INTRODUCTION:

Periodontitis is a destructive inflammatory disease that can attack the supporting tissues around teeth, consisting of the gingiva, periodontal ligament, and alveolar bone caused by specific. Microorganisms with clinical manifestation include tooth mobility, pocket formation, loss of attachment, and gingival recession^1,2. According to data from Riskesdas 2018, the prevalence of periodontitis, especially chronic periodontitis, has increased by 42.8% (1995), 70% (2001), 96.58% (2004), and 60% (2012), until in 2018, the prevalence of periodontitis, especially chronic periodontitis, in Indonesia was 67.8%³. According to the American Academy of Periodontology, periodontal disease is divided into two groups: aggressive periodontitis and chronic periodontitis .

The etiology of periodontal disease is divided into two factors, local and systemic factors. Local factors caused by the presence of plaque and calculus caused by bacteria, especially bacteria Tannerella forsythia, Prevotella intermedia, Treponema denticola in destructive periodontitis with deep pockets, removable partial dentures, fixed dentures, due to tooth extraction, braces users, missing teeth, and crowded teeth. Systemic factors caused by diabetes mellitus, psychosomatics, stress, changes in synthetic hormones in hormonal contraceptives containing progesterone and estrogen, and nutrition^3,4. In addition to local and systemic factors, behavioral factors can lead to periodontitis, namely the habit of smoking or chewing tobacco, bad habits, and others^3,5–7.

Chronic periodontitis often occurs in adulthood and includes slowly progressive periodontitis⁸. The leading cause of chronic periodontitis is the chronic accumulation of bacteria in plaque and calculus. Bacteria that play a role in chronic periodontitis are gram-negative bacteria that live in anaerobic environment such as Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Treponema denticola, and Prevotella nigrescens. However, the bacteria that more often plays a role in chronic periodontitis, according to Mahalakshmi et al. (2012) is Porphyromonas gingivalis, with around 80.5%⁹. These bacteria are located in the subgingival plaque area and can lead to pro-inflammatory prostate prostaglandins and cytokines that cause damage to the periodontal tissue¹⁰. Besides being caused by bacteria, chronic periodontitis is also associated with biological factors (diabetes, genetic factors, obesity, the presence of high blood pressure and high cholesterol) and risk factors for bad behaviour, such as a poor diet, a lack of physical activity, and the use of cigarettes^7,11,12.

Porphyromonas gingivalis:

Porphyromonas gingivalis is the second most crucial bacterial pathogen. Causing periodontal disease after Aggregatibacter actinomycetemcomitans. Porphyromonas gingivalis is one of the anaerobic gram-negative bacteria in the form of coccobacterium. Porphyromonas gingivalis belongs to the Bacteroides group, which has a black pigment. On cellular and molecular examination, the bacteria formed greenish-brown colonies on blood agar plates. In addition to these bacteria, other bacteria that can also cause disease in periodontal tissues is Prevotella intermedia, which can produce various very high virulence factors¹³. Based on a study, Porphyromonas gingivalis are thought to be able to produce collagenase, protease, hemolysin, endotoxin, fatty acids, and others. The bacterial mechanism can inhibit the movement of Polymorphonuclear cells through Endothelial cells. Porphyromonas gingivalis is found in periodontitis. Patients, especially in aggressive periodontitis. At the same time, Prevotella intermedia was found in chronic periodontitis patients.

Colonies of Porphyromonas gingivalis bacteria can attack the gingival mucosal epithelial cells and the endothelial cells of the oral cavity. The bacteria can do this by using bacterial fimbriae as a means of movement in the epithelial cells of the oral cavity. During the formation of biofilms in the oral cavity, the bacteria continue to stick together and get stronger to form colonies for a continuous period if it is not followed by dental health care. Biofilm-forming colonies were divided into first and last colonies. Among the first colonies were Streptococcus mitis, Streptococcus gordonii, Streptococcus oralis, and Streptococcus sanguis. Subsequently, the final bacterial colonies were formed by a complicated bacterial aggregation process that continues to Fusobacterium nucleatum, Treponema denticola, Porphyromonas gingivalis, A. actinomycetemcomitans, Prevotella sp., and others. In addition to bacteria that cause periodontal disease, the factors that because periodontal disease can vary. Several factors, such as biomechanical, systemic factors, and the host immune system, have an essential role in the pathology of the disease¹⁴.

BIOFILM:

A biofilm is defined as a complex microbiological ecosystem formed by a single species or many species (multispecies) linked to an organic polymer matrix¹⁵. Meanwhile, other researchers have defined biofilm as an association of microorganisms in which microbial cells attach to living and non-living surfaces in a matrix produced by themselves from extracellular polymeric materials¹⁶. Biofilms are complex groups of microbial cells embedded in an exopolysaccharide matrix on the surface of medical devices where biofilm-associated infections can pose a severe public health problem¹⁷. Biofilms are made up of several organisms that form multicellular formations and are then held together by a matrix of excreted polymeric compounds (EPS) that provide biofilm protection, adhesion, stability, and nourishment. Water makes up the majority of the biofilm matrix (91%) and can act as a solvent or directly bind to bacterial cells. Water is an essential component because it promotes the spread of the biofilm. The biofilm's microbial composition is around 5%, the EPS matrix is 2%, and DNA, RNA, and other proteins are 2%. The matrix structure varies depending on the bacterial composition and environmental conditions. The presence of the extracellular matrix protects to the constituent cells from external damage. This extracellular matrix also provides a barrier to diffusion to small molecules. In this regard, some cells in the bacterial community are metabolically inactive due to the slower diffusion of vitamins, nutrients, and co-factors in the biofilm¹⁸. Biofilm formation is complex, but in general, it can be grouped into five basic steps:

1. Reversible initial attachment:

The initial adhesion from planktonic bacteria to different surfaces is via flagella and fimbriae, among other factors ¹⁹.

2. Irreversible attachment:

Bacteria form a single layer and adhere permanently by producing an extracellular matrix consisting of structural proteins, extracellular polysaccharides, nucleic acids, or what is known as Extracellular Polymeric substances (EPS)^20,21.

3. Microcolonial formation:

At this stage, there is the formation of microcolonies and the emergence of multilayers indicating cell-to-cell growth and communication, such as quorum sensing. At this stage, microcolony formation occurs, and multilayers emerge, which shows bacterial growth and communication such as quorum sensing²¹.

4. Maturation:

Biofilms grow in three-dimensional form, and their attachments are now irreversible²¹. The three-dimensional (3D) cell masses vary in their architecture, forming a 'mushroom-like structure due to polysaccharides²⁰.

5. Dispersion

At this, the final stage of biofilm formation, cells derived from mature biofilms begin to detach and spread to the environment as re-planktonic cells. That has the potential to form new biofilm cycles²¹.

Biofilm formation is induced and regulated by many genes and environmental factors, including quorum sensing (QS) and bis-(3′-5′)-cyclic diguanosine monophosphate (c-di-GMP). The third is small RNA (sRNA), although its role in biofilms remains unclear²². Another factor responsible for shaping the structure of a biofilm and informing the final associations that will form a well-organized adult biofilm for adhering to the surface is physiological and cooperative²³. Biofilm formation is not a good thing in many ways, so there must be some way to stop biofilm formation. So there are some anti-biofilm approaches, and by using them, we can stop biofilm growth^24–26.

Pathogenesis of Periodontitis:

The oral cavity is one of the habitats that result in the colonization of various commensal microbial species because it provides various nutrients with high levels of humidity and oxygen concentrations that vary. In addition, the presence of soft (gingival) and complex (dental) tissues. Provide a potential surface for microorganisms to adhere to and interact with a variety of hosts. In healthy people, oral cavity colonization is based on a balanced bacterial host and interactions between bacteria. Meanwhile, if there is unbalanced colonization, which can result in persistent dental plaque in the gingival tissue and the interaction of the pathogen with the host cell, inflammation will occur that causes periodontitis^27–30.

Figure 1. Periodontitis Pathogenesis²⁸.

The beginning of the formation and maturation of biofilms occurs when opportunistic microorganisms enter the host cell. Various factors cause the entry of these opportunistic microorganisms. One of the factors that are often encountered is poor oral hygiene. Poor oral hygiene will result in various infections in periodontal host cells and can result in the virulence factors' expression that can trigger an inflammatory reaction at the local level. Gingivitis is one of the earliest inflammations of periodontitis and can be corrected by removing the biofilm (figure 1)^18,31.

On the other hand, an abundance of opportunistic bacterial species has accumulated, resulting in a long-term inflammation. Periodontal disease is indicated by a rise in gram-negative anaerobic bacteria ²⁸. Thus, any change in this composition can affect the host immune response and cause a dysbiosis between the oral microbiota and its host cells³². Therefore, after the onset of inflammation of the gingiva or gingivitis, periodontitis progresses from inflammatory to chronic condition.

Periodontitis is a multifactorial disorder caused by bacteria and balance disorder's host and parasite causing tissue destruction^33–35. The occurrence of periodontitis begins with the accumulation of biofilm near the teeth to trigger local inflammation or better known as gingivitis, which is the mildest form of periodontitis and can be corrected if hygiene is maintained oral, immediately³⁶. When there is an expansion of subgingival plaque into the gingival sulcus, it can interfere with the attachment to the coronal epithelium, resulting in loss of supporting connective tissue and alveolar bone, which is referred to as periodontitis and is irreversible^33,37. Several microorganisms present in subgingival plaque, including Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Prevotella intermedia, and Treponema denticola can activate immune responses against.

Periodontal pathogens and endotoxins bind neutrophils, macrophages, and lymphocytes to the gingival sulcus to maintain host tissue and control the development of bacteria³⁸. The host's susceptibility factor plays a crucial role in the process of periodontitis. Host cell body susceptibility itself can be influenced by several things such as genetics, environment, behavior such as smoking, stress, and diabetes^39–44. Inadequate host cell body response in destroying bacteria can destroy periodontal tissue. The stage of periodontal tissue destruction is the transition stage from gingivitis to periodontitis. It can occur when there is a disturbance in the balance of the number of bacteria with the host cell's response. The immune system in the host cell body tries to protect host cells from infection by activating immune cells. As neutrophils, macrophages, and lymphocytes to fight bacteria macrophages will be stimulated to produce products in the form of a cytokine matrix. Metalloproteinases (MMPs) and prostaglandin E2 (PGE2). High levels of cytokine MMPs in the tissues can mediate the destruction of the gingival cellular matrix, the attachment of collagen fibers to the apical junction of the epithelium and the periodontal ligament. Meanwhile, the cytokine PGE2 can mediate bone destruction and stimulate giant osteoclasts to resorption alveolar bone crests³⁸. Loss of collagen can cause apical fused epithelial cells to proliferate along the tooth root and the coronal portion of the fused epithelium to separate from the tooth root. Neutrophils will invade the coronal portion of the fused epithelium and increase in number. The tissue will lose its unity and detach from the tooth surface, and the sulcus will expand apically so that the gingival sulcus will turn into a periodontal pocket⁴⁵.

T Cell-Mediated Responses in Periodontitis:

T lymphocytes are the cells of the immune system that play a role in the defense of the host and regulate the progression of inflammatory diseases. Because T cells are made up of two chains of glycoproteins called (alpha) and (beta) chains, they are recognized from other lymphocytes by the presence of a T cell receptor (TCR) on their cell surface. Th, Treg, cytotoxic T (CD8+), natural killer, and memory T cells are the different types of T cells. T cell energy was also identified as a peripheral tolerance mechanism that determines T cell functional deactivation upon antigen detection in less-than-ideal settings^46,47. T lymphocytes predominate CD4+ helper T cells in healthy gingival conditions, which play a critical role in the adaptive immune response. The conventional framework of diverse Th cell subsets is formed by their secretion of cytokines in response to specific immunological challenges^48,49.

Activated Th1, Th2, and Th17 cells produce IL-1, IL-17E (IL-25), and IL-17, which activate dendritic cells, neutrophils, and other immune cells. The following activation of both T and B cells can cause the assembly of nuclear factor receptor activator B-Ligand (RANKL). It causes resorption of alveolar bone by osteoclasts and leads to tooth loss. Alternative causative factors embrace the shortage of Treg cells or the shortcoming of the present Treg cells to attenuate the native inflammatory response by immunological cells of different types that will play a task in chronic inflammatory disease related to periodontal disease⁵⁰.

T cells are also involved in tissue secretion of IL-17, a cytokine that has been linked to bone loss around teeth. In gingival lesion biopsy specimens from periodontitis patients, levels of IL-17 and IFN-, IL-17A, and T-bet mRNA was higher than in healthy restraints. It suggests thatTh17 and Th1 cells may play a role in chronic periodontitis development. Furthermore, periodontitis patients had a considerably larger percentage of CD4+ T cells that produced IL-17⁵¹. In the absence of RANKL, T cells express a cytokine known as an osteoclastogenic factor of activated T cells (SOFAT), which can stimulate osteoclastogenesis⁵².

Figure 2. T cell-mediated responses in periodontitis ⁵².

Inflammation-Induced Defect Alveolar Bone-In Periodontitis Disease

Figure 3: Inflammation-induced bone loss in periodontitis ⁵³.

Role of RANKL/ RANKL and OPG:

RANK is an Nf-Kb receptor activator and RANKL is an Nf-Kb ligand activator receptor expressed by osteoblast cells, fibroblast cells, and T and B lymphocyte cells. OPG stands for osteoprotegerin, which is produced by osteocyte cells. RANKL/OPG regulation is an indication of alveolar bone damage in patients with periodontitis. OPG deficit and increased RANKL cause more activated osteoclasts and cause alveolar bone defects. Osteoblasts can increase NFkB activation and increase RANK/RANKL expression levels. The expression of RANK/RANK-L under physiological conditions tends to be lower, but under pathological conditions, its expression is suppressed in response to bacterial infections such as Porphyromonas gingivalis⁵⁴. Osteoprotegerin (OPG) functions to regulate the role of osteocytes to reduce osteoclastogenesis. Under physiological conditions, OPG is a counterweight to RANK/RANKL⁵⁵. The shift in the OPG/RANKL ratio in osteocytes in induced periodontitis benefits osteoclasts acting as macrophages in the alveolar bone ^56,57.

The role and function of RANKL/OPG in induced alveolar bone defects in periodontitis patients was investigated in a rat study in which OPG was used to block or limit the use of RANKL. Inhibition of RANKL/RANK can prevent alveolar bone loss in periodontitis⁵⁸. Immunohistochemical examination showed that RANKL/RANK expression in the gingival tissue of periodontitis patients tended to be higher, while OPG levels decreased. It causes continuous alveolar bone defects in periodontitis patients⁵⁹.

Neutrophils:

Neutrophils in Gingival Crevicular Fluid (GCF) in the periodontal tissues increase during inflammation. Neutrophils induce monocytes to produce TFF-10 and IL-10 is anti-inflammatory and reduces the increase in pro-inflammatory cytokines such as Th1 and Th17^60,61. In addition, neutrophils influence tissue damage via the RANKL/RANK pathway. RANKL plays a role in inducing neutrophil migration and inducing degranulation⁶². Neutrophils can also cause macrophages to polarize towards an anti-inflammatory phenotype, resulting in a resolution in inflammation regulation⁶³.

Cytokine and lipid mediators:

In studies of mice lacking IL-1, TNF-alpha, IFN gamma, or IL-6 can show bone loss. Based on this study, alveolar bone loss in periodontitis induced by Porphyromonas gingivalis can express HMGB1 in response to inflammatory stimuli caused by this bacterial infection^64,65. Anti-HMGB1 antibodies can reduce the secretion of various anti-inflammatory cytokines to inhibit the continuous development of periodontitis⁶⁶. Other studies have shown the effect of biologic agents as indicative parameters of periodontitis, such as the monoclonal anti-TNF alpha monoclonal antibody, adalimumab⁶⁷. Cytokines and lipid mediators can also trigger inflammation to support the regeneration of bone tissue⁶⁸.

Protease:

Protease is an enzyme that functions to induce alveolar bone resorption induced by the inflammatory process in a study of mice with urokinase-resistant plasminogen activator knockout against Porphyromonas gingivalis via macrophages⁶⁹. The ability of bacteria to breakdown the matrix in uPA was improved by stimulation generated by macrophages in gingival pain (RgpA-Kgp complex)⁷⁰. RgpA-inducing bacteria were capable of causing significant alveolar bone loss in patients with periodontitis⁷¹. The proteolytic activation of uPA by Porphyromonas gingivalis acts as a periodontitis pathogen to inhibit loss of alveolar bone. In addition, mice infected with protease 2 (PAR2) activated receptor knockout infected with Porphyromonas gingivalis bacteria did not show significant resorption of periodontal bone⁷². PAR2 secreted by oral epithelial cells is an essential mechanism of bone defects caused by bacterial pathogens of periodontitis⁷³. RgpA activates uPA and PAR2⁷⁴.

Mesenchymal cells:

Osteocytes (DMP1-Cre)⁷⁵ and various osteogenic cells (IKK-DN)⁷⁶ in periodontal inflammatory bone defects occur progressively. RANKL (Col1-1-Cre), a protein generated by periodontal ligament and bone cells, is involved in tooth migration caused by alveolar bone resorption⁷⁷. An increase in OPG accompanied by a decrease in RANKL in synovial bone fibroblasts (Col6a-Cre) was able to show protection against bone resorption ⁷⁸. In addition, cells of the mesenchyme act as a significant source of RANKL during the inflammatory osteolysis process. In the patient's gingival tissue, it was found that T cells and B cells express RANKL and induce osteoclastogenesis. In a mouse study, it was found that inflammatory. Osteolysis occurs based on RANK/RANKL binding mainly by cells of the mesenchymal cell lineage⁷⁵.

CONCLUSION:

Periodontitis is a destructive inflammatory disease that can attack the supporting tissues around the teeth, consisting of the gingiva, cementum, periodontal ligament, and alveolar bone caused by specific microorganisms with clinical manifestations of tooth mobility pocket formation, loss of attachment, and gingival recession. The formation of oral cavity biofilm plaques is based on unbalanced substrate components and interactions between bacteria. The occurrence of dental plaque on a regular basis in the gingival tissue and the interaction of the pathogen with host cells causes inflammation of the periodontal tissue. A decrease will follow an increase in pro-inflammatory cytokines and high RANK/RANKL in OPG. It also triggers the destruction of periodontal tissue, which results in periodontitis. Patients with chronic periodontitis had relatively higher levels of IL-17 and IFN-γ compared to healthy controls. It also reveals a considerable rise in the fraction of CD4+ T cells that generate IL-17, and Th17 and Th1 cells are involved in the etiology of chronic periodontitis.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

There is no acknowledgement.

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Received on 27.09.2021 Modified on 23.05.2022

Research J. Pharm. and Tech 2023; 16(4):1754-1760.

DOI: 10.52711/0974-360X.2023.00289