JICDRO is a UGC approved journal (Journal no. 63927)

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REVIEW ARTICLE
Year : 2015  |  Volume : 7  |  Issue : 1  |  Page : 44-50

Host-bacterial interplay in periodontal disease


Department of Periodontics, Krishnadevaraya College of Dental Sciences, Bengaluru, Karnataka, India

Date of Web Publication18-Mar-2015

Correspondence Address:
Dr. Rudrakshi Chickanna
Department of Periodontics, Krishnadevaraya College of Dental Sciences, Bengaluru - 562 157, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0754.153495

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   Abstract 

A literature search was performed using MEDLINE (PubMed) and other electronic basis from 1991 to 2014. Search included books and journals based on the systematic and critical reviews, in vitro and in vivo clinical studies on molecular basis of host microbial interactions. Clearly, an understanding of the host susceptibility factor in addition to microbial factors by elucidating the molecular basis offers opportunity for therapeutic manipulation of advancing periodontal destruction. One of the hallmarks of pathogenesis is the ability of pathogenic organisms to invade surrounding tissues and to evade the host defence. This paper focuses the general overview of molecular mechanisms involved in the microbiota and host response to bacterial inimical behavior in periodontics.

Keywords: Bacterial plaque, immune response, molecular mechanisms, pathogenesis


How to cite this article:
Chickanna R, Prabhuji M, Nagarjuna M. Host-bacterial interplay in periodontal disease. J Int Clin Dent Res Organ 2015;7:44-50

How to cite this URL:
Chickanna R, Prabhuji M, Nagarjuna M. Host-bacterial interplay in periodontal disease. J Int Clin Dent Res Organ [serial online] 2015 [cited 2019 May 20];7:44-50. Available from: http://www.jicdro.org/text.asp?2015/7/1/44/153495


   Introduction Top


Periodontal diseases are bacterial-induced inflammatory disease characterized by a complex interplay between the pathogens and the host tissue. Pathogens are eliminated by innate or adaptive immune response of the host. A disturbance in the equilibrium between bacteria and host, results in periodontal tissue destruction. As periodontal disease progresses, a series of events occur in bacterial plaque, gingival sulcus, junctional epithelium, connective tissue, and bone, due to alteration in tissue homeostasis. There is a gradual shift from gram-positive aerobic and facultative anerobic flora to gram-negative anerobic flora. A literature search was performed using various search engines like MEDLINE (PubMed) and other electronic basis. Search included both books and journals based on systematic and critical reviews on molecular basis of host microbial interactions, in vitro and in vivo clinical studies conducted during 1991 to 2014. An attempt has been made to update the existing reviews on molecular basis of host microbial interactions.

Subgingival biofilm formation

Subgingival plaque is formed by the spread of supragingival plaque down into the gingival sulcus. Initial colonization appears to involve Streptococcus species, Eikenellacorrodens, Aggregatibacter actinomycetemcomitans (serotype a), Capnocytophaga species, and  Actinomyces odontolyticus Scientific Name Search  complexes, which are followed by autogenic succession in which members of orange (Fusobacterium, Prevotella, and Camphylobacter species) and red complexes (P. gingivalis, Tannerella forsythia, and Treponemadenticola) becomes more predominant. [1],[2] Later colonizers attach to the antecedent organisms and assemble into polymicrobial communities. The importance of co-aggregation or co-adhesion for the development of plaque biofilms has been demonstrated in vivo. Coaggregation bridges form among early colonizers which in turn help the early colonizers to coaggregate with numerous late colonizers. In health, the climax community is thus established between microbial and non-microbial components existing in harmony and equilibrium with the environment. Micro-organisms colonize through autogenic succession brought about where the resident microbial populations alter their surroundings so that they are replaced by species better suited to the modified habitat. Later followed by allogenic succession, where one type of community is replaced by other because the habitat is altered by non-microbial factors. [3] (e. g., changes in host).

Quorum sensing displays the communication between the bacteria. Every bacterium has a capability of producing a signaling molecule (also known as inducer) and a receptor for the inducer. When the inducer binds to receptor, there is an activation of particular gene transcription. Most quorum sensing signals are small organic molecules or peptides. (e. g., N-acyl homoserine lactones (AHLs), alkyl quinolones (AQs)). Through this signalling, the bacteria communicates, coordinate their virulence in escaping from the host immune responses, and results in establishment of infection. Metabolic interactions among different bacterial cell type are likely to play a decisive role in the change in community composition during plaque maturation. [4]

Both host immune and bacterial factors are involved in the progression from healthy to diseased state in plaque biofilm, and in the oral cavity, gingival epithelial cells are one of the first host cell types that encounter colonizing bacteria. Clinical outcome of the disease is influenced by genetic, [5] as well as epigenetic factors. [6],[7] Epigenetic modifications alter patterns of gene expression, which in turn leads to variousclinical outcomes. Furthermore, variations in epigenetic status will likely elicit diverse inflammatory responses. Modulations of chromatin structure play an important role in the regulation of transcription, and these modifications directly affect the accessibility of chromatin to transcription factors, thus on gene expression. Epigenetic modification of genes, whose function is associated with growth control and inflammation, is differentially regulated by different oral bacteria. A recent study has focused on finding answers to how epigenetic modifications brought on by exposure to oral bacteria, including periodontal pathogens, affect host innate immune responses and susceptibility to subsequent infections. [8] Immune host factors are essential for disease susceptibility. Innate host recognition and stimulation occurs through pattern recognition receptor known as toll like receptors. [9] Human susceptibility to disease is linked to variation in toll like receptors and variation in signalling pathway that leads to variations in response to bacteria. [10] Subgingival biofilm composition is altered by host influencing factors like genetic background, obesity, and habits such as cigarette smoking. Habitat is also a pre-eminent factor in determining species association among micro-organisms. [11],[12] The change in the mean microbial profile may be related directly to the increased number of deep periodontal pockets. Most species of the orange complex and all species of the red complex increased significantly with increased pocket depth. Deep pockets have greater epithelial surface area to which red complex species such as P. gingivalis and T. denticola may attach. Although bacteria must be present for periodontal disease to occur, a susceptible host is also required. [13],[14] Host responses confer protection; however, an abnormal immune response can result in exacerbated tissue destruction. Such an abnormal inflammatory response, known as a "hyper-responsive" phenotype, has been linked to multiple inflammatory processes, where the phenotype has been described as an increased inflammatory response upon stimulation by toll-like receptors (TLR). Hyper-responsiveness to bacterial antigens results in increased production of pro-inflammatory mediators, which induce tissue and bone destruction. [15],[16] While TLRs play an important role in innate immunity, they can be double-edged swords, because abnormal activation of their signalling can be detrimental to the host, such as seen in the "hyper-responsive" phenotype. [17] The monocyte/macrophage cell linemay be hyper-responding when faced with the bacterial antigenic contact. This hyper-response results in a greater production of pro-inflammatory cytokines. Peripheral blood monocytes secrete up to 10-fold greater amounts of prostaglandin E2 (PGE2), interleukin-1 (IL-l), and tumor necrosis factors (TNF) when exposed to lipopolysaccharide (LPS). [18],[19]

Micro arrays are useful for investigating bacterial cell interactions with host proteins and host cells. Confocal microscopy, signalling molecules and molecular phylogenic analyses of cultivable and yet to cultured bacteria have increased our understanding in the development of plaque. Polymerase chain reaction has been used to detect the presence of selected bacterial species in subgingival plaque sample. [20]

Oral epithelium-microbial interactions

The oral epithelium particularly the junctional and sulcular epithelia, represents a dynamic physical and chemical barrier against the pathologic properties of the microbial biofilm. [21] Both host immune and bacterial factors are involved in the progression from healthy to diseased state in plaque biofilm, and in the oral cavity, gingival epithelial cells are one of the first host cell types that encounter colonizing bacteria. Epithelial tissue challenged by bacteria reacts by mobilizing their own antimicrobial mechanisms and by permitting cells of the innate and adaptive immune system to access the pathogens. [22] Cells of the junctional epithelium and resident leukocytes express antibacterial peptides including calprotectin α and β defensins, [23] cathelicidin, and IL-37 contributing to host defense and up regulating in tissues of patients with chronic periodontitis. Reports of increased prevalence and severity of chronic periodontitis in human immunodeficiency virus (HIV)-positive subjects suggests that HIV infection predispose to chronic periodontitis. Evidence strongly suggests the presence of many strains of viruses in the periodontal environment, and possible mechanisms have also been suggested. [24] Viral deoxyribonucleic acid (DNA) has been detected in gingival tissue, gingival cervicular fluid (GCF), and subgingival plaque from periodontaly diseased sites. In addition, markers of herpes viral activation have been demonstrated in the GCF from periodontal lesions. Active human cytomegalovirus replication in periodontal sites may suggest that human cytomegalovirus (HCMV) re-activation triggers periodontal disease activity. [25]

The junctional epithelium controls the microbial challenge with its special structural framework and through collaboration of its epithelial and non-epithelial component, which provide potent antimicrobial mechanism. It attempts to wall-off the underlying tissue from bacterial biofilm. Junctional epithelium may function as a reticular epithelium, providing a favorable environment for local immune recognition process. [26] The number of desmosomes and gap junctions that connect junctional epithelium are small and intercellular spaces are wide enough facilitating leukocyte infiltration and diffusion of antigens from the gingival crevice into gingival lamina propria. Polymorphonuclear leukocytes recruited through transendothelial migration and chemotactic factors play a key role in maintaining protective response against pathogens of the plaque biofilm. Disorders of neutrophils such as chronic neutropenia, cyclic neutropenia, and leukocytes adhesion deficiency are frequently afflicted with more severe form of periodontitis, due to attenuated inflammatory response to bacterial challenges and restrict the protective response against periodontal pathogens. [27]

Gingival epithelial cells, fibroblasts, and inflammatory cells respond to LPS by increasing the expression of cytokines, growth factors, matrix components, matrix metalloproteinases (MMPs) and this is mediated through the TLRs and CD 14. [28] The LPSs activates the expression of β-defensins by oral epithelial cells and this involves p38 and C-jun N-terminal kinase. [29] Nuclear factor kappa β (NF-Kβ) has been implicated in periodontitis and it is associated with the expression of IL-6 and other molecules that activate bone resorption. [30] Bacterial LPS can subsequently interact with macrophages or dendritic cell receptors including CD-14 and TLRs to stimulate the production of inflammatory cytokines and other soluble mediators. [31] The interaction of LPS with macrophages also stimulates production of prostanoids, in particular prostaglandin E2, a bone resorbing inflammatory mediator. [32]

During bacterial challenge, host recognize the bacteria and different antigen by different receptors present in periodontal tissues. TLRs and protease-activated receptors (PARs) [33] mediate cellular responses to extracellular proteinases such as thrombin and trypsin like serine proteases. Protease activated receptor 2 messenger ribonucleic acid (mRNA) has been demonstrated to be elevated with its potential activators in chronic periodontitis, suggesting their role in periodontal inflammation. PARs are expressed in epithelial cells, human neutrophils, endothelial cells, fibroblasts, and osteoblasts. Activation of PARs on endothelial cells results in recruitment of immune cells, disruption of the endothelial cell barrier as well as migration and release of growth factors and cytokines. [34]

A connective tissue shift to bacterial challenge

Inflammatory periodontal diseases cause both qualitative and quantitative changes in the molecular composition of the periodontal connective tissue. Both the fibrous and non-fibrous components of connective tissue are affected. Many pathogenic changes occur in the molecular composition of the periodontal connective tissues. The fluid response of connective tissue is an influx of an inflammatory infiltrate following plaque accumulation within 3-4 days, sufficiently robust to initiate connective tissue destruction with developing inflammatory lesion, collagens become more soluble and ratio of collagen type begins to change with an increase in type V collagen. Simultaneously, there is a significant change in the type of proteoglycans present. An important pathologic feature of developing periodontitis involves epithelial cell proliferation and cell migration over the modified connective tissue substratum. There appears to be change in the distribution of type VII collagen, laminin-5, fibronectin, tenacin, and β1 integrin in inflamed periodontal tissues. [35]

Degradation of the extracellular matrix occurs through the activation of matrix MMPs, release of reactive oxygen species, and phagocytosis of matrix components. MMPs play a major role in connective tissue destruction. Various enzymes are synthesized and secreted as inactive precursors and conversion to their active form requires activation by plasmin, trypsin, or other proteases. A number of growth factors and cytokine also regulate MMPs; in particular, IL-1 and transforming growth factor-β are key regulators of MMPs in inflamed tissue with serum and tissue inhibitors like α2 macroglobulin which regulate matrix MMP activity by preventing the conversion of precursor form to their active form. Oxygen-derived free radicals such as superoxide radical and hydroxyl radical are reactive molecular species elevated in cells undergoing active respiratory bursts during periodontal infection. The roles of reactive oxygen species in molecular alteration of collagen proteoglycans and haluronan have been demonstrated. Its additional role in inflamed tissue may involve activation of neutrophil collagenase. Cells defective in phagocytosis may contribute to gingival overgrowth and fibrosis as well as compromise normal wound repair and tissue regeneration. [36]

In inflamed gingiva the level of cytokines IL-α, IL-1 β, TNF-α, IL-6, IL-8, transforming growth factor-β (TGF-β), platelet derived growth factor, keratinocyte growth factor, vascular endothelial growth factor, and prostaglandins are affected in inflammatory cells, fibroblasts, and epithelial cells. [37] Their expression is induced when challenged by bacterial endotoxins. Pro-inflammatory cytokines released by oral keratinocytes and normal epidermal epithelium induces the expression of genes for cell adhesion molecules, cytokines, cyclooxygenase 2, inducible nitric oxide synthase, and matrix mellatoproteinases. IL-8 an important proinflammatory cytokine induces increase expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and other cell adhesion molecules. [38] Cytokines and growth factors affect the fibroblast function and regulate the activities of cells and cell to cell interactions.

Interactions of host - pathogen

Polymorphonuclear leukocytes are the first cellular host defence and are major players in immunopathology. Neutrophils are well adapted to function in hypoxic environment, because virtually all their energy is derived from fermentation of stored glycogen rather than oxidative phosphorylation. Polymorphonuclear leukocytes (PMN) appearance in the epithelium is the result of the presence or generation of chemotactic factor in the gingival sulcus and underlying tissues. Interaction of PMNs with bacteria has been shown to damage a variety of cell types, including fibroblasts, endothelial cells, and keratinocytes. [39] Their interaction with overwhelming masses of biofilm leads to the release of lysosomal enzymes, including tissue - destructive proteases [40] into the surrounding tissues as well as the synthesis and secretion of proinflammatory molecules such as arachidonic acid metabolites, bone resorbing lipids, and other inflammatory mediators likely to contribute to the inflammatory response and attachment loss observed in periodontitis.

The primary role of neutrophils is the destruction of pathogens through phagocytosis, outside the blood including periodontium. Because they do not need to differentiate substantially to function they are suited for rapid responses. Neutrophils are attracted by chemical signals (chemotoxins) from multiple sources. The multiplicity permits the neutrophils to respond to many different insults and also provides a redundant system that enables it to respond to insult even if one receptor is defective. Neutrophils possess receptors for metabolites of the complement molecules C3, designated complement receptors are CR 1 , CR 3 , and CR 4 . They also possess receptors for the immunoglobulin G (IgG) antibody (I cγR). These receptors enable neutrophils 1) to be recruited from the blood, 2) locate (opsonize), and 3) ingest (phaocytose) and kill the offending agents. Molecular defects in PMNs with a variety of functional consequences can be shown to result in accelerated Periodontitis. [41]

Complement system is the central component of inflammation that enables endothelium and leukocytes to recognize and bind foreign substance for which lost receptors. Complement system enhances to inflammatory response and enables to eliminate the antigen. Both C5a and formyl peptides are likely to play a major role in attracting neutrophils into the gingival crevice. Innate factors such as complement activation, in response to bacterial infection results in generation of complement derived anaphylatoxins C3a and C5a. Many complement proteins are proteases and produce inflammatory response. Activation of complement system include classical pathway, alternate pathway and lectin mediate pathway. C3 fragment is important in all the three pathways. C3b molecule opsonise pathogens and phagocytise them and C3a acts as a chemo attractants for phagocytes and activate mast cells. When approximately 100 molecules of C3b are formed, membrane attack complex (MAC) is formed, i. e., when C5b component associates with C6, C7, C8, and C9. MAC can lyse certain bacteria and cells by forming a large pore in the target cell membrane. Complement system also facilitates phagocytosis and destruction of foreign substances as well as direct stimulation of cells or microorganisms through the membrane attack complex. [42]

During chronic inflammation bacterial LPS can subsequently interact with macrophage or dendritic cell receptors, including CD14 and TLRs to stimulate production of inflammatory cytokines, prostanoids, PGE 2 , and other mediators likely to be important in human periodontal bone loss. Mast cells degradation increase within the gingival connective tissue as inflammation increases. They transcribe TNF-α, TGF-β, IL-4, and IL-6. When stimulated they induce transcription of proinflammatory cytokine such as IL-1, IL-6, interferon-γ (INF-γ), and others. The stimulation of endothelial cells by IL-1β, TNF-α, and bacterial LPS results in the expression of selectins on the luminal surface of the endothelial cells and release of chemokines from the endothelial cells, which results in the movement of neutrophils into the local tissue. Pathogen itself may dictate which type of response is generated through its interaction with accessory cells and resulting in production of cytokines characteristic of the response (Th1 or Th2). [32]

During the bacterial evasion of host defense, some bacteria produce substances that suppress the activity or kill PMNs (neutrophils) and lymphocytes normally involved in host defences. One such example is the production of two toxins (leukotoxin and cytolethal distending toxins), by Aggregatibacter actinomycetemcomitans important in the virulence of the micro-organism; similarly, T. forsythia [43] and F. nucleatum [44] have been shown to induce apoptosis, a form of cellular "suicide" in lymphocytes. P. gingivalis is able to inhibit the production of IL-8 by endothelial cells, which may provide the organism with an advantage in evading PMN-mediating killing. A wide range of proteolytic enzymes have been identified by P. gingivalis, which may facilitate tissue destruction and invasion of bacteria into host tissues. The relationship between P gingivalis, T forsythia, T denticola, P intermedia, and A. actinomycetemcomitans in the sulci or pockets of patients with gingivitis (G), mild chronic periodontitis (MiCP), moderate chronic periodontitis (MoCP) and severe periodontitis (SP) showed that that the presence of P intermedia may trigger the expression of TNF-α and cause worsening of the patient's clinical status One mechanism by which bacteria may indirectly cause tissue damage is by induction of host tissue proteinases such as elastases and matrix MMPs. A well-characterized host-pathogen interactions involve the release of IL-1, TNF, and prostaglandins from monocytes, macrophages, and PMNs exposed to bacterial endotoxin (LPS). [45]

Immunologic response of host-microbial interaction

T cell plays an important immuno-regulatory role rather than a defensive or destructive role in the pathogenesis of periodontal diseases. T cells are involved in the recruitment and activation of neutrophils at the site of infection. The suppressive effect of plaque bacteria may be fundamental in the conversion of a stable lesion to a progressive lesion. Therefore in the stable lesion, activation of the neutrophils may be crucial in keeping the infection under control. [46]

Innate immune response leads to the production of IL-12 which in turn leads to a Th1 response. The production of interferon-γ then enhances the phagocytic activity of both neutrophils and macrophages; hence, containment of the infection. Th1 cells are associated stable lesion and Th2 cells are associated with disease progression. A predominated expression of Th2 cytokine could contribute to the induction of high B-cell response in local disease site. It remains clear that the balance of cytokines in inflamed periodontal tissues is what determines whether the disease remains stable or lead to progression and tissue destruction. [47] The cross talk between innate and adaptive immunity mediated by dendritic cells via TLRs and the antigen-specific immune regulation is by particular subsets of dendritic cells and T cells. [48] Most studies on TLRs have focused on TLR-2 and TLR-4 because they recognize gram- positive and gram-negative bacterial Pathogens-Associated Molecular Patterns (PAMPs), respectively. Of particular note is Porphyromonas gingivalis LPS, which preferentially utilizes TLR-2 and not TLR-4 within periodontal tissues, TLR-2 and TLR-4 expression appears to be increased in severe disease states. [9] TLRs of resident immature dendritic cell detect the PAMPs on or released from invading micro-organisms. They transmit information about the encounter through signaling pathway resulting in activation of dendritic cells. Mature dendritic cells can not only present antigens in a major histocompatibility (MHC) class II peptide complex but also produce cytokine profile and specificity of the local immune response in periodontitis lesions, reflect the presence and function of sub classes of regulatory T-cells induced by the microbial film. [49] This involves expression of Co-stimulatory molecules (CD40, CD54, CD80, and CD86), cytokines, and chemokines critical for T-cells priming and differentiation. Dendritic cells provide an important line for the generation and modulation of the immune response to PAMPs. T-cells have a fundamental role in maintaining immune homeostasis in the presence of the plague biofilm.

T-cell are dominant cell type in cell-mediated (macrophage lymphocytes) response and are necessary for polyclonal B-cell activation and specific antibody production continued B-cell activation leads to production of high level of IL-1 resulting in destruction, along with increase levels of interferon-γ and minimal IL-5. The quality of specific anti-bodies produced reflects the quality of the humoral response. If specific anti-bodies with high specific avidity with Ig subclasses are formed against immuno dominant antigen, then the inflection may be cleaned and the disease wills not progress. Early lesions of chronic periodontics are characterized by a cellular infiltrate comprising mainly macrophages and T-lymphocytes. More advanced lesions demonstrate connective tissue loss and bone resorption containing large number of β-lymphocytes and plasma cells. Early lesion is most consistent with a Th1 response due to intra cellular pathogens on the other hand advanced lesion is more consistent with Th2 response typically mounted to fight extra cellular pathogens. Th1 is characterized by IL-12 production which in turn induces interferon γ production, leading to macrophage activation, increased phagocytic activity, and protective immunity. Th2 response entails production of alternative cytokines such as IL-4, IL-10, and IL-13 leading to antibody protection. Chronic periodontitis is more associated with Th2 response. [50] The persistence of Th1 response can induce harmful molecules including nitric oxide (NO), reactive oxygen intermediate, IL-1, interferon-γ, and TNF. [51]

T lymphocyte isolated from periodontitis lesion express Receptor Activator of Nuclear Factor-κBligand (RANKL). As T-cell specific for periodontopathic bacteria exists in the peripheral blood of periodontitis patients, they might potentially express RANKL when they encounter the specific antigen. Activated T-cells might mediate bone resorption through excessive production of soluble RANKL. [52] The recruitment of new osteoclasts is dependent on the balance between RANKL and its decoy receptor osteoprotegerin [53] in osteoblasts. Osteoblasts regulate osteoclastic bone resorption which involves recruitment of new osteoclasts and activation of mature osteoclasts. Thus, the differentiation and function of osteoclasts are regulated by osteoblasts. [54] Choi et al., reported that B-lymphocytes also produce RANKL and augment osteoclastogenesis. [55] In periodontitis lesion, lymphocytes, macrophages and neutrophils infiltrate the gingival connective tissue, and interact with osteoblasts, periodontal ligament fibroblasts, gingival fibroblasts, and inflammatory infiltrate (T & B lymphocytes and macrophages) macrophages and T-lymphocytes produce inflammatory mediators, including IL-1, IL-6, TNF-α, and prostaglandin E2 which can induce bone resorption indirectly by stimulating osteoblasts to produce RANKL. T lymphocytes can promote osteoclasts differentiation by direct production of RANKL. Alveolar bone resorption might be directly or in directly induced by inflammatory infiltrate in periodontal lesions. [56]


   Conclusion and Future Directions Top


The central role of dental plaque in periodontal disease involves direct tissue destruction with the immune response-related tissue destruction process. The response of the host plays a central role in eliminating the foreign bacterial pathogens through the innate and adaptive defensing mechanism. [57] Change in oral environment conditions can disrupt the normal symbiotic relationship between the host and its resident microbes, and increase the risk of disease. Bacteria colonizing the tooth surface induce an inflammatory cascade, including generation of chemokines and upregulation of adhesion molecules on leukocytes suggesting that IL-1 and TNF participation in periodontal inflammation and bone loss.

P. gingivalis is the major pathogen of chronic periodontitis which is a global epidemic prevalent in two-thirds of the adult population and autoimmune diseases. Atherosclerosis, diabetes mellitus and rheumatoid arthritis also can be triggered and aggravated by the pathogen-driven antigenic peptide from Porphyromonas gingivalis Henoch-Schonlein purpura 60 (HSP60). [58] Complete genome sequence of bacterial strain TDC-60 porphyromonas gingivalis has been identified as a causative agent of periodontitis. [59]


   Summary Top


Elucidating the molecular basis of the signalling pathway in periodontal disease offers opportunity for therapeutic manipulation and provides potential local agents for future use in patient care. Conversion of the gingival crevice from an inhospitable milieu to one conducive is the primary goal of periodontal treatment and host modulation to be considered only after preventing the progression of the periodontal disease. The next era in the immunobiology of periodontal disease need to engage more sophisticated experimental designs for clinical studies to enable robust translation of basic biologic processes that are in action early in the transition from health to disease, those which stimulate micro environmental changes that select for a more pathogenic microbial ecology and those that represent a rebalancing of the complex host responses and a resolution of inflammatory tissue destruction.

 
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