes CKII phosphorylation of E7, and subsequently we have isolated C4-1 clones containing these mutations in E7. The cells continue to proliferate, but are somewhat more slow-growing than wild type cells, reach lower saturation densities, and are also more susceptible to low nutrient conditions. These cells are severely defective in matrigel invasion assays, partly due to downregulation of matrix metalloproteases (MMPs). Mechanistically, we find that phosphorylation of E7 plays a direct role in the ability of E7 to activate AKT signaling, which in turn is required for optimal levels of MMP secretion. These results demonstrate that the E7 CKII phospho-acceptor site thus continues to play an important role for E7's activity in cells derived from cervical cancers, and suggests that blocking this activity of E7 could be expected to have therapeutic potential.

26 citations

Journal ArticleDOI
22 Apr 2021-Vaccine
TL;DR: A review focusing on the importance of oral and laryngeal HPV infection which is present in majority of sexually active individuals at least once in their lifetime is presented in this article.

13 citations

Book ChapterDOI
01 Jan 2020
TL;DR: Analysis and interpretation issues particularly important for studying immune-related analytes, such as the impact of oral and systemic health, the interpretation of the serum–saliva correlation, and multisystem measurement and analysis techniques, are discussed.
Abstract: The study of immune and inflammatory markers in saliva has gained increased attention in recent years with the advancements in assay technology and a heightened focus on cross-systems biology and psychoneuroimmunology. Salivary immune markers are important for the study of both oral and systemic health. Salivary inflammation, in particular, has been widely examined across many fields as both an area of interest and a source of confounding variance. In this chapter, we discuss the opportunities and challenges of studying immune markers in saliva and review the current state of knowledge regarding the study of salivary immune biomeasures, including salivary cytokines, C-reactive protein, and immunoglobulins. Analysis and interpretation issues particularly important for studying immune-related analytes, such as the impact of oral and systemic health, the interpretation of the serum–saliva correlation, and multisystem measurement and analysis techniques, are discussed. Finally, we discuss future directions for the study of salivary immune markers and applications of this research to clinical care and health monitoring and surveillance programs.

12 citations

References
More filters
Journal ArticleDOI
24 Dec 2004-Science

1,949 citations

Journal ArticleDOI
TL;DR: Recent findings indicate that matrix metalloproteinases act on pro-inflammatory cytokines, chemokines and other proteins to regulate varied aspects of inflammation and immunity.
Abstract: As their name implies, matrix metalloproteinases are thought to be responsible for the turnover and degradation of the extracellular matrix. However, matrix degradation is neither the sole nor the main function of these proteinases. Indeed, as we discuss here, recent findings indicate that matrix metalloproteinases act on pro-inflammatory cytokines, chemokines and other proteins to regulate varied aspects of inflammation and immunity.

1,745 citations


"Persistent Oral Human Papillomaviru..." refers background in this paper

  • ...tissue turn over and repair as well as in innate host defence [14]....

    [...]

Journal ArticleDOI
TL;DR: The concept of the use of the natural inhibitors, such as the TIMPs, in gene based therapies is being assessed in animal models and should provide useful insights into the cell biology of degradative diseases.
Abstract: Tissue inhibitors of metalloproteinases (TIMPs) are the major cellular inhibitors of the matrix metalloproteinase (MMP) sub-family, exhibiting varying efficacy against different members, as well as different tissue expression patterns and modes of regulation. Other proteins have modest inhibitory activity against some of the MMPs, including domains of netrins, the procollagen C-terminal proteinase enhancer (PCPE), the reversion-inducing cysteine-rich protein with Kazal motifs (RECK), and tissue factor pathway inhibitor (TFPI-2), but their physiological significance is not at all clear. Alpha2-macroglobulin, thrombospondin-1 and thrombospondin-2 can bind to some MMPs and act as agents for their removal from the extracellular environment. In contrast, few effective inhibitors of other members of the metzincin family, the astacins or the distintegrin metalloproteinases, ADAMs have been identified. Many of these MMP inhibitors, including the TIMPs, possess other biological activities which may not be related to their inhibitory capacities. These need to be thoroughly characterized in order to allow informed development of MMP inhibitors as potential therapeutic agents. Over activity of MMPs has been implicated in many diseases, including those of the cardiovascular system, arthritis and cancer. The development of synthetic small molecule inhibitors has been actively pursued for some time, but the concept of the use of the natural inhibitors, such as the TIMPs, in gene based therapies is being assessed in animal models and should provide useful insights into the cell biology of degradative diseases.

1,138 citations


"Persistent Oral Human Papillomaviru..." refers background in this paper

  • ...periodontal disease, acute and chronic cardiovascular diseases, and cancer progression [30,31]....

    [...]

Journal ArticleDOI
15 Feb 2012-JAMA
TL;DR: Among men and women aged 14 to 69 years in the United States, the overall prevalence of Oral HPV infection was 6.9%, and the prevalence was higher among men than among women, and associations with age, sex, number of sexual partners, and current number of cigarettes smoked per day were independently associated with oral HPV infection in multivariable models.
Abstract: 69 years was 6.9% (95% CI, 5.7%-8.3%) and of HPV type 16 was 1.0% (95% CI, 0.7%-1.3%). Oral HPV infection followed a bimodal pattern with respect to age, with peak prevalence among individuals aged 30 to 34 years (7.3%; 95% CI, 4.6%11.4%) and 60 to 64 years (11.4%; 95% CI, 8.5%-15.1%). Men had a significantly higher prevalence than women for any oral HPV infection (10.1% [95% CI, 8.3%12.3%] vs 3.6% [95% CI, 2.6%-5.0%], P.001; unadjusted prevalence ratio [PR], 2.80 [95% CI, 2.02-3.88]). Infection was less common among those without vs those with a history of any type of sexual contact (0.9% [95% CI, 0.4%-1.8%] vs 7.5% [95% CI, 6.1%-9.1%], P.001; PR, 8.69 [95% CI, 3.91-19.31]) and increased with number of sexual partners (P.001 for trend) and cigarettes smoked per day (P.001 for trend). Associations with age, sex, number of sexual partners, and current number of cigarettes smoked per day were independently associated with oral HPV infection in multivariable models.

947 citations

Journal ArticleDOI
TL;DR: The identification of mutations in CXCR4 in individuals with WHIM syndrome represents the first example of aberrant chemokine receptor function causing human disease and suggests that the receptor may be important in cell-mediated immunity to HPV infection.
Abstract: WHIM syndrome is an immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia and extensive human papillomavirus (HPV) infection1. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis2. The susceptibility to HPV is disproportionate compared with other immunodeficiency conditions, suggesting that the product of the affected gene may be important in the natural control of this infection. We describe here the localization of the gene associated with WHIM syndrome to a region of roughly 12 cM on chromosome 2q21 and the identification of truncating mutations in the cytoplasmic tail domain of the gene encoding chemokine receptor 4 (CXCR4). Haplotype and mutation analyses in a pedigree transmitting myelokathexis as an apparently autosomal recessive trait support genetic heterogeneity for this aspect of the WHIM syndrome phenotype. Lymphoblastoid cell lines carrying a 19-residue truncation mutation show significantly greater calcium flux relative to control cell lines in response to the CXCR4 ligand, SDF-1, consistent with dysregulated signaling by the mutant receptor. The identification of mutations in CXCR4 in individuals with WHIM syndrome represents the first example of aberrant chemokine receptor function causing human disease and suggests that the receptor may be important in cell-mediated immunity to HPV infection.

644 citations

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Q1. What contributions have the authors mentioned in the paper "Persistent oral human papillomavirus (hpv) infection is associated with low salivary levels of matrix metalloproteinase 8 (mmp-8)" ?

Study design: A nested case-control setting was used to select a subgroup of 57 women with a persistent oral HPV infection and 102 controls from the Finnish Family HPV Study.