Host Response Pathogenesis PDF

# Chapter 15 Host Immune Response to Plaque Biofilm ## Section 1 The Host Response in Periodontal Disease - Factors Enhancing the Microbial Challenge - Factors Affecting the Host Immune Response - Inflammation: A Protective Host Response That Can Turn Harmful - Inflammatory Biochemical Mediators of...

# Chapter 15 Host Immune Response to Plaque Biofilm ## Section 1 The Host Response in Periodontal Disease - Factors Enhancing the Microbial Challenge - Factors Affecting the Host Immune Response - Inflammation: A Protective Host Response That Can Turn Harmful - Inflammatory Biochemical Mediators of the Host Response - Current Theory of Pathogenesis ## Section 2 Histologic Stages in the Development of Periodontal Disease ## Section 3 The Impact of Host Response on Bone Homeostasis ## Section 4 Focus on Patients - Clinical Patient Care - Evidence in Action - Ethical Dilemma **Clinical Application:** Members of the dental team will encounter many patients with gingivitis and periodontitis. Recognizing the clinical features of these conditions will become second nature to all clinicians. However, understanding the underlying body defense mechanisms that serve to protect the host but can also do damage to the periodontium will not always be so straightforward. This chapter focuses on the host responses to plaque biofilm and the tissue destruction that ensues when bacteria, present in plaque biofilm, elicit a response in the host. **Learning Objectives:** - Define the term host response and explain its primary function. - Name factors that can enhance the microbial challenge to the periodontium. - Define the term biochemical mediator and name three types of mediators. - Describe the role of cytokines in the pathogenesis of periodontitis. - Describe the role of prostaglandins in the pathogenesis of periodontitis. - Describe the effect of matrix metalloproteinases (MMPs) on periodontal tissues. - Explain the phases of the bone remodeling cycle. - Explain the significance of a balanced OPG-to-RANKL ratio. - Describe the link between periodontitis and RANKL-mediated bone resorption. - For each of the histologic stages of gingivitis and periodontitis listed below, name one change in the host immune response likely to be encountered: - Bacterial Accumulation - Early Gingivitis - Established Gingivitis - Periodontitis **Key Terms:** - Biochemical mediators - Cytokines - Prostaglandins - Host response - Virulence factor - Catabasis - Pro-resolving lipid mediators - PGE - MMP - TIMP - RANKL - Homeostatic condition - Pathogenesis - Bone remodeling - Osteoblasts - Osteoclasts - OPG - Bone resorption ## Section 1 The Host Response in Periodontal Disease Periodontal disease is a bacterial infection that induces an inflammatory response in the periodontal tissues. Research findings indicate that although bacteria are essential for disease to occur, the presence of suspected periodontal pathogens alone is insufficient to cause the tissue destruction seen in periodontitis. Rather, it appears to be the body's response to the bacteria present in plaque biofilm that is the cause of nearly all the destruction seen in periodontal disease. The body's response to bacteria is referred to as the host response. In the instance of periodontal disease, the immune system strives to defend the body against bacteria present in plaque biofilm. The body's defenses are activated to eliminate the potential pathogens and limit the spread of infection, not actually to preserve the tooth or its supporting periodontal tissues. Figure 15-1 depicts the chain of events that is theorized to lead to periodontitis. ### Factors Enhancing the Microbial Challenge The presence of bacteria is essential for the initiation and progression of periodontal disease. Certain bacteria can activate the human immune and inflammatory system, which subsequently can lead to damage of the periodontium. The term virulence factor refers to the mechanisms that enable biofilm bacteria to colonize and damage the tissues of the periodontium. Virulence factors may be either structural characteristics of the bacteria themselves or substances that are produced by the bacteria. The primary bacterial virulence factors that can enhance damage to the periodontium are: 1. **Presence of lipopolysaccharide (LPS):** Gram-negative bacteria are a component of mature plaque biofilm. Gram-negative bacteria are virulent because of lipopolysaccharide (LPS), an endotoxin present on the outer membrane of the bacteria. LPS can be responsible for initiating inflammation in periodontal tissues. 2. **Ability to invade tissues:** There is good evidence that several subgingival bacteria can invade epithelial cells. Some of the periodontal bacteria-such as *Porphyromonas gingivalis (P.g)* and *Aggregatibacter actinomycetemcomitans (A.a)* can invade host tissues. Penetration of tissues can to some degree allow the bacteria to escape host defense mechanisms. 3. **Ability to produce enzymes:** Several periodontal bacteria produce enzymes such as collagenases and proteases that can directly degrade host proteins that are a basic part of the structure of the periodontium. ### Factors Affecting the Host Immune Response Certain factors may influence the host's susceptibility to periodontal disease by modifying the host response or tissue metabolism. These factors include genetic factors, environmental factors, and acquired factors-all of which can play important roles in periodontal disease pathogenesis. 1. **Genetic Factors:** Genetic factors appear to contribute to periodontal disease. Studies in twins and families indicate an association between periodontal disease and genetic factors. Diseases with genetic origin such as Papillon-Lefèvre syndrome and leukocyte adhesion deficiency (LAD) are associated with aggressive type of periodontal diseases. Also, variations in genes controlling formation of biochemical mediators can modify the immune response to plaque biofilm, increasing the susceptibility to periodontal disease. 2. **Environmental Factors:** Tobacco smoking is a known risk factor for periodontal diseases. It has a significant effect on the immune and inflammatory system. Smoking has been shown to decrease polymorphonuclear neutrophil (PMN) phagocytic capacity, decrease vascularity of gingival tissues, and affect both T- and B-lymphocyte response to periodontal pathogens. 3. **Acquired Factors:** Diabetes mellitus is a known risk factor for periodontal diseases and its progression. Abnormal blood glucose levels seen in diabetes mellitus affects the host response by reducing PMN function, increasing interleukin (IL)-1, tumor necrosis factor-a (TNF-a), and prostaglandin E2 (PGE2) levels in gingival crevicular fluid and reducing growth and proliferation of periodontal ligament fibroblasts and osteoblasts in periodontium. ### Inflammation: A Protective Host Response That Can Turn Harmful #### 1. Acute Inflammation ##### A. Host Response to Microbes When pathogenic bacteria successfully infect the periodontium, the body responds by mobilizing defensive immune cells and releasing a series of biochemical mediators to combat the bacteria. 1. Cells involved in immune and inflammatory processes include inflammatory cells, PMNs, antigen-presenting cells (macrophages and Langerhans cells), T- and B-lymphocytes, fibroblasts, and epithelial cells. These cellular components of the immune and inflammatory processes are discussed in Chapter 14. 2. Acute inflammation has a host-protective effect. It serves as the body's first line of defense against microbial invasion, eliminates the harmful stimuli, replaces injurious host cells, and creates an environment favorable to tissue repair. 3. After the microbial challenge has been eliminated, however, the host must be able to dampen (shutdown) the acute inflammatory response. ##### B. Resolution of Acute Inflammation Following Removal of Microbial Challenge 1. **To maintain a healthy status, both the activation of acute inflammation and its resolution must be efficient.** a. It is not the extent of an acute inflammatory response, but rather how effectively the acute inflammation resolves that determines whether the inflammation is favorable or detrimental to the periodontium. b. **Periodontitis is associated with unresolved inflammation.** Indeed, uncontrolled or unresolved inflammation is now recognized as a major driver of human pathologies, including arthritis, asthma, cancers, cardiovascular diseases, and periodontitis. 2. Traditionally, resolution of inflammation was thought to be a passive process resulting from the reduction of biochemical mediators, the eventual disappearance of the inflammatory response, and a return to a state of tissue health. However, recent studies indicate that resolution of inflammation and return to a noninflammatory state is an actively regulated biologic process. This return to homeostasis is referred to as catabasis. 3. **Catabasis is thought to be a complicated biologic process that is just as complicated as the onset of inflammation.** #### a. Proinflammation Mediators 1. In periodontitis, the lipid mediators of inflammation include prostaglandins, thromboxanes, prostacyclins, and leukotrienes. 2. The mediators are associated with recruitment of PMNs, destruction of the connective tissue matrix, and resorption of alveolar bone. The overrecruitment or overactivity of PMNs can amplify the inflammatory process and result in tissue damage. #### b. Inflammation-Resolving Mediators 1. The resolution of inflammation is regulated by the activity of chemical mediators known as specialized pro-resolving lipid mediators. 2. Specialized pro-resolving lipid mediators are actively produced by the body during the resolution phase of acute inflammation. Specialized pro-resolving lipid mediators work in a programmed systematic process to (1) terminate PMN recruitment to the site, (2) stimulate macrophages to remove dead cells, (3) promote antibacterial activities, and (4) promote tissue repair and regeneration to achieve homeostasis. 3. Future research is focused on understanding the key steps that control the resolution phase of acute inflammation—rather than solely focusing on controlling the bacterial infection or suppressing the activity of pro-inflammatory mediators. This may lead to new treatment protocols. #### 2. Chronic Inflammation If the host is unable to tamp down the inflammation soon after removal of the microbial challenge, the acute inflammation will progress to uncontrolled and unresolved chronic inflammation which can have pathologic effects on host tissue. Figure 15-1 depicts the possible events in the inflammatory response and resolution of acute inflammation. <br> ## Inflammatory Biochemical Mediators of the Host Response In response to a microbial challenge, host immune cells secrete biologically active compounds called biochemical mediators. These biochemical mediators are the "middlemen" sent by the host cells to activate the inflammatory response. Biochemical mediators of importance in periodontitis are cytokines, prostaglandins, and matrix metalloproteinases (MMPs) (Table 15-1). #### 1. Cytokines <br> Cytokines are powerful regulatory proteins released by host immune cells that influence the behavior of other cells. The cytokine (literally "cell protein") is a molecule that transmits information or signals from one cell to another. When released by host cells, cytokines act as signaling molecules that alert and activate the immune system for help-that is, to send additional phagocytic cells to the site of an infection. ##### A. Sources of Cytokines Many different cells including PMNs, macrophages, B-lymphocytes, epithelial cells, gingival fibroblasts, and osteoblasts can produce cytokines in response to the bacterial challenge or tissue injury. ##### B. Functions of Cytokines 1. Cytokines bind to specific cell surface receptors expressed on the target cell. This is a necessary step for a cytokine to recruit immune cells, such as PMNs and macrophages, to the infection site. 2. Paradoxically, cytokines have diametrically opposed roles they can be tissue protective on the one hand, but tissue destructive on the other hand. Cytokines increase vascular permeability allowing immune cells and complement to move into the tissue at the infection site. However, cytokines have the potential to initiate tissue destruction and bone loss in chronic inflammatory diseases, such as periodontitis. ##### C. Key Cytokines Cytokines that play an important role in periodontitis include IL-1, IL-6, IL-8, and TNF-α. #### 2. Prostaglandins <br> Prostaglandins are a group of powerful biochemical mediators derived from fatty acids expressed on the cell surface of most cells. Biologically important prostaglandins are prostaglandin D, E, F, G, H, and I. Prostaglandins of the E series (PGE) play an important role in the bone destruction seen in periodontitis. ##### A. Sources of Prostaglandins The major source of PGE in inflamed periodontal tissues is the macrophage, although PMNs and gingival fibroblasts also produce them. ##### B. Functions of Prostaglandins 1. Prostaglandins increase the permeability and dilation of the blood vessels which facilitates the rapid influx of PMNs and monocytes to the infected site. 2. Prostaglandins can trigger osteoclasts to destroy alveolar bone. Prostaglandins initiate most of the alveolar bone destruction in periodontitis. 3. Prostaglandins can promote the overproduction of destructive MMP enzymes. #### 3. Matrix Metalloproteinases <br> MMPs are a family of at least 12 different proteolytic enzymes produced by various cells of the body. These enzymes act together to break down the connective tissue matrix. ##### A. Sources of MMPs PMNs, macrophages, gingival fibroblasts, and junctional epithelial cells can produce MMPs. The cells providing the major source of MMPS in periodontitis are PMNs and gingival fibroblasts. ##### B. Functions of MMPs 1. **MMPs Effects in Health:** In the absence of disease, MMPs facilitate the normal turnover of the periodontal connective tissue matrix. The overactivity of MMPs is tightly suppressed by host-derived tissue inhibitors of matrix metalloproteinases (TIMP). The MMP-TIMP balance is critical in maintaining the integrity and the health of the connective tissue. The balance also plays an important role in regulating normal turnover of the extracellular matrix. Any disruption in the MMP-TIMP balance will result in excessive, uncontrolled pathologic breakdown of the connective tissue matrix. 2. **MMPs Effects in Chronic Infection and Inflammation:** a. In the presence of chronic bacterial infection, the host immune system responds by releasing elevated levels of cytokines and prostaglandins. These mediators, in turn, stimulate leukocytes and fibroblasts to release MMPs. b. As the inflammation becomes more intense, leukocytes and fibroblasts produce excessive amounts of MMPs. The elevated MMP levels soon overwhelm the capacity of TIMPs to regulate the activity of MMP. c. In the presence of increased MMP levels, extensive collagen destruction occurs in the periodontal tissues. It should be noted that collagen provides the structural framework of all periodontal tissues. Without collagen, the tissues of the gingiva, periodontal ligament, and supporting alveolar bone degrade. This degradation results in gingival recession, pocket formation, periodontal attachment loss, root exposure, and tooth mobility. d. **Periostat (20-mg doxycycline):** A subantimicrobial dose of doxycycline is an oral medication that can be prescribed to patients with periodontitis. Its low dose of doxycycline does not provide it with any antimicrobial effect. Rather, it functions by inhibiting the activity of MMPs. When prescribed, it should be used as an adjunct to periodontal instrumentation. <br> ## Tissue Destruction by Biochemical Mediators in Periodontitis **Table 15-1** | Mediators | Local Effects | |--------------|------------------------------------------------------------------------------| | Cytokine IL-1 | Stimulates osteoclast activity resulting in bone resorption. Induces breakdown of collagen matrix in gingiva, periodontal ligament, and alveolar bone. | | Cytokine IL-6 | Stimulates bone resorption. Inhibits bone formation. | | Cytokine IL-8 | Stimulates connective tissue destruction. Stimulates bone resorption. | | Cytokine TNF-α| Stimulates bone resorption. Induces breakdown of collagen matrix in gingiva, periodontal ligament, and alveolar bone. | | Prostaglandin E₂ (PGE₂) | Stimulates MMP secretion. Induces breakdown of the collagen matrix in gingiva, periodontal ligament, and alveolar bone. | | MMP enzymes | Induce breakdown of the collagen matrix in gingiva, periodontal ligament, and alveolar bone. | | RANK | The receptor found on the surface of osteoclasts. When bound by its ligand (RANKL), osteoclasts become activated. | ## Current Theory of Pathogenesis In summary, the chain of events-pathogenesis that leads from health to gingivitis to periodontitis is complex and multilayered. For example, the microbial infection activates the host response. Genetic and environmental factors modify the immunoinflammatory response. Mediators, such as cytokines and antibodies, are produced by the cells of the immunoinflammatory response. Finally, advances in knowledge about resolution of inflammation have influenced our thinking about the pathogenesis of periodontitis. Figure 15-2 depicts the interaction of the various factors involved in the pathogenesis of periodontal disease. <br> ## Histologic Stages in the Development of Periodontal Disease Researchers Page and Schroeder conducted the classic, landmark research on the histologic development of gingivitis and periodontitis. They described four distinct histologic stages in the development of periodontal disease: initial lesion, early lesion, established lesion, and advanced lesion. For clarity, these terms appear in the discussion below, but more is understood today about the host immune response related to these stages than when they initially published their descriptions (Boxes 15-1 to 15-4 and Figs. 15-3 to 15-6). ### Box 15-1. Bacterial Accumulation (Initial Lesion) 1. **Bacterial Features:** Bacteria colonize the tooth surface near the gingival margin (Fig. 15-3). 2. **Cellular Features:** The presence of gram-negative bacteria and their metabolic products initiates the host immune response. a. In response to the bacterial pathogens, the junctional epithelial cells release various biochemical mediators, including cytokines, PGE2, MMPs, and TNFα. b. These mediators stimulate the immune response, recruiting polymorphonuclear leukocytes (PMNs) to the site. c. PMNs pass from blood vessels into the gingival connective tissue. 1. The PMNs need to reach the sulcus into order to fight the bacterial infection located there and so they must travel through the gingival connective tissue toward the junctional epithelium and the gingival sulcus. 2. As PMNs pass into the gingival connective tissue they release cytokines. Cytokines released by the PMNs destroy healthy gingival connective tissue creating a pathway that allows the PMNs to move quickly through the tissue. 3. The goal of the PMNs is to reach the bacteria in the sulcus and destroy them. The damage to the healthy connective tissue is not normally a concern. In a healthy body, tissue will be repaired after the bacterial infection is brought under control. d. PMNs migrate into sulcus and phagocytize bacteria. e. The presence of gram-negative bacteria activates the complement system. 3. **Tissue Level Features:** a. Initial location of the plaque biofilm is supragingival. b. There is vascular dilatation of arterioles, capillaries, and venules in the dentogingival complex. c. Gingival crevicular fluid increases in volume. 4. **Clinical Features:** a. At this stage, the gingiva looks healthy clinically. b. This initial lesion phase develops 2 to 4 days following plaque biofilm accumulation. 5. **Outcome of Host Response:** a. The host response is successful, if most of the bacteria are destroyed. b. If the bacterial infection is brought under control through the efforts of the immune system and effective plaque biofilm control the body can repair the destruction caused by the immune response. c. If the bacterial pathogens are not controlled, however, early gingivitis develops. <br> ### Box 15-2. Early Gingivitis (Early Lesion) 1. **Bacterial Features:** Bacterial accumulation continues and biofilm maturation occurs. This results in the production of bacterial toxins and byproducts that penetrate the junctional epithelium (Fig. 15-4). 2. **Cellular Features: Migration and Chemotaxis of PMNs** a. Cytokines-released by the junctional epithelial cells in response to the increased bacterial challenge-attract additional cellular defenders to the site. b. Increased permeability of the blood vessels allows larger numbers of PMNs to move into the gingival connective tissue near the infection site. On their way to the infection site, PMNs destroy additional healthy gingival connective tissue as they rush toward the bacterial invaders in the sulcus. c. PMNs then migrate through the junctional epithelium to form a “wall of cells” between the biofilm and the sulcus wall. These PMNs comprise the most important component of the local defense against bacteria. d. Cytokines released by the PMNs cause localized destruction of the connective tissue. This tissue destruction allows more PMNs to migrate through the connective tissue toward the sulcus. PMNs phagocytize bacteria in the sulcus in an effort to protect the host tissues from the bacterial challenge. 3. **Migration of Additional Cellular Defenders:** a. Macrophages are recruited to the connective tissue. These cells release biochemical mediators including cytokines, PGE2, and MMPs. These biochemical mediators recruit additional immune cells to the infection site. MMP is responsible for the excessive loss of collagen in the affected connected tissue zone. b. T-lymphocytes migrate to the connective tissue and produce cytokines and antibodies. The early lesion is predominantly a T-cell lesion. 4. **Tissue Level Features:** a. Sulcular epithelium and the adjacent connective tissue are affected the most: collagen loss of 60% to 70% is noted at this stage. b. Sulcular epithelium starts forming epithelial ridges (epithelial extensions that protrude into connective tissue) due to inflammatory changes. c. Junctional epithelial cells start to proliferate. 5. **Clinical Features:** a. Inflammatory changes such as edema and redness of gingival marginal tissue can be observed clinically. b. Early lesion phase develops 4 to 7 days following plaque biofilm accumulation. Duration of early gingivitis can vary between individuals. 6. **Outcome of Host Response at the Stage:** a. The large number of PMNs, macrophages, and T-lymphocytes may control the bacterial pathogens. b. Initiation of good patient self-care can disrupt the plaque biofilm and result in a return to health. If the bacterial infection is brought under control-through the efforts of the immune system and effective plaque biofilm control-the body can repair the destruction caused by the immune response. c. If the host immune response fails to "hold the line," the early lesion will progress to the "established gingivitis”—the next phase of disease progression. <br> ### Box 15-3. Established Gingivitis (Established Lesion) 1. **Bacterial Features:** Plaque biofilm extends subgingivally into the gingival sulcus, disrupting the attachment of the coronal-most portion of the junctional epithelium from the tooth surface (Fig. 15-5). 2. **Cellular Features: Migration of Additional Cellular Defenders to the Site.** a. Large numbers of subgingival bacteria stimulate the epithelial cells to secrete more cytokines, resulting in greater recruitment of additional PMNs, macrophages, and lymphocytes. b. The established lesion is predominated by the presence of plasma cells (leukocytes that produce antibodies) in the affected connective tissue zone. Hence, the established lesion is considered to be a plasma cell lesion. PMNs, macrophages, and lymphocytes continue to assist in fighting the bacteria in the sulcus. c. Plasma cells produce large quantities of antibodies to assist in controlling the bacterial challenge. d. The immune system sends more immune cells to fight the bacteria. More toxic chemicals are released and additional healthy connective tissue is destroyed. 1. Cytokines, PGE2, and MMPs are produced by macrophages exposed to gram-negative bacteria. 2. Cytokines recruit additional macrophages and lymphocytes to the area. 3. PGE2 and the MMPs initiate collagen destruction. 4. Gingival fibroblasts are stimulated to produce additional PGE2 and MMPs. 3. **Tissue Level Features:** a. Epithelial ridges extend deeper in connective tissue to maintain epithelial integrity. b. Junctional epithelium loosens its attachment to the root surface and starts to transform into pocket epithelium. Pocket epithelium is thinner and more permeable compared to junctional epithelium. c. Continued collagen loss in the infiltrated connective tissue zone. 4. **Clinical Features:** a. All the usual clinical features of gingivitis are evident in this phase, but are more accentuated compared to the initial stage and early stage. b. Established gingivitis is generally observed 21 days after plaque biofilm accumulation. 5. **Outcome of Host Response:** a. In many individuals, the host response is adequate to contain the bacterial challenge during this phase. b. Periodontal instrumentation and patient education, at this point, can be helpful in controlling the bacterial challenge. The combination of professional treatment and good patient self-care can stop the bacterial challenge and return the periodontium to health. c. In certain susceptible individuals if the bacterial infection is not controlled, established gingivitis progresses to periodontitis. Unfortunately, no one can predict when and if established gingivitis will progress to periodontitis. Current research is directed to trying to determine which individuals are at risk for developing periodontitis. <br> ### Box 15-4. Periodontitis (Advanced Lesion) 1. **Bacterial Features:** Plaque biofilm grows laterally and apically along the root surface. The periodontal pocket provides an ideal protected environment for continued growth of subgingival bacteria presenting a chronic, repeated challenge to the host (Fig. 15-6). 2. **Cellular Features: Host Response Intensifies** a. The bacterial infection becomes chronic, leading to chronic inflammation. The immune response becomes so intense that it begins to harm the periodontium. b. Cellular defenders intensify their defense against the bacterial pathogens. 1. PMNs, macrophages, and epithelial cells produce cytokines that cause destruction of the gingival connective tissue and periodontal ligament fibers. 2. Macrophages produce high concentrations of cytokines, PGE2, and MMPs that result in destruction of connective tissue and alveolar bone. 3. MMPs mediate destruction of the extracellular matrix of the gingiva, collagen fibers attached at the apical edge of the junctional epithelium, and the periodontal ligament. 4. PGE2 mediates bone destruction by stimulating large numbers osteoclasts to resorb the crest of the alveolar bone. The gingival pocket progresses to become a periodontal pocket. c. The tissue destruction caused by the host immune response now overwhelms any tissue repair. Tissue destruction becomes the main outcome of the immune system response. 3. **Tissue Level Features (Destruction of Periodontal Tissues Ensues)** a. Cells of the junctional epithelium migrate apically on root surface resulting in the development of a periodontal pocket. b. Gingival fibroblasts shift to a state that favors the destruction of the gingival connective tissue and periodontal ligament fibers (Fig. 15-5). c. Osteoclasts destroy the crest of the alveolar bone (Fig. 15-5). 4. **Clinical Features:** a. This advanced lesion phase is characterized by periodontal pocket formation, bleeding on probing, destruction of the periodontal ligament, alveolar bone loss, furcation involvement, and tooth mobility. b. These tissue changes (such as apical migration of junctional epithelium, connective tissue destruction, periodontal ligament destruction, and alveolar bone loss) are not reversible. 5. **Outcome of Host Response** a. Chronic infection by the periodontal pathogens induces a chronic inflammatory response. The chronic inflammation destroys periodontal tissues and causes more damage to the periodontium than the bacterial infection. Irreversible tissue damage is the hallmark of periodontitis. b. Factors influencing the host's failure to control the bacterial challenge may include: 1. Abnormal PMN function. 2. Persistence and virulence of bacteria in the biofilm. 3. Acquired and environmental factors such as smoking and stress. 4. Systemic factors such as uncontrolled diabetes mellitus or genetic factors. <br> If the modifying factors are present and if bacteria continue to challenge the host immune response, the following occurs: -The host immune response deploys more PMNs, which produce cytokines, prostaglandins, and MMPs to target the pathogenic bacteria. However, these factors also cause collateral damage by mediating the destruction of connective tissue and alveolar bone. -Clinical signs of periodontitis become evident. -This part of the pathogenesis pathway represents the advanced lesion (periodontitis). <br> <br> ## Periodontal Disease: A Multifactorial Process Periodontal disease is the result of an imbalance between the microbial biofilm challenge and the resulting host response. Microbial pathogens in the biofilm produce virulence factors such as antigens or lipopolysaccharides. In response, the host immune system fights back by deploying immune cells, such as PMNs, to the site of the infection and stimulating leukocytes to produce antibodies. If the host immune response is able to successfully eliminate the microbial challenge (i.e., plaque biofilm), the inflammation will resolve and the host tissues will be able to repair the damage. This part of the pathogenesis pathway represents the "initial, early, and established lesions" of periodontal disease.