*3.2.1 Innate immune response in periodontal disease*

The most important characteristic of periodontitis is the inflammatory reabsorption of the tooth-supporting alveolar bone due to the uncontrolled host immune response against periodontal infection, since the destructive events, which lead to the irreversible phenotype of periodontal disease, are the result of the persistence of a chronic and exacerbated inflammatory immune response [18]. Inflammation is a process of the innate immune system activation, in response to exogenous and endogenous factors, such as infection by microorganisms, tissue stress, and injuries. Inflammation is a protective response, characterized by its cardinal signs, such as redness, swelling, heat, pain, and disrupted function [19]. The inflammatory response consists of four main components: (1) endogenous or exogenous factors, such as molecular patterns associated with pathogens (PAMP) and damage (DAMP), which are derived from bacteria, viruses, fungi, parasites, and cell damage, as well as toxic cellular components or any other harmful condition; (2) cellular receptors that recognize these molecular patterns (PRR), for example, Toll-like receptors (TLR); (3) proinflammatory mediators, such as cytokines, chemokines, the complement system, etc.; and (4) target cells and tissues, where these proinflammatory mediators act [20, 21]. The inflammatory response is mainly characterized by four successive phases: (1) silent phase, where the cells synthesize and release the first proinflammatory mediators; (2) vascular phase, characterized by an increase in vascular permeability and dilatation; (3) cellular

**9**

advanced lesions.

*Pathogenesis of Periodontal Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.86548*

and (4) the resolution of the inflammatory response [22].

of the matrix metalloproteinases (MMPs) [27, 28].

subset associated with periodontitis [35–37].

phase, characterized by the infiltration of inflammatory cells at the site of injury;

The periodontal lesion is initiated as acute inflammation characterized by increased numbers of neutrophils migrating into the gingival crevice through the junctional epithelium, which have the de novo biosynthetic capacity for chemokines and cytokines with proinflammatory, anti-inflammatory, or immunoregulatory properties. Neutrophils, through the release of chemokines, can induce the recruitment of interleukin-17-producing CD4-positive T-helper 17 cells to sites of infection or inflammation. In addition, they can promote the survival, proliferation, and development of B cells into antibody-secreting plasma cells. Likewise, it was shown that activated neutrophils express membrane-bound receptor activator of nuclear factor kappa Β ligand (RANKL), a key osteoclastogenic cytokine and, thereby able of inducing osteoclastic bone resorption [29]. These recent concepts suggest that neutrophils could contribute to periodontitis not only by initiating the lesion but also by participating in its progression, by recruiting T-helper 17 cells or promoting the accumulation of B cells and plasma cells in the established and

Macrophages are an important source of proinflammatory and potentially destructive molecules for tissues, such as interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α), MMP, and prostaglandin E2 [30], which play an important role and are elevated in the gingival tissue and in the gingival crevicular fluid of patients with chronic periodontitis [28]. Therefore, studies have shown a direct correlation of macrophage infiltration with the severity of periodontal disease [31], contributing greatly to the intensification of the degradation of the collagen matrix in the connective periodontal tissue [32, 33]. These macrophages may undergo a classical (M1) or alternative (M2) activation. M1 macrophages are induced by microbial agents (e.g., LPS) or by Th1 cytokines and show high phagocytic capacity and an increased expression of proinflammatory cytokines, costimulatory, and antimicrobial molecules. In contrast, M2 macrophages are induced by Th2 cytokines and secrete high levels of IL-10 and transforming growth factor beta 1 (TGF-β1). Therefore, they have immunoregulatory properties and promote cell proliferation and tissue regeneration [29, 34]. In periodontal inflammation models, macrophages share properties of both M1 and M2. However, M1 macrophages show a predominance over M2 macrophages, suggesting that M1 macrophages probably represent a

The inflammatory immune response is triggered by the interaction of resident cells with the bacterial biofilm attached to the tooth surface. Bacterial biofilm attaches to the tooth surface, making it impossible for the immune system to eradicate the infecting microorganisms efficiently, perpetuating the insult to the periodontal tissues [18]. The junctional epithelium is the first periodontal structure to face the bacterial challenge [23]. Bacteria are capable to cross the junctional epithelium and pass to the gingival conjunctive tissue, where they stimulate the gingival epithelial cells and fibroblasts to trigger the initial inflammatory responses [24]. These resident periodontal cells detect bacterial PAMP, such as lipopolysaccharide (LPS) [25], which binds to the Toll-like receptors (TLR4/2), triggering the recruitment of several protein kinases in the cytoplasmic end of the receptors, ultimately causing the activation of proinflammatory transcription factors, such as nuclear factor kappa B (NFκB) and activator protein 1 (AP-1) [26], which induces the synthesis and release of mediators to trigger the inflammatory response. Likewise, the gingival fibroblasts and the periodontal ligament are responsible for the destruction and disorganization of the fibrous component of the extracellular matrix of the periodontal tissue by increasing the local production and the activity

#### *Pathogenesis of Periodontal Disease DOI: http://dx.doi.org/10.5772/intechopen.86548*

*Periodontal Disease - Diagnostic and Adjunctive Non-surgical Considerations*

and eventually in the loss of tissues, bones and finally, of the teeth [17].

*Innate and adaptive immune response during periodontal disease (description in the text).*

The most important characteristic of periodontitis is the inflammatory reabsorption of the tooth-supporting alveolar bone due to the uncontrolled host immune response against periodontal infection, since the destructive events, which lead to the irreversible phenotype of periodontal disease, are the result of the persistence of a chronic and exacerbated inflammatory immune response [18]. Inflammation is a process of the innate immune system activation, in response to exogenous and endogenous factors, such as infection by microorganisms, tissue stress, and injuries. Inflammation is a protective response, characterized by its cardinal signs, such as redness, swelling, heat, pain, and disrupted function [19]. The inflammatory response consists of four main components: (1) endogenous or exogenous factors, such as molecular patterns associated with pathogens (PAMP) and damage (DAMP), which are derived from bacteria, viruses, fungi, parasites, and cell damage, as well as toxic cellular components or any other harmful condition; (2) cellular receptors that recognize these molecular patterns (PRR), for example, Toll-like receptors (TLR); (3) proinflammatory mediators, such as cytokines, chemokines, the complement system, etc.; and (4) target cells and tissues, where these proinflammatory mediators act [20, 21]. The inflammatory response is mainly characterized by four successive phases: (1) silent phase, where the cells synthesize and release the first proinflammatory mediators; (2) vascular phase, characterized by an increase in vascular permeability and dilatation; (3) cellular

*3.2.1 Innate immune response in periodontal disease*

*gingivalis*, *Aggregatibacter actinomycetemcomitans*, *Tannerella forsythia*, and *Treponema denticola* [16], innate, inflammatory, and adaptive reactions are triggered. These processes result in the destruction of the tissues that surround and support the teeth,

**8**

**Figure 3.**

phase, characterized by the infiltration of inflammatory cells at the site of injury; and (4) the resolution of the inflammatory response [22].

The inflammatory immune response is triggered by the interaction of resident cells with the bacterial biofilm attached to the tooth surface. Bacterial biofilm attaches to the tooth surface, making it impossible for the immune system to eradicate the infecting microorganisms efficiently, perpetuating the insult to the periodontal tissues [18]. The junctional epithelium is the first periodontal structure to face the bacterial challenge [23]. Bacteria are capable to cross the junctional epithelium and pass to the gingival conjunctive tissue, where they stimulate the gingival epithelial cells and fibroblasts to trigger the initial inflammatory responses [24]. These resident periodontal cells detect bacterial PAMP, such as lipopolysaccharide (LPS) [25], which binds to the Toll-like receptors (TLR4/2), triggering the recruitment of several protein kinases in the cytoplasmic end of the receptors, ultimately causing the activation of proinflammatory transcription factors, such as nuclear factor kappa B (NFκB) and activator protein 1 (AP-1) [26], which induces the synthesis and release of mediators to trigger the inflammatory response. Likewise, the gingival fibroblasts and the periodontal ligament are responsible for the destruction and disorganization of the fibrous component of the extracellular matrix of the periodontal tissue by increasing the local production and the activity of the matrix metalloproteinases (MMPs) [27, 28].

The periodontal lesion is initiated as acute inflammation characterized by increased numbers of neutrophils migrating into the gingival crevice through the junctional epithelium, which have the de novo biosynthetic capacity for chemokines and cytokines with proinflammatory, anti-inflammatory, or immunoregulatory properties. Neutrophils, through the release of chemokines, can induce the recruitment of interleukin-17-producing CD4-positive T-helper 17 cells to sites of infection or inflammation. In addition, they can promote the survival, proliferation, and development of B cells into antibody-secreting plasma cells. Likewise, it was shown that activated neutrophils express membrane-bound receptor activator of nuclear factor kappa Β ligand (RANKL), a key osteoclastogenic cytokine and, thereby able of inducing osteoclastic bone resorption [29]. These recent concepts suggest that neutrophils could contribute to periodontitis not only by initiating the lesion but also by participating in its progression, by recruiting T-helper 17 cells or promoting the accumulation of B cells and plasma cells in the established and advanced lesions.

Macrophages are an important source of proinflammatory and potentially destructive molecules for tissues, such as interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α), MMP, and prostaglandin E2 [30], which play an important role and are elevated in the gingival tissue and in the gingival crevicular fluid of patients with chronic periodontitis [28]. Therefore, studies have shown a direct correlation of macrophage infiltration with the severity of periodontal disease [31], contributing greatly to the intensification of the degradation of the collagen matrix in the connective periodontal tissue [32, 33]. These macrophages may undergo a classical (M1) or alternative (M2) activation. M1 macrophages are induced by microbial agents (e.g., LPS) or by Th1 cytokines and show high phagocytic capacity and an increased expression of proinflammatory cytokines, costimulatory, and antimicrobial molecules. In contrast, M2 macrophages are induced by Th2 cytokines and secrete high levels of IL-10 and transforming growth factor beta 1 (TGF-β1). Therefore, they have immunoregulatory properties and promote cell proliferation and tissue regeneration [29, 34]. In periodontal inflammation models, macrophages share properties of both M1 and M2. However, M1 macrophages show a predominance over M2 macrophages, suggesting that M1 macrophages probably represent a subset associated with periodontitis [35–37].

### *3.2.2 Adaptive immune response in periodontal disease*

When the inflammatory response becomes chronic, the lymphocytes of the adaptive immune system invade the periodontal tissues releasing inflammatory and immune molecular mediators, which alter the balance of bone metabolism, marking the transition from gingivitis to periodontitis [29]. The activation of lymphocytes requires two types of signals: a signal induced by the antigen receptor itself when recognizing its related antigen and a costimulatory signal by professional antigenpresenting cells (APCs) [22]. In gingivitis, the predominant APCs are CD14+ and CD83<sup>+</sup> dendritic cells. While in the periodontitis, the predominant APCs are CD19+ and CD83+ B lymphocytes [38]. Therefore, the activation of adaptive immunity has a great influence on the bone loss in periodontitis, associated with B and T lymphocytes, since several studies have shown that these cells are the main cellular sources of activator of the κB ligand receptor of the nuclear factor (RANKL) during periodontal inflammation [39].

RANKL is a cytokine member of the TNF family that can be bound or secreted to the membrane and stimulates the differentiation of osteoclasts, cell fusion, and activation that leads to bone resorption [40, 41]. Osteoblasts and stromal cells of the bone marrow predominantly express RANKL bound to the membrane, which induces osteoclastogenesis through cell contact with osteoclast precursors. Likewise, activated T and B cells produce both the membrane-bound and soluble RANKL forms. Soluble RANKL can induce osteoclastogenesis independently of direct contact between infiltrating lymphocytes and osteoclast precursors on the bone surface. However, 17 T-helper cells expressing RANKL, but not T-helper 1 cells, activate osteoclasts also by direct cell-cell contact [42]. In the alveolar bone, the RANKL/OPG/RANK system controls the balance of the bone metabolism [43]. RANKL is the osteoclasts activator and the molecular signal directly responsible for the bone resorption, which interacts with its associated receptor RANK on the surface of osteoclast and osteoclast precursors, which triggers its recruitment on the bone surface and cell fusion and activation [44]. Osteoprotegerin (OPG) is a soluble protein that has the ability to block the biological functions of RANKL by competitive inhibition [45]. In periodontitis, the increase in RANKL/OPG promotes the recruitment of osteoclast precursors, their fusion, and subsequent activation, leading to bone resorption [46].

On the other hand, Th1 lymphocytes have a fundamental role in the establishment and progression of periodontitis, through the increase of IFN-γ levels [18]. Studies have shown that mice IFN-γ-deficient showed low levels of inflammatory cytokines and chemokines, as well as macrophages infiltrated in periodontal tissue, developing a less severe phenotype of alveolar bone destruction [47]. IL-1β and TNF-α are cytokines secreted by Th1 lymphocytes. TNF-α and IL-1β produce vasodilation, stimulate the activation of endothelial cells to increase the recruitment of immune cells, increase the chemokines production in most cell types, participate in the activation of neutrophils, and stimulate secretion and tissue activation of MMPs, among other functions. Although neither IL-1β nor TNF-α is directly involved in the stimulation of bone resorption, they indirectly promote bone destruction by stimulating sustained inflammation of the periodontal tissue [48]. Th2 lymphocytes are the main cellular source of IL-4, which promotes the change of class to the secretion of IgE in B cells and favors the alternative activation of macrophages in an IFN-γindependent pathway. These effector functions of the Th2 lymphocytes negatively regulate the inflammatory and Th1 lymphocyte responses, so that the polarization of a Th2-type immune response in periodontitis may represent a damaged adaptive immune response [18, 49]. Finally, RANKL can also be secreted by Th17 lymphocytes, which in cooperation with inflammatory cytokines derived from Th1 lymphocytes are capable to tilt bone metabolism favoring bone resorption [50].

**11**

*Pathogenesis of Periodontal Disease*

**4. Conclusion**

ment and prognosis.

**Acknowledgements**

support for chapter publication.

We have no conflict of interest related to this work.

**Conflict of interest**

*DOI: http://dx.doi.org/10.5772/intechopen.86548*

The main etiological factor of periodontal disease is the bacteria, which are capable of activating the innate immune response of the host inducing an inflammatory response. The evolution of this inflammatory response culminates in the destruction of periodontal tissues. For this reason, it is important to understand the different molecular and cellular mechanisms of the pathogenesis of periodontal disease, with the purpose of making an opportune diagnosis and appropriate treat-

Thanks to the authors who collaborated in the writing of this chapter: Dr. en C. José Luis Muñoz-Carrillo, Dra. Viridiana Elizabeth Hernández-Reyes, Dr. Oscar Eduardo García-Huerta, Dra. Karla Mariana Chávez-Ruvalcaba, Dra. en C. Francisca Chávez-Ruvalcaba, Dra. en C. María Isabel Chávez-Ruvalcaba, and Dra. Lizbeth Díaz-Alfaro, as well as the Universities involved, Cuauhtémoc University Aguascalientes, Autonomous University of Zacatecas, and Autonomous University of Aguascalientes for financial
