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.
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.
β2-glycoprotein I (β2GPI)-dependent anticardiolipin autoantibodies (aCl) are associated with thrombosis and fetal loss. Some microbial pathogens can induce pathogenic antibodies cross-reactive with β2GPI. Sera from a significant percentage of periodontitis patients contain aCl, and some periodontal pathogens contain antigens with peptide sequences having homology to β2GPI. We hypothesized that antibodies raised against P. gingivalis (aPg) contain pathogenic aCl that induce fetal resorption. We immunized mice with β2GPI, 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.
Aim Periodontal diseases are associated with a variety of systemic diseases, including cardiovascular disease and stroke, and patients with periodontitis demonstrate elevated levels of anticardiolipin antibodies. We sought to determine if anticardiolipin antibodies from periodontitis patients induced monocyte chemotactic protein-1 production by human vascular endothelial cells. Materials and Methods IgG was purified from sera from 53 subjects, including chronic and aggressive periodontitis patients and periodontally healthy controls, with elevated or normal IgG anticardiolipin levels. In addition, anticardiolipin antibodies were specifically removed from some sera by immunoabsorption. Results We found that, irrespective of diagnostic category, IgG from subjects with elevated anticardiolipin induced significantly greater monocyte chemotactic protein-1 production by human vascular endothelial cells than IgG from those subjects with normal anticardiolipin titers. Removal of anticardiolipin from IgG preparations from periodontitis patients significantly reduced their ability to induce monocyte chemotactic protein-1. Conclusions Since elevated titers of anticardiolipin are found in a significantly greater proportion of patients with periodontitis than in periodontally healthy individuals, and these antibodies activate endothelial cells to produce monocyte chemotactic protein-1, they may explain some of the associations noted between periodontal infections and systemic conditions.
We used two strains of Actinobacillus actinomycetemcomitans, one bearing phosphorylcholine (PC) (strain D045D-40) and one devoid of PC antigens (strain DB03A-42), as well as a nonencapsulated strain of Streptococcus pneumoniae (strain 39937), to examine the opsonic properties of physiological concentrations (30 g/ml) of purified human anti-PC immunoglobulin G (IgG). Anti-PC bound to both A. actinomycetemcomitans DO45D-40 and S. pneumoniae 39937 and induced superoxide anion production by polymorphonuclear neutrophils; induction of the oxidative burst was inhibited by antibodies to either CD16 or CD32. Thus, anti-PC IgG at concentrations present in most human sera promotes the opsonization of PC-expressing strains of A. actinomycetemcomitans in the absence of complement, implying that anti-PC may be a protective antibody against such strains of bacteria.
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