Effects of age and oral disease on systemic inflammatory and immune parameters in nonhuman primates

Abstract

This report evaluated systemic inflammatory and immune biomarkers in a cohort of Macaca mulatta (rhesus monkeys) maintained as a large family social unit, including an age range from <1 year to >24 years. We hypothesized that the systemic host responses would be affected by the age, gender, and clinical oral presentation of the population, each contributing to inflammatory and immune responses that would reflect chronic oral infections. The results demonstrated that the prevalence and severity of periodontitis, including missing teeth, increased significantly with age. Generally, minimal differences in clinical parameters were noted between the genders. Systemic inflammatory mediators, including acute-phase reactants, prostaglandin E(2) (PGE(2)), cytokines/chemokines, and selected matrix metalloproteinases (MMP), demonstrated significant differences among the various age groups of animals. Levels of many of these were increased with age, although PGE(2), RANTES, bactericidal permeability-inducing factor (BPI), MMP-1, and MMP-9 levels were significantly increased in the young group ( approximately 1 to 3 years old) relative to those for the older animals. We observed that in the adult and aged animals, levels of the systemic inflammatory mediators related to gingival inflammation and periodontal tissue destruction were significantly elevated. Serum antibody levels in response to a battery of periodontal pathogens were generally lower in the young animals, <50% of those in the adults, and were significantly related to aging in the cohort. The levels of antibodies, particularly those to Porphorymonas gingivalis, Fusobacterium nucleatum, and Tannerella forsythia, were most significantly elevated in animals with periodontal disease, irrespective of the age of the animal. These results provide a broad description of oral health and host responses in a large cohort of nonhuman primates from very young animals to the aged of this species. The findings afford a base of data with which to examine the ontogeny of host responses at mucosal sites, such as the gingival tissues.

FIG. 1.

Acute-phase reactants and inflammatory mediators in serum samples from nonhuman primates of different age groups: young (<3 years) (n = 76), adolescent (≥3 to 8 years) (n = 61), adult (8 to 15 years) (n = 32), and aged (>15 years) (n = 10). Bars represent group means; error bars, 1 standard deviation. Statistical differences among the groups are displayed.

FIG. 2.

Acute-phase reactants (A), inflammatory mediators (B), and antibodies (C) in serum samples from nonhuman primates <3 years old raised under standard housing conditions (young) (n = 76) or under SPF conditions (n = 30). Bars represent mean levels of each mediator; error bars, 1 standard deviation. Statistical differences between the groups are shown. Aa, Aggregatibacter actinomycetemcomitans; Cr, Campylobacter rectus; Fn, Fusobacterium nucleatum; Pg, Porphyromonas gingivalis; Pi, Prevotella intermedia; Td, Treponema denticola; Tf, Tannerella forsythia. For panels A and B, PGE₂, BPI, RANTES, MMP-2, and MMP-9 are measured in ng/ml; LBP and CRP are measured in μg/ml; and IL-8, MCP-1, and MMP-1 are measured in pg/ml (as in Fig. 1). For panel C, antibody levels are presented in ng/ml.

FIG. 3.

Serum IgG antibodies to individual oral bacteria and total antibodies to this battery (SUM) in nonhuman primates categorized on the basis of age (see the legend to Fig. 1). Bars represent mean antibody levels; error bars, 1 standard deviation. Statistical differences are depicted on the graph. For bacterium abbreviations, see the legend to Fig. 2.

FIG. 4.

Acute-phase reactants and inflammatory mediators in serum samples from nonhuman primates stratified on the basis of a low (<0.9) (n = 32) or high (≥0.9) (n = 9) mean index score for mouth bleeding upon probing. Bars represent group means; error bars, 1 standard deviation. PGE₂, BPI, RANTES, MMP-2, and MMP-9 are measured in ng/ml; LBP and CRP are measured in μg/ml; and IL-8, MCP-1, and MMP-1 are measured in pg/ml (as in Fig. 1).

FIG. 5.

Serum IgG antibodies to individual oral bacteria and total antibodies to this battery (SUM) in nonhuman primates stratified on the basis of a low (<0.9) or high (≥0.9) index score for mean bleeding upon probing. Bars represent mean antibody levels; error bars, 1 standard deviation. Statistical differences are depicted on the graph. For bacterium abbreviations, see the legend to Fig. 2.

FIG. 6.

Acute-phase reactants and inflammatory mediators in serum samples from nonhuman primates stratified on the basis of a low (<3 mm) (n = 25) or high (≥3 mm) (n = 16) mean pocket depth in the mouth. Bars represent group means; error bars, 1 standard deviation. Statistical differences are depicted on the graph. PGE₂, BPI, RANTES, MMP-2, and MMP-9 are measured in ng/ml; LBP and CRP are measured in μg/ml; and IL-8, MCP-1, and MMP-1 are measured in pg/ml (as in Fig. 1).

FIG. 7.

Serum IgG antibodies to individual oral bacteria and total antibodies to this battery (SUM) in nonhuman primates stratified on the basis of a low (<3 mm) or high (≥3 mm) mean pocket depth in the mouth. Bars represent mean levels; error bars, 1 standard deviation. Statistical differences are depicted on the graph. For bacterium abbreviations, see the legend to Fig. 2.