Host-microbial interactions in periodontal diseases

The microbial biofilm that forms around the teeth is the main cause of periodontal disease initiation and progression. This biofilm is a complex community of microorganisms which produces various virulence factors that initiate an inflammatory response. The enzymes released by bacteria in the biofilm include proteases that are capable of disintegrating collagen, elastin, fibronectin, fibrin and various other components of the intercellular matrix of both epithelial and connective tissue. Other proteases are leukotoxins which are capable of killing leukocytes. Endotoxins are produced by Gram -ve bacteria which are strong inducers of cytokine production. The term lipopolysaccharide (LPS) is often used interchangeably with endotoxin. As the subgingival biofilm is majorly composed of Gram -ve bacteria, endotoxins produced by them leads to the induction of cytokine production by host cells, which causes inflammatory changes, like increased vascular permeability and engorgement of blood vessels. In the present discussion, we shall read about various interactions that take place between the plaque microbiota and the host immune response.

Evolution of our understanding of periodontal disease progression

Our understanding about periodontal disease progression improved tremendously during 1960’s, when animal and human experiments demonstrated the role of bacteria in the initiation of gingivitis and periodontitis 1, 2. These studies led to the proposal of the model of bacterial etiology of periodontal disease. Further investigations in this field led to the advancement of our knowledge of pathogenic bacteria causing disease progression. Specific Gram-negative, anaerobic, or microaerophilic bacteria were implicated in the causation of periodontitis 3-7. During late 1970’s and early 1980’s protective and destructive roles of the immunoinflammatory responses were described in health and disease 8-14.

Most of the models of periodontal disease progression in the late 1980s stated that specific bacteria initiated the disease process by activating host responses, which were protective and destructive. The actual destruction of connective tissue and bone resulted primarily from inflammatory chemical mediators released by immunocompetent cells, such as matrix metalloproteinases, IL-1, and prostaglandins.

Our understanding of the pathogenesis of periodontal diseases was greatly improved by longitudinal studies published during late 1980’s and 1990’s. Löe et al. (1986) 15 in their classic study of the natural history of periodontitis on tea plantation workers in Sri Lanka found that among individuals with poor oral hygiene and no access to dental care, some developed disease at a rapid rate, whereas others experienced little or no disease. In this study, it was appreciated that some unrecognized environmental factors or some individual differences in susceptibility to the disease were present in the population under study. During the same period, the importance of genetic variations in determining the development and severity of periodontal disease, with genetic influences accounting for as much as 30% to 60% of the variability in the clinical severity of periodontitis was established 16, 17. Along with this, it was found that smoking 18-21 and diabetes 22-26 were powerful determinants of disease severity. These factors were considered as modifying factors for the final outcome of the disease progression. So, to incorporate all these factors in the pathogenesis of the periodontal disease, non- linear model of disease progression was proposed 27.

Recently, Kornman 28 (2008) put forward a biologic systems model of the pathogenesis of periodontal disease. Although the non-linear model of disease progression still holds well, this model incorporated the role of contributing factors in the pathogenesis of periodontal diseases. According to this model, disease activity depends on an ecological shift in the plaque biofilm that can lead to the emergence of a specific set of microbial pathogens 29, 30. Various environmental factors can contribute strongly to the individual patient differences in the susceptibility to periodontitis, which includes diabetes, genotype and smoking 23-25. Recent studies have strongly advocated the relationship between periodontal diseases and systemic diseases like coronary heart disease 31-36, chronic obstructive pulmonary disease 37-39, all of which involve a common inflammatory mechanism. And lastly, there is further enhancement of our knowledge about specific bacterial mechanisms and immunoinflammatory mechanisms in periodontitis 40, 41.

Models of disease progression

In the past, several patterns of disease progression have been described 42-45. The patterns of tissue destruction in the progression of periodontal diseases have been explained with the help of various models including,

  1. Continuous model: This model explained that the periodontal disease progression occurs in a slow, steady and progressive manner. However, this model did not explain the rapid progression and periodic remission of the disease activity.
  2. Episodic burst model: Subsequent studies explained the irregular periods of exacerbation and remission. They explained that disease progression occurs as an episodic burst of activity with periods of remission.
  3. Synchronous burst model: It explained that the periodontal diseases progress with periods of exacerbation and remission during a defined period.
  4. Epidemiologic model: This model proposed that the disease progression is continuous with aging and it depends only on the duration of the process.
  5. Brownian motion or stochastic model: According to this model, random periods of sharp bursts and/or remission can occur, but the underlying disease activity remains constant.
  6. Random walking model: When observed at regular intervals this model is similar to the Brownian motion model.
  7. Fractal model: It is a multi-factorial model simulating disease advancing with age with burst and remission.

Although, many models have been proposed, but it has now been recognized that linear disease progression can occur and there may be episodes of tissue destruction 46, 47.

Our current understanding of host-microbial interaction

To better understand the host-microbial interactions in periodontal diseases, one should have the basic knowledge of innate and adaptive immune response which has been discussed in the previous chapter. The initiation of inflammatory response occurs with microbial insult derived from microorganisms in the dental plaques.

Microbial insult:

As discussed in the previous chapter 5 “Microbiology of periodontal diseases”, the bacterial species in the plaque biofilm may or may not be pathogenic to the host. Various bacterial species which are not associated with the periodontal disease progression are designated as commensals. On the other hand, bacterial species which have been shown to possess virulence factors that cause damage to the host tissues are designated as periodontal pathogens. To produce insult to the host, the microorganism should be able to enter the host, should establish itself in the host, should be able to evade the host response and should be able to produce virulence factors that cause tissue damage. The microorganisms that have been shown to be associated with the periodontal disease progression and virulence factors produced by them have been discussed earlier in the previous chapter.

Host response:

The host immune response against microbial insult consists of innate and adaptive responses. The first defense against the invading periodontal pathogens and their products is junctional epithelium. The details of the structure of junctional epithelium have been discussed earlier in chapter 1, “Periodontium in health”The cells of the junctional epithelium have fewer desmosomes as compared to the normal epithelial cells, which account for its remarkable permeability 48-50. This permeability is closely related to the ingress of bacteria and their products and outwards flow of the gingival fluid and transmigration of neutrophilic granulocytes between the epithelial cells. Because of this reason the junctional epithelium and subjacent connective tissue becomes the battlefield for host-microbial interactions.

The cells involved in the first line of defense against many invading microorganisms are macrophages and neutrophils, which are important components of the innate immune response. However, these cells may not always eliminate infectious organisms, and some pathogens may not be recognized by them. The adaptive immune response which is specifically directed against these organisms is then generated to eliminate them. Cells involved in adaptive immune response are lymphocytes. Both innate and adaptive immune responses play a vital role in dealing with these infections.


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Clinical indicators of active periodontal lesion:

  • Bleeding on probing
  • Increase in sulcular temperature
  • Exudation
  • Presence of tissue destruction markers in GCF
  • Increased in Gram -ve anaerobic species in the bacterial culture

Initiation of host response in junctional epithelium

The junctional epithelium is constantly exposed to microbial flora which can initiate the inflammatory response. This inflammatory resonse in primarily mediated by neutrophils which are the key components of the host defense against bacterial infection. Phagocytic macrophages then play an important role of recognition of invading microorganism and to initiate the adaptive immune response. To better understand the host response against periodontal pathogens, we can divide it into two parts: innate immune response and adaptive immune response.  The innate immune response primarily consists of neutrophil’s response, complement system, and Toll-like receptors. The adaptive immune response consists of antigen presentation by antigen presenting cells (APC’s) and generation of T-cell and B-cell response. Let us discuss them in detail,

Innate immune response

Gingival epithelium provides a physical barrier to infection and has an active role in the innate host defense because the epithelial cells are in constant contact with the bacterial products 51.  Along with this, it is now well recognized that epithelium produces a diverse range of antimicrobial peptides which have been found to be belonging to at least four families (α-defensins, β-defensins, cathelicidins, saposins) in humans 52. It has been shown that oral, sulcular, pocket and junctional epithelia of the gingiva are associated with the expression of defensin, more specifically β-defensins (hBD-1, hBD-2 and hBD-3) 51. α and β defensins have an important role in………….


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Neutrophil response

As already stated, neutrophils are the primary cells involved in the initial immune response against invading microorganisms. These cells are very important for the maintenance of periodontal health. Individuals suffering from neutrophil disorders (i.e., leukocyte adhesion deficiency syndrome, Chédiak-Higashi syndrome, cyclic neutropenia, etc.) have an increased susceptibility to and severity of periodontal tissue destruction (for details read “Role of neutrophils in periodontal diseases”). It is well established that neutrophils are the most abundant type of leukocytes within the periodontal tissues in acute and chronic periodontal lesions 55. It should be noted that healthy tissue also demonstrates infiltration of neutrophils in junctional epithelium but their numbers are highly increased in the inflamed tissue 8. The neutrophil recruitment is along the gradient which is created by the pro-inflammatory cytokines, secreted in response to bacterial products. The most potent and abundant chemoattractants for neutrophils are CXC chemokines. The CXC chemokines are a unique family of cytokines, which participate in the regulation of angiogenesis. IL-8 is the most potent human CXC chemokine. IL-8 is secreted by various cells, including leukocytes, fibroblasts, endothelial cells, and keratinocytes, in response to both endogenous and exogenous stimuli 56. In response to IL-8 secreted by the cells in the junctional epithelium, the neutrophils migrate along the chemoattractant gradient towards the surface of the junctional epithelium. The mechanism of transendothelial migration of neutrophils has been discussed in detail in the previous chapter. The density of neutrophils within the junctional epithelium has been found to be increased towards more superficial layers of the epithelium, which are in close relationship with the subgingival plaque bacteria 57.


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Mechanism of chemotaxis:

After transendothelial migration, leukocytes come in the extra-vascular compartment and move towards the site of injury by a process called chemotaxis. In other words, we can say that chemotaxis is the movement of leukocytes towards the site of injury along a chemical gradient. Various immune cells like PMNs, monocytes and to lesser extent lymphocytes respond to the chemoattractants with varying rates of speed. The chemoattractants may be of microbial origin or endogenous. The bacterial components like LPS and peptides that possess an N-formyl-methionine terminal amino acid are strong chemoattractants. Host-derived mediators, like components of the complement system (particularly C5a), products of the lipoxygenase pathway (mainly leukotriene B4) and cytokines (particularly those of the chemokine family, such as IL-8) are strong chemoattractants.








Complement system

As already discussed in “Basic concepts in immunity and inflammation”, the complement system is a very important component of the innate immune response. It causes the destruction of the microorganisms by the formation of a membrane attack complex. The classical, alternative and lectin pathways of complement system have been well described in detail in the previous chapter.

Role of Toll-like receptors (TLRs) in host-microbial interaction

When microorganisms enter the tissue after penetrating the epithelial barrier, they are encountered by tissue macrophages, mast cells and immature dendritic cells 58. These cells must be able to distinguish between apoptotic particles generated by normal tissue turnover and particles that are indicative of infection. The molecules mainly responsible for making this pivotal distinction are those of the family of TLRs. Along with tissue macrophages, mast cells, and immature dendritic cells, these receptors are also expressed on lymphocytes, osteoclast precursors, osteoblasts and stromal and epithelial cells, each of which has different toll-like-receptor expression profiles 59-62.

Members of the TLR family are responsible for the recognition of pathogen-associated molecular patterns (PAMPs), expressed by a wide spectrum of infectious agents. The main effect of the stimulation of TLRs is the synthesis and secretion of pro-inflammatory cytokines and lipid mediators, thereby initiating the inflammatory response that recruits both soluble immune components and immune cells from the blood 63.

Structure of Toll-like receptors (TLRs):

Toll receptors were first recognized in Drosophila (fruit-fly). It was found that these were important in the development of innate immunity in adult flies. TLRs are transmembrane proteins expressed by cells of the innate immune system, which are involved in the recognition of invading organisms and initiation of immune and inflammatory responses to destroy the invaders 64. In mammals, the TLR family includes eleven proteins (TLR1−TLR11).  Recently, two new members, TLR12, and TLR13 have been discovered in murine cells, but not much information is available about them.  TLRs are characterized by an amino-terminal extracellular domain composed of repeated motifs, high in leucine and known as leucine-rich repeats (LRRs), followed by a single transmembrane domain and a globular cytoplasmic domain, called the Toll/IL-1 receptor (TIR) domain, or TIR domain due to its high similarity to that of the IL-1 receptor family. Despite this similarity, the extracellular portions of both types of receptors are structurally unrelated. The IL-1 receptors possess an immunoglobulin-like domain, whereas TLRs bear leucine-rich repeats (LRRs) in the extracellular domain.

Signaling pathways 65:

TLR signaling pathways basically consist of,

  • MyD88-dependent pathway (common to all TLRs),
  • MyD88-independent pathway (peculiar to theTLR3 and TLR4).

MyD88 (Myeloid differentiation primary-response protein-88) is an adapter molecule that functions to recruit IRAKs (IL-1 receptor associated protein kinases) to the IL-1 or TLR4 receptor complexes after IL-1 or LPS stimulation, respectively.

MyD88-dependent pathway:

The main steps involved in MyD88-dependent pathway (Figure 7.1) are as follows,

  • Upon stimulation, MyD88 recruits IL-1 receptor-associated kinase (IRAK) to TLRs.
  • IRAK is activated by phosphorylation.
  • IRAK then associates with TRAF6.
  • Then TRAF6 interacts with TAK1, TAB1, and TAB2.
  • The complex of TRAF6, TAK1, TAB1, and TAB2 further forms a larger complex with Ubc13 and Uev1A, which induces the activation of TAK1.
  • Activated TAK1 phosphorylates the IKK complex, consisting of IKKα, IKKβ, and NEMO/IKKγ, and MAP kinases, such as JNK, and thereby induces the activation of the transcription factors NF-κB and AP-1, respectively.

Figure 7.1 The MyD88- dependent pathway of TLR activation

The MyD88-dependent TLR activation mechanism

TLR- Toll-like receptor.

IRAKs- IL-1R-associated protein kinases.

TIRAP- Toll / IL-1 receptor domain-containing adapter protein

TRIF- Toll / IL-1 receptor domain containing adapter-inducing interferon-β

TRAF- Tumor necrosis factor receptor.

TAK1- TGF-β-activated kinase 1.

MyD88-independent pathway:

MyD88-deficient mice have been generated and found to be completely defective in their responses to IL-1 and IL-1-related cytokine, IL-18 66. The response to LPS was shown to also be abolished 67. Although MyD88 plays a critical role in TLR signaling, there is also present a MyD88-independent pathway. TLR3 signaling occurs mainly via MyD88-independent pathway (Figure 7.2).

Figure 7.2 The MyD-88 independent mechanism of TLR activation

The MyD-88 independent mechanism of TLR activation

In a step by step manner, it is as follows,

Although MyD88 is reported to be involved in TLR3 signaling 68, TLR3 does not appear to use the MyD88-dependent pathway to any significant extent, because the response to poly (I-C) (polyinosine–polycytidylic acid) was not impaired in MyD88-deficient mice 69. In the TLR4 and TLR3 mediated signaling pathways, a MyD88-independent pathway exists that leads to the activation of IRF-3 via TBK1 and IKKε/IKKi. The TIR domain-containing adaptor TRIF mediates this MyD88-independent pathway.

Result of TLR activation:

As already stated, TLR activation results in the production of various pro-inflammatory cytokines and chemokines. The interaction of TLR4 on dendritic cell and LPS results in the production of pro-inflammatory cytokines, such as IL-12, and the interaction of TLR3 with LPS results in the production of type-I interferon. It has been demonstrated that the most predominant TLR’s in the periodontal tissues are TLR2 and TLR4 70. It must be noted that the TLR response may vary depending upon the intracellular adapter protein. For example, after binding of LPS to TLR4, if the intracellular pathway is mediated by MyD88, the result is the formation of tumor necrosis factor alpha, IL-6 and IL-12. On the other hand, if the intracellular pathway is mediated by TRIF-related adapter molecule, the result is the release of interferon-α/β and activation of interferon regulatory factor 3 68, 71-73. It has been shown that TLR 1, 2, 4, 5 and 6 recognize specifically the products of bacterial origin and not those derived from the host. Thus, it can be concluded that TLR’s play a crucial role in innate immune response 60.


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Role of neuropeptides in innate immune response:






Substance P:

Another important chemical mediator that plays an important role during the inflammatory response is substance P. It is a member of the tachykinin family of neuropeptides. It is synthesized and secreted by neurons, monocytes, dendritic cells, eosinophils, T-lymphocytes and mast cells 76, 80. Its primary action is on the vasculature, where it increases the vascular permeability resulting in edema and subsequent plasma protein extravasation. During inflammation, vasodilatation and edema are indirectly caused by substance P by the stimulation of histamine release from the mast cells 76, 81. An in vitro study has demonstrated that when stimulated by bacterial LPS, mononuclear phagocytes, and dendritic cells produce substance P 82.


Vasoactive intestinal peptide (VIP):

It is an immune-modulatory peptide which has a regulatory action on both pro- and anti-inflammatory mediators 83-85. The primary non-neuronal source of this peptide is………






Adaptive immune response

The adaptive/acquired immune response is activated when the epithelial barrier, with its antimicrobial peptides and other components of innate systems, is breached. The pathogenic species present in the subgingival biofilm evade the anti-bacterial host defense mechanisms by releasing an array of virulence factors, which causes damage to the host tissue by immune/inflammatory interactions, which typically consist of neutrophils, monocytes/macrophages, dendritic cells (DCs), T-cells, and predominantly IgG-producing plasma cells. The majority of virulence factors include enzymes and endotoxins.

T-cell activation in adaptive immune response:

The T-cell adaptive immune response is activated by processing and presentation of bacterial antigens by lymphocytes, macrophages, and dendritic cells. After phagocytosis of bacteria, its recognizable surface antigens are presented on the surface of APC’s.

Antigen presenting cells (APC’s):

The APC’s have antigenic peptide with a major histocompatibility complex (MHC) molecule located at their surface. Cytotoxic T-lymphocytes (CTL) expressing the CD8 co-receptor recognize the peptide bound to MHC Class I molecules, whereas helper T-cells (Th) expressing the CD4 co-receptor do so with a peptide associated with MHC Class II molecules. Co-stimulatory molecules such as B7-1 (CD80) and B7-2 (CD86) are also present on APC’s that interact with CD-28 on T-cells. Adhesion molecules such as ICAM-1 present on APC’s are involved in the formation of strong immunological synapses to facilitate the proper activation of T-cells.

Interactions between APC’s and T-cells:

To understand the interaction between T-cells and antigen-presenting cells, it is important to understand the receptors present on these cells and their interactions. There is a series of intracellular signaling cascade that is activated when a receptor is activated, which ultimately leads to the synthesis and secretion of biochemical mediators like cytokines, etc. The interface between lymphocytes and targets is termed ‘immunological synapse’ (IS).

T-cell receptor (TCR):

One of the initial steps in the generation of the immune response is the recognition by T-lymphocytes of peptide fragments (antigens) derived from foreign pathogens that are presented on the surface of APC’s. This event is mediated by the TCR, which transduces these extracellular signals by initiating a wide array of intracellular signaling pathways. The TCR is a complex of ……………….


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TCR is composed of six different chains that form the TCR heterodimer responsible for ligand recognition (Figure 7.3). CD3 molecules (CD3-g, CD3-d, CD3-e, and CD3- z), which are assembled together with the TCR heterodimer, possess a characteristic sequence motif for tyrosine phosphorylation, known as ITAMs (Immunoreceptor Tyrosine-based Activation Motifs). One of the initial steps following TCR activation is the activation of Src family tyrosine kinases (p56lck) that, in turn, phosphorylate phospholipase Cg1 (PLC g1). Activation of PLC g1 leads to hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PIP2), generating diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG activates protein kinase C (PKC) that, in turn, phosphorylates Ras, a GTPase that activates Raf leading to the recruitment of the MAP kinase cascade. IP3 releases calcium from its intracellular stores in the endoplasmic reticulum (ER).

Figure 7.3 The Signaling cascade stimulated by T-cell receptor (TCR)

Intracellular T-cell receptor signalling mechanism

The Ca2+ binds to calmodulin that, in turn, activates calcineurin, a Ca2+/calmodulin dependent protein phosphatase. NFAT, a transcriptional regulator of IL-2 gene expression, is a direct target of calcineurin. Calcineurin dephosphorylates the cytosolic component of NFAT, NFATc, which migrates to the nucleus and induces transcription of the IL-2 gene.
Adhesion molecules like LFA-I interact with ICAM-I on APC’s and aid in the formation of the immunological synapsis.

To mount an immunological response, the T-cell needs to receive a second signal from an antigen-presenting cell in the form of a co-stimulatory molecule. Co-stimulatory molecules act through different TCRs, such as the CD28 and TNFR (tumor necrosis factor receptor) families, producing a second signal that induces T-cell activation and proliferation (Figure 7.4). The CD28 and TNFR co-stimulatory receptors possibly exert their effect through promoting more efficient signaling by concentrating the kinases and substrates that are required to initiate a signal whose affinity has been shown to increase upon stimulation.

Figure 7.4 The interactions between TCR and MHC

Interactions between TCR and MHC

Steps in the activation of T-cells:

  1. Antigen which is phagocytosed by a macrophage is cleaved into polypeptides which are then transported to the surface for presentation to T-cells (only foreign particles consisting of proteins are activated and processed, no other molecules like fatty acids etc. are presented).
  2. The APC complex consists of both antigen and MHC. If MHC Class-II is associated with presenting cells, CD4 or helper T-cells are activated and if MHC Class-I associated with presenting cells, CD8 or cytotoxic T-cells are activated. MHC complex is encoded by a group of genes, so different polypeptides are presented on the surface of the MHC which is responsible for its diversity of antigen presentation. MHC presents only proteins which may be derived from foreign or self-proteins. It depends on the selection of T-cells in the thymus.
  3. Macrophage which is attached to the antigen, produces IL-1 which activates CD4 cells.
  4. CD4 interacts with MHC Class-II on APC surface. This union is stabilized by other proteins LFA-1 on T-cells and ICAM 1 on APC.
  5. A co-stimulatory signal is formed by B7 protein on APC and CD28 on CD4 cells which result in the secretion of IL-2 by the helper T-cells and it is this step that is useful in the execution of all the functions i.e., regulator, effector, and memory functions. Production of IL-2 is the most crucial step in T-cell activation. If this co-stimulatory signal is not formed, anergy takes place.

Table 7.1 

Interactions between CD4-MHC II and CD8-MHC Class-I molecules

CD-4 T-cell Antigen Presenting Cell
LFA-1 ICAM-1 (adhesion)
CD2 LFA-3 (adhesion)
CD4 (Lck) MHC Class-II (co-activation with TCR)
TCR/CD3 MHC Class-II/peptide (activation of T-cell)
CD28 B7-1/B7-2 (co-activation with TCR)


CD-8 T- cell Antigen Presenting Cell
LFA-1 ICAM-1 (adhesion)
CD2 LFA-3 (adhesion)
CD8 (Lck) MHC Class-I (co-activation with TCR)
TCR/CD3 MHC Class-I/peptide (activation of T-cell through PIP2/DAG, IP3 pathway)
CD28 B7-1/B7-2 (co-activation with TCR)


Cell-mediated immune response in periodontal diseases

T-lymphocyte response to antigenic challenges is called as a cell-mediated immune response. T-lymphocytes can be functionally divided into CD4 (T-helper lymphocytes) cells and CD8 (cytotoxic T-lymphocytes) cells by the type of antigen receptors and a small number of accessory markers on their cell surface. Before we go into details of the cell-mediated immune response in periodontal diseases, let’s first try to understand Th1 and Th2 helper T-cells.

Th1 and Th2 helper T-cells:

Helper T-cells can be further differentiated into T helper 1 (Th1) and T helper 2 (Th2)-cells (Figure 7.5). They are distinguished by the cytokines they produce and respond to, and are involved in different immune responses. Th1 and Th2 cells are produced by differentiation from a non-antigen exposed precursor cell type, Thn (naïve T-cells). Differentiation of Thn cells into Th1 or Th2 cells depends on the cytokines they are exposed to. When Thn cells are exposed to antigen by APC’s, it results in the differentiation of Thn cells into Th0 cells. The stimulation of Thn cells by exposure to APCs induces the proliferation of undifferentiated cells and their expression of IL-2 and IL-2 receptor. The differentiation of Thn to Th1 or Th2 cells depend on the cytokines they are exposed to. IL-12 causes Th1 differentiation and blocks Th2 cell production, while IL-4 causes Th2 differentiation and antagonizes Th1 development. IL-18 also induces Th1 differentiation.

Figure 7.5 Differentiation of Th1 and Th2 cells from naive CD-4 Th cells

Th0, Th1 and Th2 cell-mediated immune response in periodontal diseases:

The immune response to infection is regulated by the balance between Th1 and Th2 cytokines 89. Studies have been done to find out Th1/Th2 immune response in periodontal disease. Investigations indicated a dominance of the Th1 response over the Th2 response, with other studies showing a predominance of Th0 cells in periodontitis 90, 91. Various studies have reported discrepancies with regard to the predominance of Th1 or Th2 response or the involvement of both Th1 and Th2 cells in the diseased tissue 92-95.

Role of Regulatory T-cells in the periodontal diseases

These cells are different from the Th1 or Th2 cells and they play an important role in the cell-mediated immune response. Three distinct regulatory T (Treg) cells have been described. Naturally occurring Treg cells, CD4 and CD25 T-cells, originate directly from the thymus during the early stages of fetal and neonatal T-cell development. These cells make up approximately 5-10% of the peripheral T-cell pool and constituently express several suppressing mediators, such as CD25 (α chain IL-2 receptor), glucocorticoid-induced TNF-R (GITR), cytotoxic T-lymphocyte Ag-4 (CTLA-4), CD103 and the transcription factor Foxp3 96.

The evidence regarding the exact role played by Treg cell in mediating the periodontal disease continues to be controversial. Studies demonstrated that periodontitis patients showed an increased percentage of Treg cells in the gingival connective tissue as compared to gingivitis patients. It was concluded that Tregs levels were upregulated in chronic periodontitis lesions as protection against self-antigens, such as collagen Type-I 97, 98. Another study showed that Treg cells downregulated RANKL expression in periodontal disease. However, their capacity to provide an immunoregulatory function in periodontal disease has been questioned 99. One study suggested that Treg cells may not have a regulatory function due to the lack of CTLA-4 expression that is required for cell-cell contact inhibition of T-cell proliferation 100.

Role of Th17 cells in periodontal disease

A distinct type of helper T-cell lineage, Th17 has been recently identified. This population secretes several pro-inflammatory cytokines, including the novel cytokine IL-17, and, hence, has been termed ”Th17”. It expands in the presence of IL-23 101.  IL-23 is recently discovered cytokine which belongs to the IL-12 family 102. The Th17 cell lineage is thought to play an important role in the pathogenesis of cell-mediated tissue damage caused either by autoimmunity or immune responses against microbial infection 103. Th17 has been proposed to exert both pro-inflammatory and anti-inflammatory functions. Th17 cells also expressed higher levels of RANKL than TH1 cells 104. The exact role of these cells in periodontal diseases still needs to be investigated.

B-cell activation in adaptive immune response

The B-cell mediated or the humoral immune response is mediated by the production of antibodies by cells of B-lymphocyte lineage. B-cells express a unique B-cell receptor (BCR) on their surface that recognizes and binds to only one particular antigen. The primary differences between B-cell and T-cell mediated immune response is in the mechanism by which they recognize the antigen. As already discussed, T-cell recognizes the antigen through MHC interactions, once it is presented by the APC’s. The B-cell recognizes antigens in their native form. After a B-cell recognizes the antigen and receives appropriate signals from helper T-cells, it further differentiates into an effector cell, known as a plasma cell. The plasma cells produce antibodies against that antigen. These cells are short lived cells (2-3 days). However, around 10% of plasma cells become long-lived and are referred to as antigen specific memory B-cells. The antibodies thus produced, bind to antigen, making it an easier target for phagocytes. The B-cell response may be T-cell dependent or T-cell independent, but it is primarily regulated by T-cells.

T-cell independent activation of B-cells:

T-cell independent response occurs by the cross-linking of the IgM by antigen receptors on the B-cell, responding with IgM synthesis in the absence of T-cell help.

T-cell dependent activation of B-cells:

When a pathogen is ingested by an APCs such as a macrophage or dendritic cell, the pathogen’s proteins are then digested to peptides and attached to a Class II MHC protein. This complex is then moved to the outside of the cell membrane. The APC, then interacts with the helper T-cell (which recognizes MHC II). This activation leads to the secretion of cytokines by helper T-cell, which causes B-cell proliferation and maturation. Activated B-cells subsequently produce antibodies, which assist in the inhibition of pathogens (Figure 7.6).

Figure 7.6 Development of T-cell dependent and T-cell independent B-cell response

T-cell activation

Humoral Immune response in the periodontal diseases

Although the precise role of humoral immunity in the periodontal disease progression has not been fully elucidated, however, it has been suggested that the humoral immune response has a protective role in the pathogenesis of periodontal disease 105. B-lymphocytes contribute to immunity in multiple ways, including the production of antibodies, presenta­tion of antigen to T-cells, organogenesis of secondary lymphoid organs and secretion of cytokines 106. The antibodies protect bacterial colonization primarily by two mechanisms. The direct binding of the antibodies to the bacterial surface antigens blocks adherence, colonization and aggregation of bacteria. Furthermore, these also detoxify………………….


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Immunoglobulins arriving at the periodontal lesion are from both systemic and local tissue sources. The salivary IgA is involved in trapping of the antigen in a mucin layer with the subsequent disposal of the antigen.

Immunoglobulins arriving at the periodontal lesion are from both systemic and local tissue sources. The salivary IgA is involved in trapping of the antigen in a mucin layer with the subsequent disposal of the antigen 115. The local production of IgG, which is protective in nature and found to be increased in inflamed gingival and periodontal tissues 116.


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Importance of FcγR receptors on leukocytes:

Leukocyte FcγR receptors belong to the immunoglobulin super-family and are divided into three classes: FcyRI (CD64), FcγRII (CD32) and FcγRIII (CDI6), encompassing at least 12 isoforms. Eight genes encoding for FcγR receptors are present on chromosome 1. These receptors serve as a link between the cellular and the humoral immune response as they provide binding of the constant region of lgG, thereby inducing a cellular response. FcγR induces leukocyte effector functions such as phago­cytosis, cytotoxicity, cytokine production, degranula­tion, antigen presentation and regulation of antibody production upon crosslinking e.g. after binding immune complexes 117. Polymorphism in FcγR receptors has been widely studied and is one of the factors involved in the periodontal disease progression 118-120.


Review of literature on humoral response in periodontal diseases

Many studies have examined the antibody response in various periodontal diseases. In a study, Ranney and co-workers (1982) 121 examined the presence of antibody response against A. actinomycetemcomitans in 57 juvenile periodontitis patients. The results demonstrated that 31 out of 57 patients were positive for the antibodies and antibody response was significantly higher in localized juvenile periodontitis and severe periodontitis patients as compared to healthy patients. A more extensive study was done by Gunsolley et al. (1987) 122, where they examined the antibody response against 25 Gram-negative, Gram-positive, and spirochetal microorganisms and its relationship with the attachment loss. The results of the study demonstrated that there was a positive correlation between antibody response and percentage of teeth with 2-mm, 5-mm attachment loss, and the mean attachment loss. Antibody response against 11 bacterial species demonstrated a positive correlation with the severity of the disease.

Many studies have suggested that patients with localized aggressive periodontitis have elevated antibody levels and they also demonstrate high serum concentrations of IgG2 123-125. Studies have also been done on the genetic association of high serum levels of IgG2 in aggressive periodontitis patients. They have demonstrated the heritability of serum IgG2 concentrations in families with aggressive periodontitis 126, 127. In a study, Tew et al. (1985) 128 studied the serum IgG levels in 52 severe periodontitis, 47 localized juvenile periodontitis, and 52 healthy patients. The authors examined the antibody response against Eubacterium species, Lactobacillus minutus, and Peptostreptococcus micros using RIA. These bacteria were selected because of their predominance in cultivable flora from the subgingival plaque of the patients with severe periodontitis. The results of the study demonstrated that severe periodontitis patients were seropositive for E. brachy and P. micros, but not the juvenile periodontitis and healthy patients. The juvenile periodontitis patients had elevated antibody levels against E. timidum than observed in healthy patients. It was concluded by the authors that many organisms in the subgingival flora elicit serum antibody; however, some bacteria that are present in high numbers do not elicit significant antibody responses.


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Oxidative stress:

One important aspect of host-microbial interactions is the generation of oxidative stress. Oxidative stress is altered physiological balance between oxidants and antioxidants in favor of the former leading to lesions in the body. The resultant lesion is known as ‘oxidative damage’. During health, a dynamic balance is maintained between the oxidants and anti-oxidants in our body (Fig 7.7). However, this balance may be disturbed as a result of ………….












Figure 7.7 Diagram showing balance between reactive oxygen species and anti-oxidants

Diagram showing balance between reactive oxygen species and anti-oxidants



Periodontal diseases are inflammatory diseases where virulent microbial species induce a series of host response events that results in the clinically visible inflammatory changes in the periodontal tissues. In the process of host-microbial interaction, there is a damage to the host tissue, which is clinically manifested as gingivitis, which may, later on, give rise to chronic or aggressive periodontitis. In a susceptible host, there is dysregulation of inflammatory and immune pathways which may result in excessive damage to the host tissues. The above discussion not only provides us the information regarding various aspects host response, but also about the potential therapeutic approaches which can be adopted to halt the progression of the periodontal disease.

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Periobasics: A textbook of periodontics and implantology

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