Aetiology of periodontal diseases

Periodontal diseases are mainly inflammatory diseases. If only the gums are affected, it can be reversible, but if it proceeds to the supporting structures, the process becomes irreversible (in part). The aetiology is diverse, but the main reason of cause is bacterial infection. The following figure (Fig. 2.44.)summarizes aetiological factors of periodontitis:

Ethiopathogenesis of periodontal diseases (Modified from Wolf HF.)

As far as we know today, excessive tissue destruction is not the direct effect of bacteria, but the destructive effect of proteolytic enzymes released as a course of immune reaction. Different alterations in the immune system can be spotted either in defects of the neutrophil defence line, which is reversible, or by infection related, excessively released inflammatory cytokines induced over reaction processes. Both situations result in tissue destruction and pocket forming, which provides favourable circumstances for sub-gingival Gram negative anaerobic bacteria. These lead to further progression, which was well demonstrated by the Offenbacher (1996) model on the pathogenesis of periodontitis:

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Pathogenesis of periodontitis (modified from Offenbacher 1996)

The processes above are modified by genetic and non-genetic factors as well, as we described earlier. The complex process is demonstrated in the image below:

Current model of periodontal disease (modified from Page and Kornman 1996) In the following, we will examine the role of each factor in the process.

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Direct damaging effect of bacteria

Destructive processes of bacteria are the result of the release of proteolytic enzymes and harmful metabolic products. Damage affects the tissues (connective tissue fibres, fibrin, fibronectin), the components of the immune system (immunoglobulins, complement system), and structural proteins of soft tissues. Endotoxins of Gram-negative bacteria disturb blood clotting, damages the bone and complement system.

Indirect damaging mechanisms of bacteria

Bacterial toxins can force cells to produce cytokines directly. However, their endotoxins (lipo-poli-sacharides - LPS), and cell wall antigens (gingipain, fimbrillin, or stress proteins) can initiate pronounced immune reactions.

Proteolytic enzymes released by PMN cells cause tissue destruction. This is followed by epithelial in-growth and granulation tissue forming, which is rich in plasma cells at the destructed area. Plasma cells continuously release inflammatory cytokines, which leads to further destruction. Enzyme release of PMN cells can be inhibited by alpha-2-macroglobuline and alpha-1-antitripsine, but a bacterial antigen of Porphyromonas gingivalis called gingipain can even destroy enzyme inhibitor proteins.

Role of cytokines in periodontal destruction

Cytokines are small molecule weight glycoproteins. Their role is information flow among cells, immune response, cell differentiation, and regulation of growth. A mediator released by a specific cell can affect neighbouring cells (paracrine) or even itself (autocrine). Cytokines can be either proinflammatory, anabolic cytokines or growth factors. The same cell is capable to produce both, depending on the triggering effect.

Specific receptors are responsible for their effect.

Inflammatory cytokines express adhesion molecules, which help PMN cells migrate towards the inflammation, and fixate macrophages and lymphocytes in the connective tissue matrix. Their role is to initiate the immune response. They also play a major role in connective tissue and bone catabolism. Bone resorption is activated directly and indirectly: PGE2 production, macrophage transformation into osteoclasts, stimulating collagenase MMP enzyme production. They also inhibit new bone formation. Further cellular effects are the stimulation of T-cell and macrophage response, increasing the number of circulating PMN cells, promoting their chemotaxis, and stimulating MMP production.

Anabolic (anti-inflammatory) cytokines basically unite innate and adaptive immune subsystems by modulating T-helper cells. They reduce macrophage activity, and their production of cytokines. Anabolic cytokines also block phagocytosis and intracellular destructive processes, and antigen presentation. Through T-helper cells, they can inhibit inflammatory cytokine production, cytotoxic T-cells, and chemotactic function of the rest of T-helper cells. However, they promote activated B-cell growth and differentiation.

Growth factors play a role in the healing processes, attract differentiating cells (fibroblasts, mesenchymal cells, osteoprogenitor cells), promote differentiation, increase collagen, glucose-amino-glycane and other growth factors production and secretion. If these reparative procedures overweigh destructive procedures, regeneration (tissues as original) or reparation (tissues replacing original) takes place.

Products of the arachidonic acid cascade

As a result of insults damaging the membrane, phospholipids of the membrane are transformed into arachidonic acid by phospholiase-A2 enzyme. This metabolises further into leukotrienes (lipoxigenase), prostaglandines and tromboxanes (cyclooxigenase/COX). Enzyme COX-1, is responsible for protective measures (protection of mucosa, blood clotting). The other COX enzyme (COX-2) is responsible for pain sensation by releasing prostaglandins, and for fever, by affecting the heat control centre of the hypothalamus.

Prostaglandins induce oedema by vasodilatation, potentiate the effects of cytokines, stimulate MMP production, cause bone resorption in a direct and indirect way, and reduce the production of antibodies. Patientsh a hyper-reactive monocyte genotype are prone to extensive prostaglandin release, even under low bacterial insult.

Role of cellular elements

The main role of PMN cells is to eliminate opsonized material by phagocytosis. In order to achieve this, it has to react adequately to chemotactic stimuli, move through blood vessels, exit the blood stream, and destroy the opsonized foreign material by phagocytosis at the location of immune response. Any functional disorder can

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lead to severe periodontal destruction. Hyper-reactive PMN genotype comes with increased release of proteolytic enzymes, which ends up in severe tissue destruction.

More types of macrophages take part in the defence mechanisms of the periodontium. Some examples are the myeloid originated Langerhans-cells, and lymphoid originated natural killer (NK) cells. They play an important role in adaptive immune response. They use phagocytosis and proteolytic enzymes for antigen elimination.

Besides bacteria, they eliminate decomposed cells, too. They bind to immunoglobulins and complement proteins with surface receptors. They also produce inflammatory anabolic cytokines, prostaglandins, and leukotrienes.

Periodontal bone loss

A continuous remodelling takes place in bones: building and resorption are in balance. This makes it adaptive to altering loading forces (occlusial, orthodontic forces). The main cells in this process are osteoblasts and osteoclasts. Activated osteoclasts induce reapportion, which stimulates osteoblasts to rebuild bone. Systemic (Vitamin-D, parathormone), and local hormonal factors modify these processes. In a paradox way, osteoblasts are also responsible for bone resorption by producing RANKL (receptor activator ligand), which activate osteoclasts. This process is inhibited by osteoprotegerin (binding to RANK receptor, taking the place of RANKL), which synthesises in both osteoblasts and gingival fibroblasts. The RANKL-OPG connection is regulated indirectly through cytokines. This determines whether resorptive processes dominate, or there is a stable balance. Inflammatory cytokines promote RANKL production.

Several locally produced paracrine growth factors influence bone formation, matrix formation, and mineralising procedures. These factors are PDGF, IGF, TGF-beta, FGF, BMP, and EMD.

RISK FACTORS IN THE AETIOLOGY OF PERIODONTITIS Role of plaque microorganisms in periodontal diseases

In Chapter 2.12., the role of plaque bacteria has been mentioned in the aetiopathogenesis of periodontal diseases. From oral cultivated bacteria, 12 species have shown connection with periodontal diseases. Bacteria are considered to be periodonto-pathogenic, if they fulfil the Koch-postulates modified by Socransky:

Connection – has a greater probability of existence in periodontal patients Eliminating – eliminating the bacteria causes remission

Host response – provokes immune response, serum and salivary antibodies are increased in number

Virulence factor – production and facilitation of enzyme production, which make changes in the function of immune system elements

Animal study model – proven disease inducing effect, bacteria can be found in case of experimentally induced destruction.

The figure below describes periodonto-pathogenic bacteria and their relationship with aetiopathogenesis of periodontitis (Fig. 2.47.):

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Causal relation between an infectious agents and disease (modified from Wolf HE)

Besides the mentioned Streptococcus milleri can be found in a greater amount during the progression of the disease. Pink coded ones resemble close relationship, while yellow code stands for a more distant relationship with the disease.

Another group of bacteria can also influence periodontal diseases. These bacteria are not part of the natural oral flora and sub-gingival plaque (enteric bacteria, staphylococcus), but can be the initiators or contributors of periodontal diseases. They can be found in those who did not receive or did not react well to treatment (Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter agglomerans, and staphylococci).

We are deliberately speaking about microorganisms as the causes of disease. Recently viruses have been found to influence periodontitis. Viruses (Herpes simplex, Epstein-Barr, Human Cytomegalovirus and Papilloma virus) can alter the host response to sub-gingival plaque bacteria. They can be found more frequently in the periodontally compromised than in healthy patients.

The elements of sub-gingival flora are not randomly distributed, they are well organised spatially. Socransky and co-workers examined more than 13000 plaque samples to determine the spatial orientation of bacteria in the sub-gingival plaque. They were divided into colour coded groups named complexes.

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Microbial complexes in subgingival plaque (Socransky 1992)

Members of the blue, yellow, green, and purple complex are called early colonising bacteria. Gram-negative bacteria of the orange and red complex can bind to them.

Pathogenic effect of bacteria is influenced by the effectiveness of oral hygiene, plaque retentive factors, smoking, hormonal changes, and diet.

Genetic factors

Monogenicly transmitted, autosomal dominant and recessive illnesses, which come with PMN function disorder, or collagen metabolism disturbances, can be the cause of rapidly progressing, severely destructive periodontitis.

In case of aggressive periodontitis, no systemic background can be revealed, and the family history is positive for the disease. Genetic polymorphism is a common sequential alteration in the genome structure. It can be the result of the transition of a base or insertion, deletion. Periodontitis is a multifactoral disease; therefore, several genes play a role in its development, both environmental and behavioural factors. These gene alterations are not always manifested, only a connection between the disease and the gene alteration can be discovered. Cytokines (IL-1, IL-6, TNF), HLA-antigens, Fc-receptors and structural protein coding genes can be made responsible for the altered immune reactions. Genetics can explain the differences in likeliness of periodontal diseases among the various races.

Hormonal factors, smoking, systemic diseases influencing periodontitis have been discussed in Chapter 5.13.

Other risk factors

The beginning of this chapter, the immune status of the body has already been discussed. In case of occlusal overloading, it has to be mentioned that it cannot cause attachment loss by itself, but it can change the resistance to plaque in the periodontium, and increase in damage and tissue destruction of the inflammatory process.

Regarding nutrition, some nutrition deficiencies can only influence plaque induced illnesses: protein, Vitamin-D, calcium, Vitamin-C withdrawal can be mentioned as risk factors.

Psychological conditions: Indirectly, depression can cause negligence of oral hygiene, and antidepressant drugs can induce mouth dryness. Cytokines isolated from the saliva proved the influencing effect of negative stress in the pathogenesis of periodontitis.

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In poor social status population, several risk factors are combined (environmental and behavioural), therefore being influencing factors of periodontal diseases. Low degree of education comes usually with poor oral hygiene; however, high degree education does not necessarily come with appropriate oral care.