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1.  Transcriptome Analysis of B Cell Immune Functions in Periodontitis: Mucosal Tissue Responses to the Oral Microbiome in Aging 
Evidence has shown activation of T and B cells in gingival tissues in experimental models and in humans diagnosed with periodontitis. The results of this adaptive immune response are noted both locally and systemically with antigenic specificity for an array of oral bacteria, including periodontopathic species, e.g., Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. It has been recognized through epidemiological studies and clinical observations that the prevalence of periodontitis increases with age. This report describes our studies evaluating gingival tissue transcriptomes in humans and specifically exploiting the use of a non-human primate model of naturally occurring periodontitis to delineate gingival mucosal tissue gene expression profiles focusing on cells/genes critical for the development of humoral adaptive immune responses. Patterns of B cell and plasmacyte genes were altered in aging healthy gingival tissues. Substantial increases in a large number of genes reflecting antigen-dependent activation, B cell activation, B cell proliferation, and B cell differentiation/maturation were observed in periodontitis in adults and aged animals. Finally, evaluation of the relationship of these gene expression patterns with those of various tissue destructive molecules (MMP2, MMP9, CTSK, TNFα, and RANKL) showed a greater frequency of positive correlations in healthy tissues versus periodontitis tissues, with only MMP9 correlations similar between the two tissue types. These results are consistent with B cell response activities in healthy tissues potentially contributing to muting the effects of the tissue destructive biomolecules, whereas with periodontitis this relationship is adversely affected and enabling a progression of tissue destructive events.
PMCID: PMC4947588  PMID: 27486459
B cells; periodontitis; aging; gingival tissues; non-human primates
2.  Systemic Immune Responses in Pregnancy and Periodontitis: Relationship to Pregnancy Outcomes in the Obstetrics and Periodontal Therapy (OPT) Study 
Journal of periodontology  2009;80(6):953-960.
Our previous studies reported on the obstetric, periodontal, and microbiologic outcomes of women participating in the Obstetrics and Periodontal Therapy (OPT) Study. This article describes the systemic antibody responses to selected periodontal bacteria in the same patients.
Serum samples, obtained from pregnant women at baseline (13 to 16 weeks; 6 days of gestation) and 29 to 32 weeks, were analyzed by enzyme-linked immunosorbent assay for serum immunoglobulin G (IgG) antibody to Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans), Campylobacter rectus, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia (previously T. forsythensis), and Treponema denticola.
At baseline, women who delivered live preterm infants had significantly lower total serum levels of IgG antibody to the panel of periodontal pathogens (P = 0.0018), to P. gingivalis (P = 0.0013), and to F. nucleatum (P = 0.0200) than women who delivered at term. These differences were not significant at 29 to 32 weeks. Changes in IgG levels between baseline and 29 to 32 weeks were not associated with preterm birth when adjusted for treatment group, clinical center, race, or age. In addition, delivery of low birth weight infants was not associated with levels of antibody at baseline or with antibody changes during pregnancy.
Live preterm birth is associated with decreased levels of IgG antibody to periodontal pathogens in women with periodontitis when assessed during the second trimester. Changes in IgG antibody during pregnancy are not associated with birth outcomes.
PMCID: PMC4133130  PMID: 19485826
Antibody; bacteria; periodontitis; pregnancy; preterm birth
3.  Effects of aging on apoptosis gene expression in oral mucosal tissues 
Apoptotic processes are important for physiologic renewal of an intact epithelial barrier and contribute some antimicrobial resistance for bacteria and viruses, as well as anti-inflammatory effects that benefits the mucosa. The oral cavity presents a model of host-bacterial interactions at mucosal surfaces, in which a panoply of microorganisms colonizes various niches in the oral cavity and creates complex multispecies biofilms that challenge the gingival tissues. This report details gene expression in apoptotic pathways that occur in oral mucosal tissues across the lifespan, using a nonhuman primate model. Macaca mulatta primates from 2 to 23 years of age (n = 23) were used in a cross-sectional study to obtain clinical healthy gingival tissues specimens. Further, mRNA was prepared and evaluated using the Affymetrix Rhesus GeneChip and 88 apoptotic pathway genes were evaluated. The results identified significant positive correlations with age in 12 genes and negative correlations with an additional five genes. The gene effects were predicted to alter apoptosis receptor levels, extrinsic apoptotic pathways through caspases, cytokine effects on apoptotic events, Ca+2-induced death signaling, cell cycle checkpoints, and potential effects of survival factors. Both the positively and negatively correlated genes within the apoptotic pathways provided evidence that healthy tissues in aging animals exhibit decreased apoptotic potential compared to younger animals. The results suggested that decreased physiologic apoptotic process in the dynamic septic environment of the oral mucosal tissues could increase the risk of aging tissues to undergo destructive disease processes through dysregulated inflammatory responses to the oral microbial burden.
PMCID: PMC3592930  PMID: 23334583
Aging; Apoptosis; Oral mucosa; Inflammation; Infection
4.  Caloric Restriction and Chronic Inflammatory Diseases 
Oral diseases  2011;18(1):16-31.
A reduction in calorie intake (Caloric restriction), appears to consistently decrease the biological rate of aging in a variety of organisms as well as protect against age-associated diseases including chronic inflammatory disorders such as cardiovascular disease and diabetes. Although the mechanisms behind this observation are not fully understood, identification of the main metabolic pathways affected by caloric restriction has generated interest in finding molecular targets that could be modulated by caloric restriction mimetics. This review describes the general concepts of caloric restriction and caloric restriction mimetics as well as discusses evidence related to their effects on inflammation and chronic inflammatory disorders. Additionally, emerging evidence related to the effects of caloric restriction on periodontal disease in non-human primates is presented. While the implementation of this type of dietary intervention appears to be challenging in our modern society where obesity is a major public health problem, caloric restriction mimetics could offer a promising alternative to control and perhaps prevent several chronic inflammatory disorders including periodontal disease.
PMCID: PMC3193874  PMID: 21749581
Caloric restriction; mimetics; chronic inflammation; periodontal disease; aging
5.  The Effects of a Calorie Reduced Diet on Periodontal Inflammation and Disease in a Non Human Primate Model 
Journal of periodontology  2008;79(7):1184-1191.
Low calorie diets are commonplace for reducing body weight. However, no information is available on the effects of a reduced calorie diet on periodontal inflammation and disease. The purpose of this study was to evaluate the clinical effects of a long term calorie restricted diet (CR) on periodontitis in an animal model of periodontitis.
Periodontitis was induced in 55 young, healthy, adult rhesus monkeys (Macaca mulatta) by tying 2.0 silk ligatures at the gingival margins of maxillary premolar/molar teeth. Animals on a CR diet (30% CR; n=23) were compared to ad libitum diet controls (n=32). Clinical measures including plaque (PLI), probing pocket depth (PD), clinical attachment level (CAL), modified Gingival Index (GI) and bleeding on probing (BOP) were taken at baseline and 1, 2, and 3 months after ligature placement.
Significant effects of CR were observed on the development of inflammation and the progression of periodontal destruction in this model. When compared to controls, CR resulted in a significant reduction in ligature induced GI (p<0.0001), BOP (p<0.0015), PD (p<0.0016), and CAL (p<0.0038). When viewed over time, periodontal destruction, as measured by CAL, progressed significantly more slowly in the CR animals than in the controls (p<0.001).
These clinical findings are consistent with available evidence that CR has anti-inflammatory effects. Moreover, these experimental findings are the first observations that CR dampens the inflammatory response and reduces active periodontal breakdown associated with an acute microbial challenge.
PMCID: PMC2519872  PMID: 18597600
Caloric restriction; periodontitis; ligature model; inflammation; non human primate
6.  Maternal Periodontitis Treatment and Child Neurodevelopment at 24 to 28 Months of Age 
Pediatrics  2011;127(5):e1212-e1220.
Some maternal infections are associated with impaired infant cognitive and motor performance. Periodontitis results in frequent bacteremia and elevated serum inflammatory mediators.
The purpose of this study was to determine if periodontitis treatment in pregnant women affects infant cognitive, motor, or language development.
Children born to women who had participated in a previous trial were assessed between 24 and 28 months of age by using the Bayley Scales of Infant and Toddler Development (Third Edition) and the Preschool Language Scale (Fourth Edition). Information about the pregnancy, neonatal period, and home environment was obtained through chart abstractions, laboratory test results, and questionnaires. We compared infants born to women treated for periodontitis before 21 weeks' gestation (treatment group) or after delivery (controls). In unadjusted and adjusted analyses, associations between change in maternal periodontal condition during pregnancy and neurodevelopment scores were tested by using Student's t tests and linear regression.
A total of 411 of 791 eligible mother/caregiver-child pairs participated. Thirty-seven participating children (9.0%) were born at <37 weeks' gestation. Infants in the treatment and control groups did not differ significantly for adjusted mean cognitive (90.7 vs 91.4), motor (96.8 vs 97.2), or language (92.2 vs 92.1) scores (all P > .5). Results were similar in adjusted analyses. Children of women who experienced greater improvements in periodontal health had significantly higher motor and cognitive scores (P = .01 and .02, respectively), although the effect was small (∼1-point increase for each SD increase in the periodontal measure).
Nonsurgical periodontitis treatment in pregnant women was not associated with cognitive, motor, or language development in these study children.
PMCID: PMC3081189  PMID: 21482606
child neurodevelopment; periodontitis; pregnancy; treatment
7.  Serum Inflammatory Mediators in Pregnancy: Changes Following Periodontal Treatment and Association with Pregnancy Outcomes 
Journal of periodontology  2009;80(11):1731-1741.
To determine: 1) if periodontal treatment in pregnant women before 21 weeks of gestation alters levels of inflammatory mediators in serum; and 2) if changes in these mediators are associated with birth outcomes.
823 pregnant women with periodontitis were randomly assigned to receive scaling and root planing before 21 weeks of gestation or after delivery. Serum obtained between 13 weeks and 16 weeks 6 days (study baseline) and 29–32 weeks gestation was analyzed for C-reactive protein, prostaglandin E2, matrix metalloproteinase-9, fibrinogen, endotoxin, interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α. Cox regression, multiple linear regression, t-tests, chi-square and Fisher’s exact tests were used to examine associations between the biomarkers, periodontal treatment, and gestational age at delivery and birthweight.
796 women had baseline serum data; 620 had baseline and follow-up serum and birth data. Periodontal treatment did not significantly alter the level of any biomarker (P>0.05). Neither baseline levels nor change from baseline in any biomarker was significantly associated with preterm birth or infant birthweight (P>0.05). In treatment subjects, change in endotoxin was negatively associated with change in probing depth (P<0.05).
Non-surgical mechanical periodontal treatment in pregnant women delivered before 21 weeks of gestation did not reduce systemic (serum) markers of inflammation. In pregnant women with periodontitis, levels of these markers at 13–17 weeks and 29–32 weeks gestation were not associated with risk for preterm birth or with infant birthweight.
PMCID: PMC2922720  PMID: 19905943
Pregnancy; preterm birth; periodontitis; inflammation; cytokines
8.  Change in Periodontitis during Pregnancy and Risk of Preterm Birth and Low Birthweight 
Determine if periodontitis progression during pregnancy is associated with adverse birth outcomes.
Materials and Methods
We used clinical data and birth outcomes from the OPT Study, which randomized women to receive periodontal treatment before 21 weeks gestation (N=413) or after delivery (410). Birth outcomes were available for 812 women and follow-up periodontal data for 722, including 75 whose pregnancies ended <37 weeks. Periodontitis progression was defined as ≥ 3mm loss of clinical attachment. Birth outcomes were compared between non-progressing and progressing groups using the log rank and t tests, separately in all women and in untreated controls.
The distribution of gestational age at the end of pregnancy (P > 0.1) and mean birthweight (3295 versus 3184 grams, P = 0.11) did not differ significantly between women with and without disease progression. Gestational age and birthweight were not associated with change from baseline in percent of tooth sites with bleeding on probing or between those who did versus did not progress according to a published definition of disease progression (P > 0.05).
In these women with periodontitis and within this study’s limitations, disease progression was not associated with increased risk for delivering a preterm or low birthweight infant.
Clinical Relevance
Scientific Rationale
Maternal periodontitis and disease progression during pregnancy have been associated with elevated risk for preterm birth. We used data from a recent clinical trial to explore possible associations between progressive periodontitis and birth outcomes.
Principal Findings
The distribution of gestational age at delivery and mean birthweights did not differ significantly between women who experienced progressive periodontitis and those who did not.
Clinical Implication
While it is important to treat dental diseases, including periodontitis, during pregnancy, women whose periodontal condition worsens during pregnancy are not at elevated risk for adverse pregnancy outcomes.
PMCID: PMC2741139  PMID: 19426177
preterm birth; low birthweight; periodontal disease; pregnancy; disease progression
9.  Effects of Caloric Restriction on Inflammatory Periodontal Disease 
Dietary caloric restriction (CR) has been found to reduce systemic markers of inflammation and may attenuate the effects of chronic inflammatory conditions. The purpose of this study was to examine the effects of long-term CR on naturally occurring chronic inflammatory periodontal disease in a nonhuman primate model.
The effects of long-term CR on extent and severity of naturally occurring chronic periodontal disease, local inflammatory and immune responses, and periodontal microbiology, were evaluated in a cohort of 81 (35 female and 46 male; 13–40 years of age) rhesus monkeys (M. mulatta) with no previous exposure to routine oral hygiene. The CR monkeys had been subjected to 30% CR for 13–17 years relative to control-fed (CON) animals starting at 3–5 years of age. Clinical and laboratory parameters were submitted to analysis of covariance, including Tukey's test for post hoc comparisons, linear regression analysis, and nonparametric correlation analysis.
Same sex CR and CON monkeys exhibited comparable mean scores for plaque index, calculus index, and bleeding on probing. Among CON animals, males showed significantly greater periodontal breakdown, as reflected by higher mean clinical attachment level (CAL) and periodontal probing depth (PD) scores, than females (p ≤ 0.05). CR males had significantly less periodontal pocketing compared to CON males (p ≤ 0.05). CR males demonstrated a significantly lower IgG antibody response and lower levels of IL-8 and β-glucuronidase in gingival crevicular fluid compared to control males. A similar but nonsignificant reduction was found for IL-1β in CR male monkeys. In contrast, CR females exhibited mean PD and CAL scores comparable to CON females. CR females had a lower IgG antibody response but comparable levels of inflammatory markers in GCF compared to CON females. The CR diet had no demonstrable effects on the periodontal microbiota in male or female monkeys.
Males exhibited a greater risk for naturally occurring periodontal disease than females, consistent with findings from human populations. Moreover, long-term CR appears to differentially reduce the production of local inflammatory mediators and the risk for inflammatory periodontal disease among males but not females.
PMCID: PMC2610430  PMID: 18929461
monkey; caloric restriction; inflammation; periodontal disease; sex

Results 1-9 (9)