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Increased PD-1 Level in Severe Cervical Injury Is Associated With the Rare Programmed Cell Death 1 (PDCD1) rs36084323 A Allele in a Dominant Model

The high-risk oncogenic human papillomavirus (HPV) has developed mechanisms for evasion of the immune system, favoring the persistence of the infection. The chronic inflammation further contributes to the progression of tissue injury to cervical cancer. The programmed cell death protein (PD-1) after...

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Autores principales: da Silva, Mauro César, Medeiros, Fernanda Silva, da Silva, Neila Caroline Henrique, Paiva, Larissa Albuquerque, Gomes, Fabiana Oliveira dos Santos, Costa e Silva, Matheus, Gomes, Thailany Thays, Peixoto, Christina Alves, Rygaard, Maria Carolina Valença, Menezes, Maria Luiza Bezerra, Welkovic, Stefan, Donadi, Eduardo Antônio, Lucena-Silva, Norma
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288189/
https://www.ncbi.nlm.nih.gov/pubmed/34290992
http://dx.doi.org/10.3389/fcimb.2021.587932
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author da Silva, Mauro César
Medeiros, Fernanda Silva
da Silva, Neila Caroline Henrique
Paiva, Larissa Albuquerque
Gomes, Fabiana Oliveira dos Santos
Costa e Silva, Matheus
Gomes, Thailany Thays
Peixoto, Christina Alves
Rygaard, Maria Carolina Valença
Menezes, Maria Luiza Bezerra
Welkovic, Stefan
Donadi, Eduardo Antônio
Lucena-Silva, Norma
author_facet da Silva, Mauro César
Medeiros, Fernanda Silva
da Silva, Neila Caroline Henrique
Paiva, Larissa Albuquerque
Gomes, Fabiana Oliveira dos Santos
Costa e Silva, Matheus
Gomes, Thailany Thays
Peixoto, Christina Alves
Rygaard, Maria Carolina Valença
Menezes, Maria Luiza Bezerra
Welkovic, Stefan
Donadi, Eduardo Antônio
Lucena-Silva, Norma
author_sort da Silva, Mauro César
collection PubMed
description The high-risk oncogenic human papillomavirus (HPV) has developed mechanisms for evasion of the immune system, favoring the persistence of the infection. The chronic inflammation further contributes to the progression of tissue injury to cervical cancer. The programmed cell death protein (PD-1) after contacting with its ligands (PD-L1 and PD-L2) exerts an inhibitory effect on the cellular immune response, maintaining the balance between activation, tolerance, and immune cell-dependent lesion. We evaluated 295 patients exhibiting or not HPV infection, stratified according to the location (injured and adjacent non-injured areas) and severity of the lesion (benign, pre-malignant lesions). Additionally, we investigated the role of the promoter region PDCD1 -606G>A polymorphism (rs36084323) on the studied variables. PD-1 and PDCD1 expression were evaluated by immunohistochemistry and qPCR, respectively, and the PDCD1 polymorphism was evaluated by nucleotide sequencing. Irrespective of the severity of the lesion, PD-1 levels were increased compared to adjacent uninjured areas. Additionally, in cervical intraepithelial neoplasia (CIN) I, the presence of HPV was associated with increased (P = 0.0649), whereas in CIN III was associated with decreased (P = 0.0148) PD-1 levels, compared to the uninjured area in absence of HPV infection. The PDCD1 -606A allele was rare in our population (8.7%) and was not associated with the risk for development of HPV infection, cytological and histological features, and aneuploidy. In contrast, irrespective of the severity of the lesion, patients exhibiting the mutant PDCD1 -606A allele at single or double doses exhibited increased protein and gene expression when compared to the PDCD1 -606GG wild type genotype. Besides, the presence of HPV was associated with the decrease in PDCD1 expression and PD-1 levels in carriers of the -606 A allele presenting severe lesions, suggesting that other mediators induced during the HPV infection progression may play an additional role. This study showed that increased PD-1 levels are influenced by the -606G>A nucleotide variation, particularly in low-grade lesions, in which the A allele favors increased PDCD1 expression, contributing to HPV immune system evasion, and in the high-grade lesion, by decreasing tissue PD-1 levels.
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spelling pubmed-82881892021-07-20 Increased PD-1 Level in Severe Cervical Injury Is Associated With the Rare Programmed Cell Death 1 (PDCD1) rs36084323 A Allele in a Dominant Model da Silva, Mauro César Medeiros, Fernanda Silva da Silva, Neila Caroline Henrique Paiva, Larissa Albuquerque Gomes, Fabiana Oliveira dos Santos Costa e Silva, Matheus Gomes, Thailany Thays Peixoto, Christina Alves Rygaard, Maria Carolina Valença Menezes, Maria Luiza Bezerra Welkovic, Stefan Donadi, Eduardo Antônio Lucena-Silva, Norma Front Cell Infect Microbiol Cellular and Infection Microbiology The high-risk oncogenic human papillomavirus (HPV) has developed mechanisms for evasion of the immune system, favoring the persistence of the infection. The chronic inflammation further contributes to the progression of tissue injury to cervical cancer. The programmed cell death protein (PD-1) after contacting with its ligands (PD-L1 and PD-L2) exerts an inhibitory effect on the cellular immune response, maintaining the balance between activation, tolerance, and immune cell-dependent lesion. We evaluated 295 patients exhibiting or not HPV infection, stratified according to the location (injured and adjacent non-injured areas) and severity of the lesion (benign, pre-malignant lesions). Additionally, we investigated the role of the promoter region PDCD1 -606G>A polymorphism (rs36084323) on the studied variables. PD-1 and PDCD1 expression were evaluated by immunohistochemistry and qPCR, respectively, and the PDCD1 polymorphism was evaluated by nucleotide sequencing. Irrespective of the severity of the lesion, PD-1 levels were increased compared to adjacent uninjured areas. Additionally, in cervical intraepithelial neoplasia (CIN) I, the presence of HPV was associated with increased (P = 0.0649), whereas in CIN III was associated with decreased (P = 0.0148) PD-1 levels, compared to the uninjured area in absence of HPV infection. The PDCD1 -606A allele was rare in our population (8.7%) and was not associated with the risk for development of HPV infection, cytological and histological features, and aneuploidy. In contrast, irrespective of the severity of the lesion, patients exhibiting the mutant PDCD1 -606A allele at single or double doses exhibited increased protein and gene expression when compared to the PDCD1 -606GG wild type genotype. Besides, the presence of HPV was associated with the decrease in PDCD1 expression and PD-1 levels in carriers of the -606 A allele presenting severe lesions, suggesting that other mediators induced during the HPV infection progression may play an additional role. This study showed that increased PD-1 levels are influenced by the -606G>A nucleotide variation, particularly in low-grade lesions, in which the A allele favors increased PDCD1 expression, contributing to HPV immune system evasion, and in the high-grade lesion, by decreasing tissue PD-1 levels. Frontiers Media S.A. 2021-07-01 /pmc/articles/PMC8288189/ /pubmed/34290992 http://dx.doi.org/10.3389/fcimb.2021.587932 Text en Copyright © 2021 Silva, Medeiros, Silva, Paiva, Gomes, Costa e Silva, Gomes, Peixoto, Rygaard, Menezes, Welkovic, Donadi and Lucena-Silva https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular and Infection Microbiology
da Silva, Mauro César
Medeiros, Fernanda Silva
da Silva, Neila Caroline Henrique
Paiva, Larissa Albuquerque
Gomes, Fabiana Oliveira dos Santos
Costa e Silva, Matheus
Gomes, Thailany Thays
Peixoto, Christina Alves
Rygaard, Maria Carolina Valença
Menezes, Maria Luiza Bezerra
Welkovic, Stefan
Donadi, Eduardo Antônio
Lucena-Silva, Norma
Increased PD-1 Level in Severe Cervical Injury Is Associated With the Rare Programmed Cell Death 1 (PDCD1) rs36084323 A Allele in a Dominant Model
title Increased PD-1 Level in Severe Cervical Injury Is Associated With the Rare Programmed Cell Death 1 (PDCD1) rs36084323 A Allele in a Dominant Model
title_full Increased PD-1 Level in Severe Cervical Injury Is Associated With the Rare Programmed Cell Death 1 (PDCD1) rs36084323 A Allele in a Dominant Model
title_fullStr Increased PD-1 Level in Severe Cervical Injury Is Associated With the Rare Programmed Cell Death 1 (PDCD1) rs36084323 A Allele in a Dominant Model
title_full_unstemmed Increased PD-1 Level in Severe Cervical Injury Is Associated With the Rare Programmed Cell Death 1 (PDCD1) rs36084323 A Allele in a Dominant Model
title_short Increased PD-1 Level in Severe Cervical Injury Is Associated With the Rare Programmed Cell Death 1 (PDCD1) rs36084323 A Allele in a Dominant Model
title_sort increased pd-1 level in severe cervical injury is associated with the rare programmed cell death 1 (pdcd1) rs36084323 a allele in a dominant model
topic Cellular and Infection Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288189/
https://www.ncbi.nlm.nih.gov/pubmed/34290992
http://dx.doi.org/10.3389/fcimb.2021.587932
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