RESUMO
Anticardiolipin antibodies, found at elevated serum concentrations in 15% to 20% of individuals with periodontitis, are associated with adverse pregnancy outcomes, thrombotic conditions, and accelerated atherosclerosis in autoimmune disease such as the antiphospholipid syndrome. Our previous studies demonstrated that antibodies raised in mice against Porphyromonas gingivalis caused fetal loss in a mouse pregnancy model due to anticardiolipin antibodies. Such antibodies are induced via molecular mimicry with the serum protein ß2-glycoprotein 1 (ß2GP1), the target antigen of anticardiolipin. Furthermore, human anticardiolipin IgG is associated with increased serum markers of vascular inflammation, and IgG purified from periodontitis subjects with elevated anticardiolipin stimulates inflammatory cytokine production by endothelial cells and a trophoblastic cell line. Activation of the trophoblastic cells by anticardiolipin occurs through Toll-like receptor 4. In the present study, we observed that IgG anticardiolipin from periodontitis subjects also causes fetal loss in mice. Displacement of the protective 2-dimensional lattice formed by annexin V on trophoblast surfaces by anticardiolipin, via its interaction with its target antigen ß2GP1, leading to fibrin clot formation due to exposure of anionic phospholipids to plasma, is a plausible pathogenic mechanism explaining adverse obstetrical outcomes in antiphospholipid syndrome. Therefore, we assessed such interactions in periodontitis. We observed that anticardiolipin from periodontitis subjects competes for annexin V on an artificial phosphatidylserine monolayer, replicating a key activity of autoantibodies found in patients with antiphospholipid syndrome. In addition, we found that anticardiolipin from periodontitis subjects increases annexin V levels on the BeWo choriocarcinoma cell line, consistent with mobilization of annexin V to the cell surface to facilitate repair following membrane damage. The data indicate that sera and IgG from periodontitis subjects with elevated anticardiolipin levels may influence pregnancy outcomes due to interactions with annexin V.
Assuntos
Periodontite , Adulto , Animais , Anexina A5 , Anticorpos Anticardiolipina , Células Endoteliais , Feminino , Humanos , Camundongos , Gravidez , beta 2-Glicoproteína IRESUMO
Interrelationships between periodontal infection and systemic conditions such as cardiovascular disease, adverse pregnancy outcomes, and head-and-neck cancer have become increasingly appreciated in recent years. Periodontitis is associated with cardiovascular disease (CVD) and, experimentally, with measures of atherosclerosis and endothelial dysfunction. Periodontal therapy may reduce atherosclerotic changes and improve endothelial function. Preliminary findings suggest a role for the genetic locus ANRIL in the pathobiology of both CVD and periodontitis. Periodontal pathogens induce anticardiolipin in periodontitis patients by molecular mimicry of the serum protein ß-2 glycoprotein I. These antibodies have biological and pathological activities consistent with those reported for other infection-induced antiphospholipid antibodies. Anticardiolipin may explain some of the observed associations between periodontitis and systemic conditions such as CVD and adverse pregnancy outcomes. The oral commensal Fusobacterium nucleatum (Fn) becomes pathogenic on migration to extra-oral sites. Fn infection of the fetal-placental unit has been linked to pregnancy complications, including preterm birth, stillbirth, and early-onset neonatal sepsis. Reagents aimed at inhibiting or resolving inflammatory responses may be used to treat or prevent pregnancy complications due to bacterial infection. Chronic periodontitis may be independently associated with head-and-neck squamous cell carcinoma (HNSCC) through direct toxic effects of bacteria and their products, and/or through indirect effects of inflammation. Additionally, chronic periodontitis may facilitate the acquisition and persistence of oral HPV infection, a recently emerged risk factor for HNSCC.
Assuntos
Aterosclerose/complicações , Neoplasias de Cabeça e Pescoço/complicações , Doenças Periodontais/complicações , Resultado da Gravidez , Feminino , Humanos , GravidezRESUMO
ß2-glycoprotein I (ß2GPI)-dependent anticardiolipin autoantibodies (aCl) are associated with thrombosis and fetal loss. Some microbial pathogens can induce pathogenic antibodies cross-reactive with ß2GPI. Sera from a significant percentage of periodontitis patients contain aCl, and some periodontal pathogens contain antigens with peptide sequences having homology to ß2GPI. We hypothesized that antibodies raised against P. gingivalis (aPg) contain pathogenic aCl that induce fetal resorption. We immunized mice with ß2GPI, P. gingivalis W83, or an arg-gingipain-defective mutant of P. gingivalis (HF18). IgG fractions of aPg were immunoabsorbed to remove aCl-like antibodies (abs-aPg). IgG fractions were administered intravenously into tail veins of mated BALB/c females at day 0 of pregnancy. At day 15, the proportions of fetal resorptions were evaluated. The prevalence of fetal loss was significantly greater in the aPg group than in the control IgG group (21.2% vs. 5.3%, p = .001), and greater in the aPg group than in the abs-aPg group (21.2% vs. 12%, p < .05). There were no fetal resorptions observed in the aPgHF18 group (p = .0005 compared with aPg, p = .17 compared with control). aPg antibody contains activity consistent with pathogenic aCl, and the antigen inducing the antibodies that cause increased fetal loss may be on the arg-gingipain protease of P. gingivalis.
Assuntos
Anticorpos Anticardiolipina/imunologia , Reabsorção do Feto/etiologia , Fatores Imunológicos/imunologia , Porphyromonas gingivalis/imunologia , Adesinas Bacterianas/genética , Animais , Anticorpos Antibacterianos/imunologia , Anticoagulantes/imunologia , Reações Cruzadas/imunologia , Cisteína Endopeptidases/genética , Feminino , Cisteína Endopeptidases Gingipaínas , Hemaglutininas/genética , Imunização , Imunoglobulina G/imunologia , Técnicas de Imunoadsorção , Camundongos , Camundongos Endogâmicos BALB C , Mutação/genética , Gravidez , Homologia de Sequência de Aminoácidos , beta 2-Glicoproteína I/imunologiaRESUMO
Periodontitis appears to promote chronic inflammatory diseases, including atherosclerosis, but relevant mechanisms need clarification. Oral bacteria induce antibodies that bind not only bacteria, but also oxLDL. Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans induce remarkable IgG responses that are dominated by IgG2, and IgG2 is IFN-γ-dependent and is promoted by dendritic cells (DCs). LDL-reactive antibodies induced by P. gingivalis and A. actinomycetemcomitans include anti-phosphorylcholine (α-PC) and ß2-glycoprotein-1-dependent anticardiolipin (α-CL), and these antibodies may link chronic inflammatory diseases at a mechanistic level. Antibody-mediated uptake of oxLDL or bacteria dramatically enhances DC-IL-12, and DC-IL-12 induces NK-cell-IFN-γ responses that promote Th-1 responses and sustained inflammation. DCs may be derived from monocytes, and this is striking in cultures of aggressive periodontitis (AgP) monocytes, where DC numbers are about double control levels. Moreover, serum α-CL levels in individuals with AgP are frequently elevated, and these antibodies promote atherosclerosis in persons with antiphospholipid syndrome. Elevated serum levels of soluble-intercellular adhesion molecule, soluble-vascular cell adhesion molecule, and soluble-E-selectin are atherosclerosis-associated indicators of vascular inflammation, and these markers are elevated in the subset of AgP patients with high α-CL. We reason that periodontitis patients with elevated antibodies reactive with oxLDL could be a subgroup at high risk for cardiovascular sequelae.
Assuntos
Periodontite Agressiva/imunologia , Periodontite Crônica/imunologia , Células Dendríticas/imunologia , Lipoproteínas LDL/imunologia , Vasculite/imunologia , Aggregatibacter actinomycetemcomitans/imunologia , Periodontite Agressiva/complicações , Periodontite Agressiva/microbiologia , Anticorpos Anticardiolipina/sangue , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/imunologia , Aterosclerose/imunologia , Periodontite Crônica/complicações , Periodontite Crônica/microbiologia , Citocinas/biossíntese , Células Dendríticas/metabolismo , Humanos , Imunoglobulina G/imunologia , Mediadores da Inflamação/metabolismo , Células Matadoras Naturais/imunologia , Porphyromonas gingivalis/imunologia , Fatores de Risco , Molécula 1 de Adesão de Célula Vascular/imunologia , Vasculite/etiologiaRESUMO
BACKGROUND AND OBJECTIVE: Periodontitis is a multifactorial disease influenced partly by genetics. Activation of pattern recognition receptors (PRRs) can lead to the up-regulation of inflammatory pathways, resulting in periodontal tissue destruction. Hence, functional polymorphisms located in PRRs can explain differences in host susceptibility to periodontitis. This study investigated single nucleotide polymorphisms of PRRs including toll-like receptor (TLR)2 (G2408A), TLR4 (A896G), TLR9 (T1486C), TLR9 (T1237C) and CD14 (C260T) in patients with chronic periodontitis and in periodontally healthy subjects. METHODS: One-hundred and fourteen patients with chronic periodontitis and 77 periodontally healthy subjects were genotyped using TaqMan® allelic discrimination assays. Fisher's exact test and chi-square analyses were performed to compare genotype and allele frequencies. RESULTS: The frequency of subjects with the CC genotype of CD14 (C260T) (24.6% in the chronic periodontitis group vs. 13% in the periodontally healthy group) and those expressing the T allele of CD14 (C260T) (CT and TT) (75.4% in the chronic periodontitis group vs. 87% in the periodontally healthy group) was statistically different among groups (p = 0.04). Homozygocity for the C allele of the CD14 (C260T) polymorphism (CC) was associated with a two--fold increased susceptibility to periodontitis (p = 0.04; odds ratio, 2.49; 95% confidence interval, 1.06-6.26). Individuals with the CC genotype of TLR9 (T1486C) (14.9% in the chronic periodontitis group vs. 28.6% in the periodontally healthy group) and those expressing the T allele of TLR9 (T1486C) (CT and TT) (85.1% in the chronic periodontitis group vs. 71.4% in the periodontally healthy group) were also significantly differently distributed between groups without adjustment (p = 0.03). Further analysis of nonsmokers revealed a significant difference in the distribution of genotypes between groups for TLR9 (T1486C; p = 0.017) and CD14 (C260T; p = 0.03), polymorphisms again without adjustment. CONCLUSION: The CC genotype of CD14 (C260T) is related to susceptibility to chronic periodontitis in Caucasians. In addition, differences observed in the distribution of TLR9 (T1486C) genotypes between groups warrant further investigation.
Assuntos
Periodontite Crônica/genética , Receptores de Lipopolissacarídeos/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Toll-Like/genética , Adenina , Citosina , Índice de Placa Dentária , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Guanina , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Perda da Inserção Periodontal/genética , Índice Periodontal , Bolsa Periodontal/genética , Fumar , Timina , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Receptor Toll-Like 9/genéticaRESUMO
BACKGROUND AND OBJECTIVE: Epidemiological and animal studies suggest that periodontal infections increase atherosclerosis risk. Periodontitis patients have elevated levels of anti-phosphorylcholine (anti-PC) reactive not only with numerous periodontal organisms but also with minimally modified low-density lipoprotein (mmLDL). Dendritic cells (DCs) reside in arterial walls and accumulate in atherosclerotic lesions. The ability of anti-PC to bind mmLDL prompted the hypothesis that opsonized mmLDL would stimulate DCs and enhance the production of proinflammatory cytokines that promote atherogenic plaque development. MATERIAL AND METHODS: Monocyte-derived DCs (mDCs) were generated using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, then stimulated with mmLDL or with anti-PC-opsonized mmLDL. The anti-PC effect was determined using flow cytometry, cofocal microscopy and cytokine assays. The production of CD83, IL-12p35 mRNA, IL-12p40 mRNA, IL-12p70 and IL-10 by DCs was monitored. RESULTS: Dendritic cells stimulated with mmLDL expressed little CD83 and produced little IL-12p70. However, anti-PC-opsonized mmLDL enhanced DC maturation, as indicated by upregulated CD83 and rapid (≤ 48 h) production of IL-12p70 if a source of interferon-γ (IFN-γ) was available. In leukocyte cultures, natural killer (NK) cells rapidly produced IFN-γ (≤ 48 h) when interacting with IL-12-producing DCs activated by anti-PC-opsonized mmLDL. Moreover, IFN-γ promoted DC IL-12 responses that were further augmented when mmLDL was opsonized with anti-PC. CONCLUSION: Minimally modified LDL-stimulated DCs and NK cells were mutually stimulatory, with DC IL-12p70 needed by NK cells and with NK cell IFN-γ needed by DCs. Moreover, production of these proinflammatory cytokines was markedly enhanced when LDL was opsonized by anti-PC. In short, the data suggest that the elevated anti-PC levels in periodontitis patients could promote a mechanism that facilitates atherosclerosis.
Assuntos
Citocinas/biossíntese , Células Dendríticas/metabolismo , Células Matadoras Naturais/metabolismo , Lipoproteínas LDL/imunologia , Proteínas Opsonizantes/imunologia , Fosforilcolina/imunologia , Aggregatibacter actinomycetemcomitans , Análise de Variância , Anticorpos , Antígenos CD/biossíntese , Aterosclerose/etiologia , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/imunologia , Humanos , Imunoglobulinas/biossíntese , Mediadores da Inflamação/metabolismo , Interferon gama/metabolismo , Subunidade p35 da Interleucina-12/biossíntese , Subunidade p40 da Interleucina-12/biossíntese , Células Matadoras Naturais/imunologia , Glicoproteínas de Membrana/biossíntese , Porphyromonas gingivalis , Estatísticas não Paramétricas , Antígeno CD83RESUMO
Interleukin-17 (IL-17), the prototype cytokine produced by the Th17 subset of T-helper cells, plays a role in inflammatory responses, autoimmunity, and antimicrobial responses in a variety of infectious and inflammatory diseases. In view of the inflammatory nature and severity of aggressive periodontitis, we hypothesized that IL-17 might be detected in sera from patients with aggressive periodontitis. We used ELISA to measure IL-17 serum concentrations from 67 periodontally healthy (NP) individuals and from 53 patients with localized (LAgP) and 49 patients with generalized (GAgP) aggressive periodontitis. IL-17 was barely detectable in sera from periodontally healthy individuals (1.9 +/- 2.0 pg/mL), but was present at significantly higher concentrations in sera from those with LAgP (7.6 +/- 2.2 pg/mL) and GAgP (17.1 +/- 2.3 pg/mL). Multivariate analyses demonstrated associations of IL-17 concentrations with periodontal attachment loss, but not with current smoking. Therefore, Th17 responses may be characteristic of AgP, and IL-17 may play a role in the pathogenesis of aggressive periodontitis.
Assuntos
Periodontite Agressiva/sangue , Periodontite Agressiva/imunologia , Interleucina-17/sangue , Análise de Variância , População Negra , Estudos de Casos e Controles , Feminino , Gengiva/imunologia , Humanos , Masculino , Perda da Inserção Periodontal/sangue , Índice Periodontal , Análise de Regressão , Linfócitos T Auxiliares-Indutores/imunologia , Adulto JovemRESUMO
Toll-like receptor 9 (TLR9) expression is increased in periodontally diseased tissues compared with healthy sites indicating a possible role of TLR9 and its ligand, bacterial DNA (bDNA), in periodontal disease pathology. Here, we determine the immunostimulatory effects of periodontal bDNA in human monocytic cells (THP-1). THP-1 cells were stimulated with DNA of two putative periodontal pathogens: Porphyromonas gingivalis and Tannerella forsythia. The role of TLR9 in periodontal bDNA-initiated cytokine production was determined either by blocking TLR9 signaling in THP-1 cells with chloroquine or by measuring IL-8 production and nuclear factor-kappaB (NF-kappaB) activation in HEK293 cells stably transfected with human TLR9. Cytokine production (IL-1beta, IL-6, and TNF-alpha) was increased significantly in bDNA-stimulated cells compared with controls. Chloroquine treatment of THP-1 cells decreased cytokine production, suggesting that TLR9-mediated signaling pathways are operant in the recognition of DNA from periodontal pathogens. Compared with native HEK293 cells, TLR9-transfected cells demonstrated significantly increased IL-8 production (P < 0.001) and NF-kappaB activation in response to bDNA, further confirming the role of TLR9 in periodontal bDNA recognition. The results of PCR arrays demonstrated upregulation of proinflammatory cytokine and NF-kappaB genes in response to periodontal bDNA in THP-1 cells, suggesting that cytokine induction is through NF-kappaB activation. Hence, immune responses triggered by periodontal bacterial nucleic acids may contribute to periodontal disease pathology by inducing proinflammatory cytokine production through the TLR9 signaling pathway.
Assuntos
Bacteroides/imunologia , Citocinas/biossíntese , DNA Bacteriano/imunologia , Porphyromonas gingivalis/imunologia , Receptor Toll-Like 9/fisiologia , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Rim/citologia , Rim/embriologia , Monócitos/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Transfecção , Fator de Necrose Tumoral alfa/biossínteseRESUMO
BACKGROUND AND OBJECTIVE: Certain types of chronic infection increase the plasma level of very-low-density lipoprotein, leading to formation of the particularly atherogenic low-density lipoprotein subclass, small dense low-density lipoprotein. In the present study, we examined whether aggressive forms of periodontitis are associated with these atherogenic lipoprotein parameters. MATERIAL AND METHODS: Twelve healthy control subjects without periodontitis, 12 subjects with localized aggressive periodontitis and 12 subjects with generalized aggressive periodontitis were studied. Lipoprotein subclass levels were determined using nuclear magnetic resonance methodology. RESULTS: Healthy control subjects, localized aggressive periodontitis subjects and generalized aggressive periodontitis subjects had progressively higher plasma levels of very-low-density lipoprotein and progressively smaller average low-density lipoprotein size (p < 0.05, one-way analysis of variance). In pairwise comparisons, differences were only significant between healthy controls and generalized aggressive periodontitis subjects (p < 0.05, Tukey's post test). After adjustment for body mass index, the mean periodontal pocket depth correlated positively with plasma very-low-density lipoprotein levels (p = 0.047). Very-low-density lipoprotein concentrations correlated positively with small dense low-density lipoprotein levels and negatively with average low-density lipoprotein size. Prevalence of the atherogenic lipoprotein pattern-B in healthy controls, localized aggressive periodontitis subjects and generalized aggressive periodontitis subjects was 8.3%, 33.3% and 66.6%, respectively. CONCLUSION: These results indicate that periodontal infection is associated with elevated plasma levels of atherogenic lipoprotein species. This association may account for the increased risk of periodontitis patients for cardiovascular disease.
Assuntos
Aterosclerose/sangue , Lipoproteínas VLDL/sangue , Periodontite/sangue , Doença Aguda , Adulto , Análise de Variância , Aterosclerose/complicações , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Perda da Inserção Periodontal/sangue , Periodontite/complicações , Análise de RegressãoRESUMO
BACKGROUND AND OBJECTIVE: Platelet-activating factor is elevated in localized aggressive periodontitis. We previously demonstrated that the elevated level of platelet-activating factor in localized aggressive periodontitis is at least partially attributable to low levels of platelet-activating factor acetylhydrolase, the enzyme that catabolizes platelet-activating factor. The objective of this study was to determine if platelet-activating factor synthesis was also elevated in localized aggressive periodontitis. To test this, platelet-activating factor synthesis was quantified in the monocytes and polymorphonuclear neutrophils of periodontally healthy patients and of subjects with localized aggressive periodontitis. MATERIAL AND METHODS: Cells were labeled with [(3)H]acetate and treated with vehicle or stimulated with calcium ionophore A23187. Platelet-activating factor was extracted and quantified by scintillation counting. RESULTS: For both subject groups, resting monocytes and polymorphonuclear neutrophils produced platelet-activating factor, and calcium ionophore A23187 stimulated platelet-activating factor production in both cell types. However, calcium ionophore A23187-activated monocytes from subjects with localized aggressive periodontitis produced less platelet-activating factor than did activated periodontally healthy monocytes (p < 0.0001), suggesting an aberrant calcium ionophore A23187 response in monocytes from subjects with localized aggressive periodontitis. Indeed, when the data were expressed as fold induction of platelet-activating factor synthesis in response to calcium ionophore A23187, monocytes from subjects with localized aggressive periodontitis exhibited only a fourfold increase in platelet-activating factor synthesis, whereas calcium ionophore A23187-stimulated monocytes from periodontally healthy, chronic periodontitis and generalized aggressive periodontitis subjects produced approximately 12 times more platelet-activating factor than did resting monocytes. In contrast, both resting and activated localized aggressive periodontitis polymorphonuclear neutrophils synthesized more platelet-activating factor than did periodontally healthy polymorphonuclear neutrophils. CONCLUSION: These data suggest that high levels of platelet-activating factor in subjects with localized aggressive periodontitis result from both increased synthesis and reduced catabolism. While localized aggressive periodontitis polymorphonuclear neutrophils contribute to increased platelet-activating factor mass through synthesis, the contribution of monocytes is probably the result of reduced catabolism by platelet-activating factor acetylhydrolase.
Assuntos
Monócitos/metabolismo , Neutrófilos/metabolismo , Periodontite/metabolismo , Fator de Ativação de Plaquetas/biossíntese , Adulto , Análise de Variância , Animais , Calcimicina/metabolismo , Estudos de Casos e Controles , Bovinos , Intervalos de Confiança , Humanos , Fator de Ativação de Plaquetas/análiseRESUMO
OBJECTIVE: High levels of serum anti-Actinobacillus actinomycetemcomitans immunoglobulin G (IgG) correlate with reduced extent and severity of periodontal disease and the present study was undertaken to begin testing the hypothesis that proinflammatory cytokines are important in the induction of optimal anti-A. actinomycetemcomitans IgG responses. BACKGROUND: Studies with pokeweed mitogen indicate that interleukin-1alpha (IL-1alpha) and IL-1beta are necessary for optimal IgG1 and IgG2 production and that prostaglandin E(2) (PGE(2)) and interferon-gamma (IFN-gamma) selectively promote IgG2, which is a major component of the anti-A. actinomycetemcomitans response in vivo. The pokeweed mitogen results suggest that these proinflammatory cytokines would also be necessary for optimal production of IgG specific for A. actinomycetemcomitans. METHODS: Peripheral blood mononuclear cells from A. actinomycetemcomitans-seropositive subjects with localized aggressive periodontitis were stimulated with A. actinomycetemcomitans in immune complexes capable of binding follicular dendritic cells that participate in the induction of recall responses in vivo. Cultures were manipulated with anti-IL-1alpha, anti-IL-1beta, anti-IFN-gamma, anti-IL-12, anti-CD21, indomethacin, and PGE(2). Actinobacillus actinomycetemcomitans specific IgG production was monitored by enzyme-linked immunosorbent assay (ELISA). RESULTS: Addition of follicular dendritic cells to peripheral blood mononuclear cells cultures resulted in follicular dendritic cell-lymphocyte clusters and increased anti-A. actinomycetemcomitans IgG responses (3-40-fold increases) compared with controls lacking follicular dendritic cells. Anti-IL-1alpha, anti-IL-1beta, anti-IFN-gamma, anti-IL-12, anti-CD21 and indomethacin suppressed anti-A. actinomycetemcomitans IgG production by half or more. PGE(2) restored IgG responses suppressed by indomethacin. CONCLUSIONS: The cytokines IL-1alpha, IL-1beta, IFN-gamma, IL-12, and PGE(2) were all necessary for optimal production of human anti-A. actinomycetemcomitans and the need for proinflammatory cytokines including the T helper 1 (Th1) cytokines is consistent with a response with a significant IgG2 component.
Assuntos
Aggregatibacter actinomycetemcomitans/imunologia , Citocinas/imunologia , Imunoglobulina G/imunologia , Mediadores da Inflamação/imunologia , Infecções por Actinobacillus/sangue , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Complexo Antígeno-Anticorpo/imunologia , Células Dendríticas Foliculares/imunologia , Dinoprostona/imunologia , Humanos , Indometacina/farmacologia , Interferon gama/imunologia , Interleucina-1/imunologia , Interleucina-12/imunologia , Leucócitos Mononucleares/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Periodontite/sangue , Periodontite/microbiologia , Receptores de Complemento 3d/imunologia , Células Th1/imunologiaRESUMO
Patients with localized aggressive periodontitis have type-1 cytokines in gingival crevicular fluid and high titers of IFN-gamma-dependent IgG2 reactive with P. gingivalis in gingival crevicular fluid and serum. Localized aggressive periodontitis monocytes spontaneously differentiate into dendritic cells that can stimulate IFN-gamma production by NK cells. These relationships prompted the hypothesis that P. gingivalis-dendritic cell-NK cell interactions might promote type-1 cytokine responses. Although P. gingivalis is not a potent inducer of Th1 responses, it stimulated strong IL-12 responses by monocyte-derived dendritic cells in the presence of IFN-gamma, and IFN-gamma was produced by NK cells within 24 hrs in the presence of dendritic cells. Anti-P. gingivalis IgG2 responses were enhanced by dendritic cells, and removal of NK cells reduced IFN-gamma- and P. gingivalis-specific IgG2. Thus, P. gingivalis-dendritic cell-NK cell interactions apparently resulted in reciprocal stimulation and increased type-1 cytokine production by both dendritic cells and NK cells, and increased P. gingivalis-specific IgG2.
Assuntos
Comunicação Celular , Células Dendríticas/fisiologia , Células Matadoras Naturais/fisiologia , Periodontite/imunologia , Porphyromonas gingivalis/imunologia , Adulto , Análise de Variância , Animais , Anticorpos Antibacterianos/biossíntese , Antígenos de Bactérias/metabolismo , Células Cultivadas , Células Dendríticas/metabolismo , Células Dendríticas/microbiologia , Humanos , Imunoglobulina G/biossíntese , Interferon gama/biossíntese , Interleucina-10/biossíntese , Interleucina-12/biossíntese , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/microbiologia , Camundongos , Neutrófilos/metabolismo , Periodontite/metabolismo , Periodontite/microbiologiaRESUMO
Human immunoglobulin G2 (IgG2) responses are gamma interferon (IFN-gamma) dependent, and monocyte-derived dendritic cells (mDCs) promote IgG2 production. DCs spontaneously emerge from monocytes in cultures prepared from localized aggressive periodontitis (LagP) patients, and these patients have high levels of IgG2 that is reactive with Actinobacillus actinomycetemcomitans. These results prompted the hypothesis that an interaction between mDCs and A. actinomycetemcomitans promotes IFN-gamma production, and IFN-gamma is known to promote both immunopathology and protective IgG2. A. actinomycetemcomitans induced mDCs to produce interleukin-12 (IL-12), and the addition of A. actinomycetemcomitans and DCs to cultured peripheral blood lymphocytes elicited high levels of IFN-gamma within just 24 h. In contrast, IL-4 was not detectable although DC-derived IL-10 production was apparent. A. actinomycetemcomitans-stimulated macrophages prepared from the same monocytes lacked the ability to induce IL-12 or IFN-gamma responses. NK cells of the innate immune system were the primary source of this early IFN-gamma, although CD8 T cells also contributed some. The NK cell-derived IFN-gamma was IL-12 dependent, and A. actinomycetemcomitans-DC interactions were Toll-like receptor 4 dependent. A. actinomycetemcomitans and A. actinomycetemcomitans lipopolysaccharide (LPS) were more potent than Escherichia coli and E. coli LPS in the ability to induce DC IL-12 and IFN-gamma. The ability of A. actinomycetemcomitans-stimulated DCs to induce NK cells to rapidly produce IFN-gamma in the absence of detectable IL-4 suggests their potential for skewing responses toward Th1. This may help explain the presence of Th1-associated cytokines in gingival crevicular fluid (GCF) from LagP patients and the high levels of IgG2 in their serum and GCF that is reactive with A. actinomycetemcomitans.
Assuntos
Aggregatibacter actinomycetemcomitans/imunologia , Células Dendríticas/imunologia , Interferon gama/biossíntese , Células Matadoras Naturais/imunologia , Humanos , Interleucina-12/imunologia , Interleucina-12/metabolismo , Células Matadoras Naturais/metabolismo , Lipopolissacarídeos/imunologia , Glicoproteínas de Membrana/metabolismo , Monócitos/citologia , Monócitos/imunologia , Subunidades Proteicas/imunologia , Subunidades Proteicas/metabolismo , Receptores de Superfície Celular/metabolismo , Receptor 4 Toll-Like , Receptores Toll-LikeRESUMO
Antiphospholipid antibodies are commonly found in patients with systemic lupus erythematosus or the antiphospholipid syndrome, and a subset of such antibodies is associated with prothrombotic events such as stroke and with adverse pregnancy outcomes and fetal loss. We examined sera from 411 patients who were clinically characterized as to their periodontal disease status for serum levels of beta2-glycoprotein I-dependent anti-cardiolipin autoantibodies (anti-CL). The prevalence of patients with chronic periodontitis (CP) and generalized aggressive periodontitis (GAgP) positive for anti-CL (16.2% and 19.3%, respectively) was greater than that in healthy controls (NP) and localized aggressive periodontitis (LAgP) patients (6.8% and 3.2%). Patients with these autoantibodies demonstrated increased pocket depth and attachment loss compared with patients lacking the antibodies. Analysis of the data indicates that patients with generalized periodontitis have elevated levels of autoantibodies reactive with phospholipids. These antibodies could be involved in elevated risk for stroke, atherosclerosis, or pre-term birth in periodontitis patients.
Assuntos
Anticorpos Anticardiolipina/sangue , Periodontite/sangue , Periodontite/imunologia , Adulto , Análise de Variância , Feminino , Humanos , Modelos Logísticos , Masculino , Razão de Chances , Índice PeriodontalRESUMO
IgG2 is elevated in localized but not in generalized aggressive periodontitis (AgP). Exposure to pathogenic bacteria is essential for disease. Immune responses are dominated by IgG2 reactive with bacterial surface carbohydrates. We used variance component analyses to assess IgG2 heritability and determine whether genes that influence IgG2 are the same genes that influence disease susceptibility. We studied 17 Caucasian and 43 African American families with two or more localized or generalized AgP-affected members (274 subjects with IgG2 measurements). Only 16% of the variance in IgG2 was attributable to age, race, and smoking. Even with the addition of localized AgP, the model still explained only 19% of IgG2 variance. By contrast, heritability of IgG2 levels was estimated to be 38% and highly significant (P = 0.0006), demonstrating a substantial genetic basis. Bi-trait variance component analyses of IgG2 and quantitative measures of AgP indicate that different genes appear to control IgG2 levels and disease susceptibility.
Assuntos
Imunoglobulina G/genética , Periodontite/genética , Adolescente , Adulto , Fatores Etários , Idoso , População Negra/genética , Feminino , Predisposição Genética para Doença , Variação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Perda da Inserção Periodontal/genética , Perda da Inserção Periodontal/imunologia , Periodontite/imunologia , Fatores de Risco , Fumar/genética , Fumar/imunologia , População Branca/genéticaRESUMO
BACKGROUND: Serum concentrations of immunoglobulin G2 (IgG2) are elevated in localized aggressive periodontitis (LAgP) patients, and secretory products of monocytes from LAgP patients enhance IgG2 responses of lymphocytes from healthy subjects. Furthermore, genes regulating production of interleukin (IL)-1 influence the risk for both aggressive periodontitis (AgP) and chronic periodontitis. These observations, and the fact that IgG2 dominates responses to carbohydrates from Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis, prompted the hypothesis that IL-1 alpha, IL-1 beta, and IL-RA may help regulate human IgG2 responses. METHODS: Human peripheral blood leukocytes (PBL) were stimulated in culture with pokeweed mitogen (PWM); the levels of available IL-1 gene products were manipulated; and the effect on IgG2 production was monitored. Manipulations of IL-1 were accomplished by adding specific neutralizing monoclonal antibodies or recombinant IL-1RA, IL-1 alpha, or IL-1 beta. RESULTS: Blocking the IL-1 receptor with IL-1RA or neutralizing IL-1 alpha or IL-1 beta with specific antibody dramatically suppressed IgG2 production (50% to 70%). Additionally IL-1 alpha did not compensate for neutralized IL-1 beta, and additional IL-1 beta did not compensate for neutralized IL-1 alpha, suggesting the 2 monokines have separate roles in promoting IgG2. Furthermore, combinations of anti-IL-1 alpha and anti-IL-1 beta were more inhibitory than either antibody alone, and IL-1 alpha and IL-1 beta in combination appeared to work additively in promoting IgG2. Moreover, PBL cultures from a group of LAgP patients with high IgG2 levels had elevated levels of IL-1 beta. CONCLUSION: IL-1 alpha and IL-1 beta appear to have critical and non-redundant roles in the generation and regulation of potent IgG2 responses, which appear to be important in human responses to carbohydrate-bearing bacteria.
Assuntos
Imunoglobulina G/imunologia , Interleucina-1/imunologia , Periodontite/imunologia , Adulto , Aggregatibacter actinomycetemcomitans/imunologia , Análise de Variância , Anticorpos Monoclonais , Carboidratos/imunologia , Células Cultivadas , Doença Crônica , Regulação da Expressão Gênica , Humanos , Imunoglobulina G/sangue , Interleucina-1/sangue , Interleucina-1/genética , Leucócitos Mononucleares/imunologia , Linfócitos/imunologia , Monócitos/metabolismo , Monocinas/imunologia , Periodontite/sangue , Periodontite/classificação , Mitógenos de Phytolacca americana , Porphyromonas gingivalis/imunologia , Receptores de Interleucina-1/imunologia , Proteínas Recombinantes , Estatística como AssuntoRESUMO
Antibodies reactive with phosphorylcholine (PC) are ubiquitous in human sera, but the antigens stimulating their production and their function are not clear. Previous studies have shown that a significant proportion of dental plaque bacteria contain PC as determined by reactivity with PC-specific mouse myeloma proteins and monoclonal antibodies. Additionally, serum antibody concentrations of immunoglobulin (IgG) G anti-PC are higher in sera of individuals who have experienced periodontal attachment loss than those who are periodontally healthy. These data implicate the oral microflora as a source of antigen-stimulating anti-PC responses. Recent data also indicate that antibodies with specificity for PC are elevated in ApoE-deficient mice, a model for studies of athersclerosis, and that such antibodies bound oxidized low-density lipoproteins (LDL) (oxLDL) in atherosclerotic plaques. These data prompted the hypothesis that human anti-PC could bind to both oral bacteria and human oxLDL, and that these antigens are cross-reactive. We therefore examined the ability of human anti-PC to bind to PC-bearing strains of oral bacteria using enzyme-linked immunosorbent inhibition assays and by assessment of direct binding of affinity-purified human anti-PC to PC-bearing Actinobacillus actinomycetemcomitans. Our results indicated that PC-bearing strains of Streptococcus oralis, Streptococcus sanguis, Haemophilus aphrophilus, Actinomyces naeslundii, Fusobacterium nucleatum, and A. actinomycetemcomitans, as well as a strain of Streptococcus pneumoniae, absorbed up to 80% of anti-PC IgG antibody from human sera. Furthermore, purified anti-PC bound to a PC-bearing strain of A. actinomycetemcomitans but only poorly to a PC-negative strain. OxLDL also absorbed anti-PC from human sera, and oxLDL but not LDL reacted with up to 80% of the anti-PC in human sera. Furthermore, purified anti-PC bound directly to oxLDL but not to LDL. The data indicate that PC-containing antigens on a variety of common oral bacteria are cross-reactive with neoantigens expressed in oxLDL. We propose that PC-bearing dental plaque microorganisms may induce an antibody response to PC that could influence the inflammatory response associated with atherosclerosis.
Assuntos
Placa Dentária/microbiologia , Lipoproteínas LDL/imunologia , Fosforilcolina/imunologia , Actinomyces/imunologia , Aggregatibacter actinomycetemcomitans/imunologia , Anticorpos Antibacterianos/imunologia , Bactérias/imunologia , Reações Cruzadas , Fusobacterium nucleatum/imunologia , Haemophilus/imunologia , Humanos , Streptococcus oralis/imunologia , Streptococcus sanguis/imunologiaRESUMO
To determine the characteristics of new dental faculty and what factors influenced them to choose academic careers, a survey was sent to deans at all U.S. dental schools to be distributed to faculty with length of service of four years or less. Responses were received from 240 individuals. About half of the respondents had been in private practice for an average of eight years, and 20 percent had military experience averaging almost sixteen years. A majority had postgraduate training and 60 percent had specialty training. Nearly 32 percent of new faculty were female and 80 percent were U.S. citizens. Analyses of responses to survey items indicated that correlated factors in the survey fell into the following empirical categories: teaching and scholarship, income and indebtedness, research, work schedule, influence of mentors and role models, and long-term aspirations. In general, the respondents identified factors relating to teaching and scholarship to be the most important influences on their choice of academic careers, while concerns about income and indebtedness were the most important negative considerations in this regard. Other positive factors identified by the survey related to the influence of mentors and role models, long-term aspirations, and research. Age, private practice experience, and military experience were found to particularly influence the new faculty members' responses to items concerning income and indebtedness, and citizenship influenced responses to factors relating to research. The data from this select group of dentists support the current view that inequities in income of dental faculty compared to private practitioners and student debt are important concerns in choosing academic careers. Importantly, the desire to teach and participate in scholarly activities are important attractions in academic careers. Mentoring activities and creation of opportunities for career development are crucial factors in developing interest in academics among graduate dentists.
Assuntos
Escolha da Profissão , Docentes de Odontologia , Adulto , Fatores Etários , Análise de Variância , Atitude do Pessoal de Saúde , Pesquisa em Odontologia , Economia em Odontologia , Educação em Odontologia/economia , Educação de Pós-Graduação em Odontologia , Etnicidade , Feminino , Humanos , Renda , Masculino , Mentores , Pessoa de Meia-Idade , Odontologia Militar , Motivação , Prática Privada , Fatores Sexuais , Especialidades Odontológicas/educação , Desenvolvimento de Pessoal , Estatística como Assunto , Ensino , Fatores de Tempo , Apoio ao Desenvolvimento de Recursos HumanosRESUMO
BACKGROUND: A few previous studies have suggested that risk for adult periodontitis (AP) has a genetic (heritable) component. We estimated genetic and environmental variances and heritability for gingivitis and adult periodontitis using data from twins reared together. METHODS: One hundred seventeen (117) pairs of adult twins (64 monozygotic [MZ] and 53 dizygotic [DZ] pairs) were recruited. Probing depth (PD), attachment loss (AL), plaque, and gingivitis (GI) were assessed on all teeth by two examiners. Measurements were averaged over all sites, teeth, and examiners. Extent of disease in subjects was defined at four thresholds: the percentage of teeth with AL > or = 2, AL > or = 3, PD > or = 4, or PD > or = 5 mm. Genetic and environmental variances and heritability were estimated using path models with maximum likelihood estimation techniques. RESULTS: MZ twins were more similar than DZ twins for all clinical measures. Statistically significant genetic variance was found for both the severity and extent of disease. AP was estimated to have approximately 50% heritability, which was unaltered following adjustments for behavioral variables including smoking. In contrast, while MZ twins were also more similar than DZ twins for gingivitis scores, there was no evidence of heritability for gingivitis after behavioral covariates such as utilization of dental care and smoking were incorporated into the analyses. CONCLUSIONS: These results confirm previous studies and indicate that approximately half of the variance in disease in the population is attributed to genetic variance. The basis for the heritability of periodontitis appears to be biological and not behavioral in nature.
Assuntos
Predisposição Genética para Doença/genética , Periodontite/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Distribuição de Qui-Quadrado , Assistência Odontológica/estatística & dados numéricos , Índice de Placa Dentária , Feminino , Variação Genética , Humanos , Funções Verossimilhança , Masculino , Pessoa de Meia-Idade , Índice Periodontal , Fatores de Risco , FumarRESUMO
Strains of the periodontal pathogen Actinobacillus actinomycetemcomitans are variable with respect to display of phosphorylcholine (PC)-bearing antigens. We have examined strains of A. actinomycetemcomitans with and without PC to assess their ability to invade endothelial cells via the receptor for platelet-activating factor (PAF). Results of antibiotic protection assays indicate that PC-bearing A. actinomycetemcomitans invade human vascular endothelial cells by a mechanism inhibitable by CV3988, a PAF receptor antagonist, and by PAF itself. The invasive phenotype was verified by transmission electron microscopy. A PC-deficient strain of this organism was not invasive. This property, in addition to the established ability of A. actinomycetemcomitans to invade epithelial cells, may provide this organism with access to the systemic circulation. The ability of PC-bearing oral bacteria to access the circulation may also explain the elevated levels of anti-PC antibody in serum found in patients with periodontitis.