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1.
Ann Rheum Dis ; 79(9): 1194-1202, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32532752

RESUMO

OBJECTIVES: Porphyromonas gingivalis (P.g.) is discussed to be involved in triggering self-reactive immune responses. The aim of this study was to investigate the autocitrullinated prokaryotic peptidylarginine deiminase (PPAD) from P.g. CH2007 (RACH2007-PPAD) from a rheumatoid arthritis (RA) patient and a synthetic citrullinated PPAD peptide (CPP) containing the main autocitrullination site as potential targets for antibody reactivity in RA and to analyse the possibility of citrullinating native human proteins by PPAD in the context of RA. METHODS: Recombinant RACH2007-PPAD was cloned and expressed in Escherichia coli. Purified RACH2007-PPAD and its enzymatic activity was analysed using two-dimensional electrophoresis, mass spectrometry, immunoblot and ELISA. Autoantibody response to different modified proteins and peptides was recorded and bioinformatically evaluated. RESULTS: RACH2007-PPAD was capable to citrullinate major RA autoantigens, such as fibrinogen, vimentin, hnRNP-A2/B1, histone H1 and multiple peptides, which identify a common RG/RGG consensus motif. 33% of RA patients (n=30) revealed increased reactivity for α-cit-RACH2007-PPAD before RA onset. 77% of RA patients (n=99) presented α-cit-specific signals to CPP amino acids 57-71 which were positively correlated to α-CCP2 antibody levels. Interestingly, 48% of the α-CPP-positives were rheumatoidfactor IgM/anti-citrullinated peptide/protein antibodies (ACPA)-negative. Anti-CPP and α-RACH2007-PPAD antibody levels increase with age. Protein macroarrays that were citrullinated by RACH2007-PPAD and screened with RA patient sera (n=6) and controls (n=4) uncovered 16 RACH2007-PPAD citrullinated RA autoantigens and 9 autoantigens associated with lung diseases. We showed that the α-CPP response could be an important determinant in parenchymal changes in the lung at the time of RA diagnosis (n=106; p=0.018). CONCLUSIONS: RACH2007-PPAD induced internal citrullination of major RA autoantigens. Anti-RACH2007-PPAD correlates with ACPA levels and interstitial lung disease autoantigen reactivity, supporting an infection-based concept for induction of ACPAs via enzymatic mimicry.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Infecções por Bacteroidaceae/imunologia , Epitopos/imunologia , Porphyromonas gingivalis/imunologia , Artrite Reumatoide/microbiologia , Infecções por Bacteroidaceae/microbiologia , Citrulinação/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Immunoblotting , Peptídeos/imunologia , Desiminases de Arginina em Proteínas/imunologia
2.
Infect Immun ; 88(4)2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-31932327

RESUMO

The serine-glycine dipeptide lipid classes, including lipid 430 and lipid 654, are produced by the periodontal pathogen Porphyromonas gingivalis and can be detected in lipid extracts of diseased periodontal tissues and teeth of humans. Both serine-glycine lipid classes were previously shown to engage human and mouse Toll-like receptor 2 (TLR2) and to inhibit mouse osteoblast differentiation and function through engagement of TLR2. It is not clear if other lipids related to serine-glycine lipids are also produced by P. gingivalis The goal of this investigation was to determine whether P. gingivalis produces additional lipid classes similar to the serine-glycine lipids that possess biological properties. P. gingivalis (ATCC 33277) was grown in broth culture, and lipids were extracted and fractionated by high-performance liquid chromatography (HPLC). Lipids were separated using semipreparative HPLC, and specific lipid classes were identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography-multiple reaction monitoring (LC-MRM) mass spectrometric approaches. Two glycine lipid classes were identified, termed lipid 567 and lipid 342, and these lipid classes are structurally related to the serine-glycine dipeptide lipids. Both glycine lipid classes were shown to promote TLR2-dependent tumor necrosis factor alpha (TNF-α) release from bone marrow macrophages, and both were shown to activate human embryonic kidney (HEK) cells through TLR2 and TLR6 but not TLR1. These results demonstrate that P. gingivalis synthesizes glycine lipids and that these lipids engage TLR2 similarly to the previously reported serine-glycine dipeptide lipids.


Assuntos
Fatores Imunológicos/metabolismo , Lipopeptídeos/metabolismo , Porphyromonas gingivalis/imunologia , Receptor 2 Toll-Like/agonistas , Animais , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos , Fatores Imunológicos/isolamento & purificação , Lipopeptídeos/isolamento & purificação , Macrófagos/efeitos dos fármacos , Camundongos , Espectrometria de Massas em Tandem , Fator de Necrose Tumoral alfa/metabolismo
3.
Immunol Lett ; 218: 11-21, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31863783

RESUMO

Aging humans display an increased prevalence and severity of periodontitis, although the mechanisms underlying these findings remain poorly understood. This report examined antigenic diversity of P. gingivalis related to disease presence and patient demographics. Serum IgG antibody to P. gingivalis strains ATCC33277, FDC381, W50 (ATCC53978), W83, A7A1-28 (ATCC53977) and A7436 was measured in 426 participants [periodontally healthy (n = 61), gingivitis (N = 66) or various levels of periodontitis (N = 299)]. We hypothesized that antigenic diversity in P. gingivalis could contribute to a lack of "immunity" in the chronic infections of periodontal disease. Across the strains, the antibody levels in the oldest age group were lower than in the youngest groups, and severe periodontitis patients did not show higher antibody with aging. While 80 % of the periodontitis patients in any age group showed an elevated response to at least one of the P. gingivalis strains, the patterns of individual responses in the older group were also substantially different than the other age groups. Significantly greater numbers of older patients showed strain-specific antibody profiles to only 1 strain. The findings support that P. gingivalis may demonstrate antigenic diversity/drift within patients and could be one factor to help explain the inefficiency/ineffectiveness of the adaptive immune response in managing the infection.


Assuntos
Anticorpos Antibacterianos/imunologia , Infecções por Bacteroidaceae/diagnóstico , Infecções por Bacteroidaceae/imunologia , Variação Biológica Individual , Periodontite/diagnóstico , Periodontite/etiologia , Porphyromonas gingivalis/imunologia , Adulto , Idoso , Anticorpos Antibacterianos/sangue , Infecções por Bacteroidaceae/microbiologia , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância da População , Adulto Jovem
4.
Anaerobe ; 61: 102140, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31838319

RESUMO

Porphyromonas gingivalis is a keystone pathogen in periodontitis. Analysis of the immunogenicity of its virulence factors may provide insight into the host response to this infection. The Kgp12 (IEDB Epitope ID 763561), an epitope of Lys-gingipain (Kgp) virulence factor from P. gingivalis ATCC 33277, elicits an immunoglobulin G (IgG) immunoreactivity with low cross-reactivity and, therefore, more specificity. The aim of the present study was to determine in silico the localization of Kgp12 within the protein and to evaluate the IgG host response to this novel Kgp peptide through its capacity to differentiate individuals with different periodontal status. Sera of 71 volunteers were tested by indirect ELISA to detect the IgG immunoreactivity specific to Kgp12, as well as to the protein HmuY and to the sonicated total extract of P. gingivalis ATCC33277, both used as gold standard. The participants had no systemic disease and were classified according to periodontal clinical parameters to comparison, firstly, into periodontitis (P) and without periodontitis (WP) groups and, secondly, into periodontitis (P), gingivitis (G) and clinically health (CH) ones. All the antigens tested, Kgp12 (p = 0.02), HmuY (p = 0.00) and P. gingivalis extract (p = 0.03), could differentiate P from WP groups considering IgG serum levels. P group also had higher IgG levels specific to Kgp12 (p = 0.03), HmuY (p < 0.01) and P. gingivalis extract (p = 0.01) when compared to G group. We conclude that the Kgp12 synthetic peptide was useful to detect the IgG-mediated host response signaling that it is a promising epitope to analyze the immunogenicity of P. gingivalis.


Assuntos
Infecções por Bacteroidaceae/metabolismo , Infecções por Bacteroidaceae/microbiologia , Cisteína Endopeptidases Gingipaínas/metabolismo , Imunoglobulina G/imunologia , Fragmentos de Peptídeos/metabolismo , Periodontite/etiologia , Porphyromonas gingivalis/enzimologia , Infecções por Bacteroidaceae/imunologia , Bases de Dados de Proteínas , Suscetibilidade a Doenças , Epitopos/imunologia , Feminino , Cisteína Endopeptidases Gingipaínas/química , Cisteína Endopeptidases Gingipaínas/imunologia , Humanos , Imunoglobulina G/sangue , Masculino , Modelos Moleculares , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Porphyromonas gingivalis/imunologia , Transporte Proteico , Relação Estrutura-Atividade
5.
Int J Med Sci ; 16(10): 1320-1327, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692996

RESUMO

Porphyromonas gingivalis is a pivotal periodontal pathogen, and the epithelial cells serve as the first physical barrier to defend the host from bacterial attack. Within this host-bacteria interaction, P. gingivalis can modify the host immune reaction and adjust the gene expression, which is associated with periodontitis pathogenesis and developing strategies. Herein, a meta-analysis was made to get the differential gene expression profiles in epithelial cells with or without P. gingivalis infection. The network-based meta-analysis program for gene expression profiling was used. Both the gene ontology analysis and the pathway enrichment analysis of the differentially expressed genes were conducted. Our results determined that 290 genes were consistently up-regulated in P. gingivalis infected epithelial cells. 229 gene ontology biological process terms of up-regulated genes were discovered, including "negative regulation of apoptotic process" and "positive regulation of cell proliferation/migration/angiogenesis". In addition to the well-known inflammatory signaling pathways, the pathway associated with a transcriptional misregulation in cancer has also been increased. Our findings indicated that P. gingivalis benefited from the survival of epithelial cells, and got its success as a colonizer in oral epithelium. The results also suggested that infection of P. gingivalis might contribute to oral cancer through chronic inflammation. Negative regulation of the apoptotic process and transcriptional misregulation in cancer pathway are important contributors to the cellular physiology changes during infection development, which have particular relevance to the pathogenesis and progressions of periodontitis, even to the occurrence of oral cancer.


Assuntos
Infecções por Bacteroidaceae/imunologia , Interações Hospedeiro-Patógeno/genética , Neoplasias Bucais/patologia , Periodontite/imunologia , Porphyromonas gingivalis/imunologia , Infecções por Bacteroidaceae/genética , Infecções por Bacteroidaceae/microbiologia , Infecções por Bacteroidaceae/patologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Progressão da Doença , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Perfilação da Expressão Gênica , Ontologia Genética , Gengiva/citologia , Gengiva/imunologia , Gengiva/microbiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Mucosa Bucal/citologia , Mucosa Bucal/imunologia , Mucosa Bucal/microbiologia , Neoplasias Bucais/genética , Neoplasias Bucais/imunologia , Neoplasias Bucais/microbiologia , Periodontite/genética , Periodontite/microbiologia , Periodontite/patologia , Porphyromonas gingivalis/isolamento & purificação , Porphyromonas gingivalis/patogenicidade , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Regulação para Cima
6.
Infect Immun ; 87(12)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31570556

RESUMO

The Porphyromonas gingivalis strain ATCC 33277 (33277) and 381 genomes are nearly identical. However, strain 33277 displays a significantly diminished capacity to stimulate host cell Toll-like receptor 2 (TLR2)-dependent signaling and interleukin-1ß (IL-1ß) production relative to 381, suggesting that there are strain-specific differences in one or more bacterial immune-modulatory factors. Genomic sequencing identified a single nucleotide polymorphism in the 33277 fimB allele (A→T), creating a premature stop codon in the 33277 fimB open reading frame relative to the 381 fimB allele. Gene exchange experiments established that the 33277 fimB allele reduces the immune-stimulatory capacity of this strain. Transcriptome comparisons revealed that multiple genes related to carboxy-terminal domain (CTD) family proteins, including the gingipains, were upregulated in 33277 relative to 381. A gingipain substrate degradation assay demonstrated that cell surface gingipain activity is higher in 33277, and an isogenic mutant strain deficient for the gingipains exhibited an increased ability to induce TLR2 signaling and IL-1ß production. Furthermore, 33277 and 381 mutant strains lacking CTD cell surface proteins were more immune-stimulatory than the parental wild-type strains, consistent with an immune-suppressive role for the gingipains. Our data show that the combination of an intact fimB allele and limited cell surface gingipain activity in P. gingivalis 381 renders this strain more immune-stimulatory. Conversely, a defective fimB allele and high-level cell surface gingipain activity reduce the capacity of P. gingivalis 33277 to stimulate host cell innate immune responses. In summary, genomic and transcriptomic comparisons identified key virulence characteristics that confer divergent host cell innate immune responses to these highly related P. gingivalis strains.


Assuntos
Proteínas de Fímbrias/genética , Proteínas de Fímbrias/imunologia , Cisteína Endopeptidases Gingipaínas/metabolismo , Porphyromonas gingivalis/genética , Porphyromonas gingivalis/imunologia , Infecções por Bacteroidaceae/imunologia , Infecções por Bacteroidaceae/microbiologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Interleucina-1beta/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Transdução de Sinais/imunologia , Células THP-1 , Receptor 2 Toll-Like/metabolismo
7.
Int J Mol Sci ; 20(18)2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31540277

RESUMO

The association between rheumatoid arthritis (RA) and periodontal disease (PD) has been the focus of numerous investigations driven by their common pathological features. RA is an autoimmune disease characterized by chronic inflammation, the production of anti-citrullinated proteins antibodies (ACPA) leading to synovial joint inflammation and destruction. PD is a chronic inflammatory condition associated with a dysbiotic microbial biofilm affecting the supporting tissues around the teeth leading to the destruction of mineralized and non-mineralized connective tissues. Chronic inflammation associated with both RA and PD is similar in the predominant adaptive immune phenotype, in the imbalance between pro- and anti-inflammatory cytokines and in the role of smoking and genetic background as risk factors. Structural damage that occurs in consequence of chronic inflammation is the ultimate cause of loss of function and disability observed with the progression of RA and PD. Interestingly, the periodontal pathogen Porphyromonas gingivalis has been implicated in the generation of ACPA in RA patients, suggesting a direct biological intersection between PD and RA. However, more studies are warranted to confirm this link, elucidate potential mechanisms involved, and ascertain temporal associations between RA and PD. This review is mainly focused on recent clinical and translational research intends to discuss and provide an overview of the relationship between RA and PD, exploring the similarities in the immune-pathological aspects and the possible mechanisms linking the development and progression of both diseases. In addition, the current available treatments targeting both RA and PD were revised.


Assuntos
Anticorpos Anti-Proteína Citrulinada/metabolismo , Artrite Reumatoide/imunologia , Periodontite/microbiologia , Citocinas/metabolismo , Progressão da Doença , Disbiose/imunologia , Disbiose/microbiologia , Regulação da Expressão Gênica , Humanos , Periodontite/imunologia , Porphyromonas gingivalis/imunologia
8.
Int Heart J ; 60(5): 1142-1146, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31447467

RESUMO

The aim of this study was to assess whether a specific cardiovascular disease was related to an increased antibody level against a periodontal pathogen.A strong association between cardiovascular disease and periodontitis was shown, however, the causal relationship was not proven. Increased inflammatory reaction of patients with periodontitis was a possible factor, which connected periodontal infection and vascular diseases.We assessed medical history, blood data, and periodontal conditions in patients with cardiovascular diseases. Serum IgG antibody titers against major periodontal pathogens and existence of salivary periodontal bacteria were analyzed.In total, 348 subjects were enrolled in this study. The patients who exhibited 10,000 counts/mL or more of salivary Porphyromonas gingivalis were divided into two groups according to the antibody level of the pathogen. Patients with a high antibody level against Porphyromonas gingivalis exhibited a high rate of heart failure compared to the low antibody group. Mean probing pocket depth and clinical attachment level significantly increased in the high antibody group. We found that the high anti-Porphyromonas gingivalis antibody group also experienced enhanced antibody levels against other periodontal bacteria.An increased heart failure prevalence was found in patients with a high antibody level against a major periodontal pathogen, Porphyromonas gingivalis.


Assuntos
Anticorpos Antibacterianos/sangue , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/imunologia , Periodontite/epidemiologia , Periodontite/imunologia , Porphyromonas gingivalis/imunologia , Idoso , Estudos Transversais , Feminino , Insuficiência Cardíaca/diagnóstico , Hospitais Universitários , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Periodontite/microbiologia , Porphyromonas gingivalis/isolamento & purificação , Prevalência , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença
9.
Infect Immun ; 87(10)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31331955

RESUMO

Porphyromonas gingivalis is considered a keystone pathogen that contributes to the initiation and progression of periodontitis in humans. P. gingivalis has also been detected in human placentas associated with adverse pregnancy outcomes. The spread of P. gingivalis from the oral cavity to the reproductive tract thus represents a potential mechanism whereby periodontitis can lead to adverse pregnancy outcomes. In a murine model of pregnancy and oral infection with P. gingivalis, C57BL/6J mice developed low fetal weight, whereas C57BL/6NCrl mice did not. Although C57BL/6NCrl mice harbor segmented filamentous bacteria that drive a Th17 response, fetal weight was independent of frequency of Th17 or Th1 in either substrain. Low fetal weight was instead correlated with increasing amounts of P. gingivalis DNA in the placentas of the C57BL/6J dams. In contrast, fetal weight in C57BL/6NCrl mice was independent of P. gingivalis in the placenta. Differences in genetics or microbiome that influence the ability of P. gingivalis to colonize the placenta may drive differential fetal weight outcomes between C57BL/6J and C57BL/6NCrl mice and, potentially, between diverse human populations.


Assuntos
Infecções por Bacteroidaceae/microbiologia , Peso Fetal , Periodontite/microbiologia , Porphyromonas gingivalis/patogenicidade , Complicações Infecciosas na Gravidez/microbiologia , Células Th17/microbiologia , Animais , Infecções por Bacteroidaceae/imunologia , Infecções por Bacteroidaceae/patologia , Modelos Animais de Doenças , Feminino , Feto , Expressão Gênica , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Boca/imunologia , Boca/microbiologia , Periodontite/imunologia , Periodontite/patologia , Placenta/imunologia , Placenta/microbiologia , Porphyromonas gingivalis/imunologia , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/patologia , Especificidade da Espécie , Células Th17/imunologia
10.
FEMS Microbiol Lett ; 366(12)2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265058

RESUMO

Periodontitis is a chronic inflammatory disease. Both inflammation and dysbiosis have been implicated in periodontitis development. However, the relationship between local inflammation and dysbiosis, and the precise roles of local inflammation in periodontitis are not well-elucidated. In present study, we explored the role of local inflammation in periodontitis. We established a periodontitis model by administration of Pam3CSK4 to local oral area and compared the difference of outcome between local and systemic administration. We monitored the pro-inflammatory cytokine expression, local inflammation and alveolar bone loss. We also evaluated the dysbiosis, NF-κB activation. Local but not systemic administration of Pam3CSK4-induced pro-inflammatory cytokines productions and finally resulted in periodontitis. Pam3CSK4 caused dysbiosis and promoted Porphyromonas gingivalis growth. The bacterial growth and NF-κB activation were required for Pam3CSK4-induced periodontitis. We evaluated the effect of local inflammation by inducing TLR2 activation on dysbiosis and periodontitis. Activation of local innate immune signal induces periodontitis in microbiota-dependent manner.


Assuntos
Imunidade Inata/fisiologia , Periodontite/metabolismo , Periodontite/microbiologia , Animais , Infecções por Bacteroidaceae , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Microbiota/fisiologia , NF-kappa B/metabolismo , Porphyromonas gingivalis/imunologia , Porphyromonas gingivalis/patogenicidade , Transdução de Sinais
11.
JCI Insight ; 4(13)2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31292292

RESUMO

Rheumatoid arthritis is linked with altered host immune responses and severe joint destruction. Recent evidence suggests that loss of gut homeostasis and barrier breach by pathobionts, including Porphyromonas gingivalis, may influence disease severity. The mechanism(s) leading to altered gut homeostasis and barrier breakdown in inflammatory arthritis are poorly understood. In the present study, we found a significant reduction in intestinal concentrations of several proresolving mediators during inflammatory arthritis, including downregulation of the gut-protective mediator resolvin D5n-3 DPA (RvD5n-3 DPA). This was linked with increased metabolism of RvD5n-3 DPA to its inactive 17-oxo metabolite. We also found downregulation of IL-10 expression in the gut of arthritic mice that was coupled with a reduction in IL-10 and IL-10 receptor (IL-10R) in lamina propria macrophages. These changes were linked with a decrease in the number of mucus-producing goblet cells and tight junction molecule expression in the intestinal epithelium of arthritic mice when compared with naive mice. P. gingivalis inoculation further downregulated intestinal RvD5n-3 DPA and Il-10 levels and the expression of gut tight junction proteins. RvD5n-3 DPA, but not its metabolite 17-oxo-RvD5n-3 DPA, increased the expression of both IL-10 and IL-10R in macrophages via the upregulation of the aryl hydrocarbon receptor agonist l-kynurenine. Administration of RvD5n-3 DPA to arthritic P. gingivalis-inoculated mice increased intestinal Il-10 expression, restored gut barrier function, and reduced joint inflammation. Together, these findings uncover mechanisms in the pathogenesis of rheumatoid arthritis, where disruption of the gut RvD5n-3 DPA-IL-10 axis weakens the gut barrier, which becomes permissive to the pathogenic actions of the pathobiont P. gingivalis.


Assuntos
Artrite Reumatoide/imunologia , Translocação Bacteriana/imunologia , Microbioma Gastrointestinal/imunologia , Mucosa Intestinal/patologia , Porphyromonas gingivalis/imunologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/microbiologia , Artrite Reumatoide/microbiologia , Ácidos Docosa-Hexaenoicos/imunologia , Ácidos Docosa-Hexaenoicos/metabolismo , Regulação para Baixo , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Porphyromonas gingivalis/patogenicidade , Receptores de Interleucina-10/imunologia , Receptores de Interleucina-10/metabolismo , Organismos Livres de Patógenos Específicos
12.
Curr Opin Rheumatol ; 31(5): 517-524, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31268867

RESUMO

PURPOSE OF REVIEW: To explore the pathogenic association between periodontal disease and rheumatoid arthritis focusing on the role of Porphyromonas gingivalis. RECENT FINDINGS: In the last decades our knowledge about the pathogenesis of rheumatoid arthritis substantially changed. Several evidences demonstrated that the initial production of autoantibodies is not localized in the joint, rather in other immunological-active sites. A central role seems to be played by periodontal disease, in particular because of the ability of P. gingivalis to induce citrullination, the posttranslational modification leading to the production of anticitrullinated protein/peptide antibodies, the most sensitive and specific rheumatoid arthritis biomarker. SUMMARY: The pathogenic role of P. gingivalis has been demonstrated in mouse models in which arthritis was either triggered or worsened in infected animals. P. gingivalis showed its detrimental role not only by inducing citrullination but also by means of other key mechanisms including induction of NETosis, osteoclastogenesis, and Th17 proinflammatory response leading to bone damage and systemic inflammation.


Assuntos
Anticorpos Antibacterianos/imunologia , Artrite Reumatoide/etiologia , Autoanticorpos/imunologia , Infecções por Bacteroidaceae/complicações , Periodontite/complicações , Porphyromonas gingivalis/imunologia , Animais , Artrite Reumatoide/imunologia , Artrite Reumatoide/microbiologia , Infecções por Bacteroidaceae/imunologia , Infecções por Bacteroidaceae/microbiologia , Humanos , Periodontite/imunologia , Periodontite/microbiologia
13.
Int J Mol Sci ; 20(11)2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167516

RESUMO

It has been suggested that Porphyromonas gingivalis (P. gingivalis), a keystone pathogen in chronic periodontitis, is associated with a variety of cancers, including oral cancer. Recently, studies have shown the effects of persistent exposure to P. gingivalis on the promotion of tumorigenic properties of oral epithelial cells, suggesting that chronic P. gingivalis infection is a potential risk factor for oral cancer. On the other hand, Fusobacterium nucleatum (F. nucleatum), one of the major periodontal pathogens, has emerged as an important factor in the colon cancer progression. Here, we investigated the diagnostic potential of serum immunoglobulin G antibody against periodontal pathogens, P. gingivalis and F. nucleatum, and serum IL-6 for oral squamous cell carcinoma (OSCC). An enzyme-linked immunosorbent assay (ELISA) was used to determine and compare the serum levels of interleukin 6 (IL-6), F. nucleatum IgG, and P. gingivalis IgG in 62 OSCC patients with 46 healthy controls. The serum levels of P. gingivalis IgG and IL-6 were higher in OSCC patients than in non-OSCC controls, and the difference was statistically significant. In addition, a high serum level of IL-6 was associated with a worse prognosis in OSCC patients. Thus, P. gingivalis IgG and IL-6 could be utilized as potential serum biomarkers for the diagnosis of OSCC, and the serum level of IL-6 contributes to improved prognostic performance.


Assuntos
Anticorpos Antibacterianos/imunologia , Biomarcadores , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/metabolismo , Interleucina-6/sangue , Neoplasias Bucais/etiologia , Neoplasias Bucais/metabolismo , Porphyromonas gingivalis/imunologia , Anticorpos Antibacterianos/sangue , Infecções por Bacteroidaceae/microbiologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Humanos , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Curva ROC
14.
Metallomics ; 11(7): 1207-1218, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31179464

RESUMO

Periodontitis is the leading cause of severe tooth loss and edentulism in adults worldwide and is closely linked to systemic conditions such as diabetes and cardiovascular disease. Porphyromonas gingivalis is the key pathogen in periodontitis. Herein, we provided the first evidence that bismuth drugs suppress P. gingivalis in its planktonic, biofilm, and intracellular states. In total, 42 bismuth-associated proteins were identified including its major virulent factors (e.g., gingipains, hemagglutinin HagA, and fimbriae). Bismuth perturbed its iron acquisition, disturbed the energy metabolism and virulence, and deactivated multiple key enzymes (e.g., superoxide dismutase and thioredoxins). Moreover, bismuth inhibited its biofilm formation and disrupted the 3-day matured biofilms. Notably, the internalized P. gingivalis in various human cells (e.g., human gingival epithelium progenitors, HGEPs) was oppressed by bismuth but not the commonly used antibiotic metronidazole. Importantly, bismuth drugs enabled the counteraction of immuno-inflammatory responses in different host cells perturbed by P. gingivalis. The production of IL-6 and IL-8 attenuated by P. gingivalis in both of native and IL-1ß-stimulated HGEPs was restored, while the bacterium-enhanced expression of IL-6, IL-1ß, and TNFα in THP-1 macrophages was alleviated. This proof-of-concept study brings prospects for the potential reposition of the routinely used anti-Helicobacter pylori bismuth drugs to better manage inflammatory diseases such as periodontitis and P. gingivalis-related complex systemic disorders.


Assuntos
Antibacterianos/farmacologia , Infecções por Bacteroidaceae/tratamento farmacológico , Bismuto/farmacologia , Citocinas/imunologia , Periodontite/tratamento farmacológico , Porphyromonas gingivalis/efeitos dos fármacos , Proteínas de Bactérias/imunologia , Infecções por Bacteroidaceae/imunologia , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Linhagem Celular , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Periodontite/imunologia , Porphyromonas gingivalis/imunologia , Porphyromonas gingivalis/fisiologia
15.
Int J Mol Sci ; 20(10)2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117164

RESUMO

Chemotherapy is not a first-line therapy for oral squamous cell carcinoma (OSCC), which is the most common type of oral cancer, because most OSCC shows resistance to chemotherapeutic reagents. Inflammatory signals are suggested to be associated with chemoresistance as well as carcinogenesis in many different cancers, and thus chronic periodontitis, the most common chronic inflammatory disease of the oral cavity, could modulate responsiveness to chemotherapeutic agents used against oral cancer. This study was performed to define the role of chronic periodontitis in oral cancer progression and to determine the responsiveness of oral cancer to a chemotherapeutic reagent. First, we quantified the tumor growth rate and changes in serum cytokine profiles of mice administered Porphyromonas gingivalis, a major pathogen of chronic periodontitis. Compared with uninfected mice, the mice that were chronically administered P. gingivalis showed increased resistance to paclitaxel and a decreased tumor growth rate. In addition, P. gingivalis-treated mice exhibited higher serum levels of interleukin-6 (IL-6) than uninfected mice. Furthermore, the sensitivity of tumor xenografts to paclitaxel in mice administered P. gingivalis was dramatically increased when the mice were administered ibuprofen, an anti-inflammatory drug which supports the modulatory effect of periodontal pathogen-induced inflammation in chemoresistance.


Assuntos
Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/fisiopatologia , Resistencia a Medicamentos Antineoplásicos , Inflamação/complicações , Porphyromonas gingivalis/imunologia , Administração Oral , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/microbiologia , Linhagem Celular Tumoral , Humanos , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Masculino , Camundongos , Paclitaxel/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Front Immunol ; 10: 933, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114581

RESUMO

BET bromodomain proteins are important epigenetic regulators of gene expression that bind acetylated histone tails and regulate the formation of acetylation-dependent chromatin complexes. BET inhibitors suppress inflammatory responses in multiple cell types and animal models, and protect against bone loss in experimental periodontitis in mice. Here, we analyzed the role of BET proteins in inflammatory activation of gingival fibroblasts (GFs) and gingival epithelial cells (GECs). We show that the BET inhibitors I-BET151 and JQ1 significantly reduced expression and/or production of distinct, but overlapping, profiles of cytokine-inducible mediators of inflammation and bone resorption in GFs from healthy donors (IL6, IL8, IL1B, CCL2, CCL5, COX2, and MMP3) and the GEC line TIGK (IL6, IL8, IL1B, CXCL10, MMP9) without affecting cell viability. Activation of mitogen-activated protein kinase and nuclear factor-κB pathways was unaffected by I-BET151, as was the histone acetylation status, and new protein synthesis was not required for the anti-inflammatory effects of BET inhibition. I-BET151 and JQ1 also suppressed expression of inflammatory cytokines, chemokines, and osteoclastogenic mediators in GFs and TIGKs infected with the key periodontal pathogen Porphyromonas gingivalis. Notably, P. gingivalis internalization and intracellular survival in GFs and TIGKs remained unaffected by BET inhibitors. Finally, inhibition of BET proteins significantly reduced P. gingivalis-induced inflammatory mediator expression in GECs and GFs from patients with periodontitis. Our results demonstrate that BET inhibitors may block the excessive inflammatory mediator production by resident cells of the gingival tissue and identify the BET family of epigenetic reader proteins as a potential therapeutic target in the treatment of periodontal disease.


Assuntos
Azepinas/farmacologia , Células Epiteliais , Fibroblastos , Gengiva , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Periodontite/tratamento farmacológico , Porphyromonas gingivalis/imunologia , Triazóis/farmacologia , Animais , Citocinas/imunologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Células Epiteliais/patologia , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Fibroblastos/imunologia , Fibroblastos/microbiologia , Fibroblastos/patologia , Gengiva/imunologia , Gengiva/microbiologia , Gengiva/patologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia , Camundongos , Periodontite/imunologia , Periodontite/patologia
17.
PLoS Pathog ; 15(5): e1007773, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31107907

RESUMO

Neutrophil-derived networks of DNA-composed extracellular fibers covered with antimicrobial molecules, referred to as neutrophil extracellular traps (NETs), are recognized as a physiological microbicidal mechanism of innate immunity. The formation of NETs is also classified as a model of a cell death called NETosis. Despite intensive research on the NETs formation in response to pathogens, the role of specific bacteria-derived virulence factors in this process, although postulated, is still poorly understood. The aim of our study was to determine the role of gingipains, cysteine proteases responsible for the virulence of P. gingivalis, on the NETosis process induced by this major periodontopathogen. We showed that NETosis triggered by P. gingivalis is gingipain dependent since in the stark contrast to the wild-type strain (W83) the gingipain-null mutant strain only slightly induced the NETs formation. Furthermore, the direct effect of proteases on NETosis was documented using purified gingipains. Notably, the induction of NETosis was dependent on the catalytic activity of gingipains, since proteolytically inactive forms of enzymes showed reduced ability to trigger the NETs formation. Mechanistically, gingipain-induced NETosis was dependent on proteolytic activation of protease-activated receptor-2 (PAR-2). Intriguingly, both P. gingivalis and purified Arg-specific gingipains (Rgp) induced NETs that not only lacked bactericidal activity but instead stimulated the growth of bacteria species otherwise susceptible to killing in NETs. This protection was executed by proteolysis of bactericidal components of NETs. Taken together, gingipains play a dual role in NETosis: they are the potent direct inducers of NETs formation but in the same time, their activity prevents P. gingivalis entrapment and subsequent killing. This may explain a paradox that despite the massive accumulation of neutrophils and NETs formation in periodontal pockets periodontal pathogens and associated pathobionts thrive in this environment.


Assuntos
Adesinas Bacterianas/imunologia , Infecções por Bacteroidaceae/imunologia , Cisteína Endopeptidases/imunologia , Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , Peritonite/imunologia , Porphyromonas gingivalis/imunologia , Porphyromonas gingivalis/patogenicidade , Receptor PAR-2/metabolismo , Adesinas Bacterianas/metabolismo , Animais , Infecções por Bacteroidaceae/metabolismo , Infecções por Bacteroidaceae/microbiologia , Infecções por Bacteroidaceae/patologia , Células Cultivadas , Cisteína Endopeptidases/metabolismo , Armadilhas Extracelulares/microbiologia , Feminino , Cisteína Endopeptidases Gingipaínas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/microbiologia , Neutrófilos/patologia , Peritonite/metabolismo , Peritonite/microbiologia , Receptor PAR-2/imunologia , Transdução de Sinais
18.
Int J Mol Sci ; 20(8)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022963

RESUMO

Tet-eleven translocation 1 (TET1) is a dioxygenase that plays an important role in decreasing the abundance of DNA methylation and changing the expression levels of specific genes related to inflammation. Porphyromonas gingivalis (Pg.) lipopolysaccharide (LPS) can induce periodontal diseases that present with severe bone loss and collagen fiber destruction accompanied by a high number of M1 macrophages. M1-polarized macrophages are pivotal immune cells that promote the progression of the periodontal inflammatory response, but the function of TET1 during M1 macrophage activation is still unknown. Our results showed that the mRNA and protein expression levels of TET1 decreased in THP-1 cells during M1 macrophage differentiation. TET1 knockdown resulted in a significant decrease in the production of proinflammatory markers such as IL-6, TNF-α, CCL2, and HLA-DR in Pg. LPS/IFN-γ- and Escherichia coli (E. coli) LPS/IFN-γ-induced M1 macrophages. Mechanistically, TET1 knockdown downregulated the activity of the NF-κB signaling pathway. After treatment with the NF-κB inhibitor BAY 11-7082, M1 marker expression showed no significant difference between the TET1 knockdown group and the control group. Taken together, these results suggest that TET1 depletion inhibited Pg. LPS/IFN-γ-induced M1 macrophage polarization through the NF-κB pathway in THP-1 cells.


Assuntos
Interferon gama/imunologia , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Oxigenases de Função Mista/genética , NF-kappa B/imunologia , Porphyromonas gingivalis/imunologia , Proteínas Proto-Oncogênicas/genética , Técnicas de Silenciamento de Genes , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Ativação de Macrófagos , Macrófagos/microbiologia , Oxigenases de Função Mista/imunologia , Proteínas Proto-Oncogênicas/imunologia , Transdução de Sinais , Células THP-1
19.
Angiology ; 70(6): 479-491, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30596254

RESUMO

There is some evidence that periodontitis increases the risk of atherothrombosis. Abdominal aortic aneurysm (AAA) is a cardiovascular disease with specific risk factors and physiopathological mechanisms that can lead to rupture in the absence of treatment. The aim of the present systematic review was to explore the influence of periodontitis on the progression of AAAs as a specific disease. A systematic search in PubMed/MEDLINE and Embase databases was performed. Human and animal studies exploring the influence of periodontal pathogens on the progression of AAA were considered for inclusion. After systematic screening, 5 articles were included in the review. Due to the heterogeneity of the selected studies, a meta-analysis could not be performed. The descriptive analyses of the studies emphasized that periodontal pathogens or their by-products contribute to systemic and local innate immunity likely to be associated with AAA physiopathology. Periodontitis seems to play a role in the development and progression of AAA. The present systematic review suggests that the presence of periodontal bacteria in the bloodstream or in situ in the vascular lesion is a risk associated with aneurysmal disease progression.


Assuntos
Aneurisma da Aorta Abdominal/microbiologia , Placa Dentária/microbiologia , Periodontite/microbiologia , Porphyromonas gingivalis/patogenicidade , Animais , Aneurisma da Aorta Abdominal/epidemiologia , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/fisiopatologia , Placa Dentária/imunologia , Progressão da Doença , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Periodontite/epidemiologia , Periodontite/imunologia , Porphyromonas gingivalis/imunologia , Prognóstico , Fatores de Risco
20.
J Periodontal Res ; 54(2): 115-127, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30284741

RESUMO

BACKGROUND AND OBJECTIVE: Although previous studies revealed the potential use of probiotics in the control of periodontitis, little is known about their interactions with gingival epithelial cells (GECs). Since GECs comprise the first defense in the subgingival microenvironment, the aim of this study was to evaluate the effect of probiotic lactobacilli and bifidobacteria strains on OBA-9 cells challenged with Porphyromonas gingivalis. METHODS: Immortalized human GECs (OBA-9) were challenged with live P. gingivalis (strains W83 and ATCC33277) and co-infected with one of 12 tested probiotic strains at a multiplicity of infection (MOI) of 1:1000 for 2 hours. Bacterial adhesion and invasion were determined by antibiotic exclusion analysis and CFU counting. OBA-9 viability was assessed by MTT assay, and levels of inflammatory mediators (TNF-α, IL-1ß, and CXCL8) in the supernatants were determined by ELISA. The expression of genes encoding Toll-like receptors (TLR2, TLR4) was evaluated by RT-qPCR. RESULTS: Both strains of P. gingivalis were able to adhere and invade OBA-9 cells, with significant loss in cell viability, increase in the levels of TNF-α and IL-1ß, and upregulation of TLR4. However, co-infection with probiotics attenuated these effects in P. gingivalis challenged GECs. Most probiotics maintained OBA-9 viability and reduced pathogens adhesion and invasion. Furthermore, probiotics were able to adhere to GECs, which was enhanced for most strains in the presence of P. gingivalis. The synthesis of IL-1ß and TNF-α by P. gingivalis in challenged GECs was reduced in co-culture with most of the tested probiotics, whereas the secretion of CXCL8 increased, and TLR4 was downregulated. CONCLUSION: Probiotics can alter the interaction of GECs with P. gingivalis by modulating the pathogen's ability to adhere and invade these cells, as well as by regulating the innate immune response. Such properties are strain-specific and may indicate the most efficient probiotics to control periodontitis.


Assuntos
Antibiose/imunologia , Bifidobacterium/fisiologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Gengiva/citologia , Gengiva/imunologia , Imunidade Inata , Lactobacillus/fisiologia , Periodontite/prevenção & controle , Periodontite/terapia , Porphyromonas gingivalis/imunologia , Porphyromonas gingivalis/patogenicidade , Probióticos , Células Cultivadas , Microambiente Celular/imunologia , Humanos , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Periodontite/imunologia , Periodontite/microbiologia , Porphyromonas gingivalis/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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