Several studies have shown that periodontal treatment improves the systemic levels of antibodies specific to periopathogens.40-42 Also improves the periodontal clinical
parameters used in the diagnosis of periodontal disease.
It was demonstrated throughout multiple reports in the medical literature that
therapies designed to reduce oxidative stress have been related to improved outcomes in viral infections and improved cell-mediated immune function in animal models and human clinical trials.43, 44
Thus our goal is to determine the association of systemic levels of oxidative stress with serum levels of IgG antibody to commensal and pathogenic microorganisms’
response/alteration to periodontal therapy within the periodontal patient population.
The loss of homeostatic balance between proteolytic enzymes (e.g. neutrophil elastase) and their inhibitors (e.g. a1-antitrypsin) and reactive oxygen species (ROS) and the antioxidant defense systems to protect and repair vital tissue, cell, and molecular components is believed to be responsible for periodontal tissue destruction. The basis for such dysregulation is in part genetic and in part the result of environmental factors (e.g. smoking).6
1
Our findings demonstrate that serum concentrations of 8-isoprostane above the median are related to decreased response of the serum IgG antibodies to oral bacteria. These findings were controlled for smoking status and other known contributors to oxidative stress and periodontal severity (e.g., , age and BMI) (Table 1). These findings are in exact accordance with the Singer, Beck and Offenbacher39 report which was the first to
demonstrate an association between serum 8-isoprostane concentrations and serum IgG antibody levels to mucosal microbes. Thus, this investigation demonstrates that systemic oxidative stress consistently suppresses serum IgG antibody responses to total oral biofilm microbes.
In our study population which could be considered a large representative population (108 subjects), extremes of oxidative stress have been related to changes in a variety of immune-response mechanisms.45
The bacteria in our panel of antibodies included gram-negative and gram-positive bacteria, strict anaerobes, aerobes, and facultative anaerobes, as well as species associated with periodontal disease and oral health.46
Singer et al.39 showed that serum IgG antibody responses to the oral biofilm microflora
are suppressed in the presence of systemic oxidative stress. Additional studies are needed to clarify the role of IgG subtype and avidity to these findings.
Singer et al.39 suggested possible studies to explore the clinical impact of oxidative
stress in mucosal disease progression, in the response to therapy, and in the potential use of antioxidant therapies as modifiers.
2
Our study investigated the response to non-surgical periodontal therapy in subjects with high oxidative stress as compared to low oxidative stress subjects; the findings
supported our initial hypothesis that periodontal subjects with high oxidative stress at baseline will respond less favorably to treatment, as shown on the immunological level by investigating the total oral biofilm serum IgG titers response.
Although these titers reflect whole-bacterial titers, a high degree of specificity occurs in organism-specific IgG without significant cross-reactivity across various microbes under the stringency conditions of the immunobinding.47
Thus, the effect of oxidative stress on IgG responses appears to reflect a suppression of IgG across a wide range of potential antigenic stimuli.
8-Isoprostane is a stable product of the oxidative metabolism of arachidonic acid,47
and 8-isoprostane concentrations in serum and urine have been used as markers of systemic oxidative stress,48 and are related to the accumulation of oxidized-LDL.49
The serum concentration of 8-isoprostane has been reported to be related to body mass index and race.50
To understand the mechanism for the association of 8-isoprostane concentrations with decreased IgG antibody levels, it will be necessary to define better the specific
mediators of lipid-based redox signaling, specific cellular and molecular targets, and correlations of IgG subclass antibody levels (and antibody isotypes) to serum 8- isoprostane concentrations.39
3
It is expected that clinical and mechanistic insights from these future investigations will enable interventions that better target populations and mechanisms likely to have impact on the systemic diseases that have been associated with systemic exposure to the mucosal biofilm microflora.
8-isoprostane concentrations reflect whole-body lipid oxidation, including enzymatic and nonspecific free-radical lipid oxidative pathways; it is likely that these variables and physiologic or pathologic factors (or both) that influence oxidative lipid metabolism contributed to the serum 8-isoprostane concentrations. Singer et al.39 further indicated
that an increased prevalence of deep probing depths (periodontal disease) is associated with increased (1.6-fold) serum concentrations of 8-isoprostane. The theory that was proposed to explain this elevation was that the epithelial lining of the periodontal pocket is adjacent to the subgingival biofilm and is structurally unique without tight junctions or keratin. Even in health, the epithelial attachment to the teeth is a site that has a natural IL-8 chemotactic gradient, which brings neutrophils into the periodontal pocket such that they flush around the teeth and appear in the saliva. Activated
neutrophils within the crevice and saliva may serve to increase salivary 8-isoprostane, as recently reported by Wolfram et al.51
Thus, the periodontal tissues may represent a source of systemic oxidative stress because of the presence of high numbers of activated neutrophils.39
4
It is known that the presence of periodontitis is associated with lower serum concentrations of vitamin C, 52 even after adjusting for smoking, suggesting that
periodontal disease may pose an oxidative stress that consumes ascorbate.
Also, the mucosal tissue wounding associated with deep periodontal pockets has been associated with an increased occurrence of bacteremia.53
Herzenberg et al.45 found that extreme high levels of oxidative stress have been related
to changes in a variety of immune-response mechanisms.45
It was hypothesized50 that infiltrating neutrophils or macrophages, or both, capable of
mounting an oxidative burst might control the periodontal microflora and thereby limit consequent serum IgG antibody responses, leading to an inverse relation between serum 8-isoprostane and IgG antibody levels. An increased presence of periodontal pockets of PD greater than 5mm would provide a greater reservoir of activated periodontal PMNs and macrophages and was associated here with increased serum 8- isoprostane levels; however, the greater number of deep pockets also was associated with significant increases in levels of serum IgG antibodies.
The second part of this study was to look at the clinical response for periodontal subjects with high oxidative stressto periodontal therapy as evaluated by BOP and PD; the present study suggests that the outcome in high oxidative stress subjects is less favorable than in low oxidative stress periodontal subjects.
In this study we mainly looked at the changes in PD even though clinical attachment level (CAL) has been more frequently used than PD to evaluate the effect of periodontal
5
treatment. However, even if teeth have high CAL, their PD may be less than 3 mm. IgG titer levels, transient in nature, must be influenced more by the size of the area of current infection than by the history of tissue destruction. Therefore, we preferred PD to CAL as a measure of periodontal severity, and particularly as a predictor of systemic immune response. As expected based on previous reports (Alexander et al., 1996; Behle
et al., 2009), the IgG titers against total oral biofilm bacteria were significantly decreased by periodontal treatment, corresponding to improvement in periodontal condition.54
The results suggested that this test is useful for evaluating treatment effects from the perspective of infection levels, and the test would be useful as a self-evaluation system for the effects of periodontal treatment.
In our study, both study sub-groups (High and Low oxidative stress with treatment) showed improvement in PD and BOP after treatment. The pattern, however, was that subjects with high oxidative stress exhibited less improvement in both parameters than those with low oxidative stress. The reduction in whole-mouth mean PD was 0.33 mm vs. 0.50 mm (P<0.01) in high vs. low oxidative stress subjects.
To conclude the major findings in this study are
1- Scaling and root planing results in an increase in 2 week total oral biofilm IgG levels in low oxidative stress subjects.
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2- High oxidative stress at baseline was associated with lower IgG antibody at 2 weeks after treatment in subjects with moderate to severe periodontitis. 3- At baseline, subjects assigned to the treatment group who had low oxidative
stress exhibited less BOP as compared to controls with high oxidative stress. 4- Subjects with low oxidative stress responded better to non-surgical periodontal
therapy as measured by mean percentage of BOP reduction at 6, 12 and 24- week time-points and mean PD reduction at 12 and 24 weeks as compared to controls with high oxidative stress.
5- Subjects who presented with consistently low oxidative stress throughout the study responded better to non-surgical periodontal therapy by measure of PD reduction observed at 6 months.
This report suggests further studies to investigate the role of oxidative stress as a modifier of periodontal therapy response in subjects with periodontitis.
These findings suggest possible studies to explore the potential impact of antioxidative therapy as a modifier and possible enhancer of the response to periodontal therapy.