Periodontal disease is the consequence of complex interactions between a diverse oral bacterial community and host tissues. This condition is initiated by bacterial colonization of the tooth pellicle, generating plaque. If this material is not mechanically removed, it may become mineralized as tartar. Extended contact with plaque and/or tartar results in a localized inflammatory response known as gingivitis. Gingivitis is a marked by reddened, sore, and bleeding gums and, if left untreated, may progress to involve more extensive host tissue damage. In prolonged cases, bacterial colonization advances to subgingival tooth surfaces, forming pockets of infection below the gum line. The progressing bacterial infection results in chronic production of the pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-a) by host immune cells (24). These cytokines, in turn, induce endogenous host pathways that promote destruction of connective tissues and osteoclastic bone resorption. Gradual loss of support due to advanced periodontal disease is an important cause of tooth loss in the United States (35). Periodontal lesions are estimated to be among the most common bacterial infections in the United States today. Gingivitis and periodontal disease have been reported to affect 50.3% and 35% of the adult population, respectively (1, 2). Thus, over 85% of the adult population is thought to suffer from some form of gingival disease.
Periodontal disease has been classified into several diagnostic categories depending upon the age of onset, rate of progression, and responsiveness to clinical therapy (46). Despite the diversity of clinical presentations, these conditions may be classified into one of three histologically distinguishable states – acute, stable, and progressive lesions (15).
Acute lesions primarily involve a local innate immune response to the microflora of the oral biofilm. Gingival epithelial cells (Ep) recognize bacterial cell components via toll-like receptors and respond by producing IL-1 and TNF-a. Bacteria and bacterial products also penetrate into the underlying tissues. There they interact with fibroblasts (F) and dendridic cells (D). These cells also produce proinflammatory cytokines. Additional immune signals are generated by alternative complement activation (C). These bacterial products and pro-inflammatory cytokines affect vascular endothelial cells (En) as well. Endothelial cells express cellular adhesion molecules (ICAM and VCAM) that recruit circulating immune cells. Vascular permeability is also increased – allowing the influx of phagocytic cells and serum into the gingival tissue. Neutrophils (N) and macrophages (MF) are attracted to the site of infection by chemotaxis following gradients of complement proteins, cytokines, and bacterial products. Activated macrophages produce interleukin-12 (IL-12) and interferon-gamma (IFN-g). In Toto, these processes result in gingival inflammation, and are responsible for the clinical manifestations of gingivitis. A strong acute inflammatory response can limit the spread of periodontal pathogens. However, complete elimination of these bacteria requires the action of lymphocytes as well.
Stable lesions are histologically similar to delayed type hypersensitivity reactions like those caused by Mycobacterium tuberculosis (37, 41). A strong initial response by the innate defenses results in IL-12 accumulation. This promotes the recruitment and activation of macrophages (MF) and type I helper T lymphocytes (Th1). Phagocytosis by activated macrophages and neutrophils (N) serve to keep the bacterial infection in check. However, continued exposure to the oral biofilm present on the tooth’s surface results in a chronic infection. Limited host tissue damage occurs in stable lesions. Bacterial metabolic products (like butyric acid) and virulence factors cause necrosis or apoptosis of host cells. In addition, bacterial proteases can directly damage connective tissues such as fibrinogen or elastin fibers. These effects are relatively minor in stable lesions. Long-term infections do not cause bone resorption or extensive connective tissue remodeling.
Progressive lesions, in contrast, are associated with the most severe loss of host tissues. These lesions seem to follow after a weak or ineffective innate response. The cells that predominate in these tissues are B-lymphocytes (B), plasma cells (P), and type 2 helper T-lymphocytes (Th2). If the humoral response has sufficient strength and specificity, the infection is cleared. If the bacteria evade this response, however, host tissue damage may result. Stimulation of these immune cells by bacterial products (such as LPS) results in the excessive production of proinflammatory cytokines like IL-1 and TNF-a. These cytokines affect the function of host cells, and ultimately cause most of the tissue damage associated with periodontal disease. Fibroblasts (F) cease to produce fibrinogen and protease inhibitors. Instead, these cells and dendrocytes (D) now make matrix metalloproteases (MMP). These proteases, along with bacterially produced ones, degrade connective tissues within the periodontium. The production of other proinflammatory molecules (e.g. prostaglandins) is also stimulated. In addition, cytokines and prostaglandins affect alveolar bone homeostasis. Bone formation by osteoblasts (Ob) is inhibited. Conversely, osteoclasts (Oc) are stimulated to demineralize and degrade bone tissues. This combined effect results in bone resorption and is ultimately responsible for tooth loss in advanced periodontal disease.
The bacterial virulence and host factors that determine whether a stable or progressive lesion will form are clearly important. Conditions that favor a Th1 response should result in decreased host morbidity. Likewise, bacterial factors that evade or prevent a robust innate response may result in more frequent progression to advanced periodontal disease. Our research is focused upon determining if the lipopolysaccharide from Fusobacterium nucleatum is capable of playing such a role.
In addition to premature tooth loss, periodontal infections have been implicated in a variety of clinical conditions. Although relatively rare, periodontal pathogens have been shown to cause focal infections at other body sites including the heart (44) and brain (10). Moreover, a review of several studies suggests that chronic bacterial infections due to periodontal disease may contribute to the onset of atherosclerosis (7). It has also been suggested that dental plaque may act as a reservoir for non-dental pathogens. Specific interactions have been demonstrated between F. nucleatum and Helicobacter pylori (3), the causative agent of gastric ulcers. F. nucleatum has also been shown to bind to the opportunistic eukaryotic pathogen Candida dubliniensis (21). Due to the importance of gingival infections, much work has focused upon identification of the bacteria responsible.