Pathophysiology of oral cavity diseases. Textbook

The Mucous Membrane as a Barrier

The intact mucous membrane serves as a barrier to most microbes. Epithelial cells are in constant contact with the bacterial products of supra- and subgingival biofilms on the tooth surface, as well as with bacteria attached to the mucosal surfaces. Oral keratinocytes and dendritic cells in the oral mucosa, through Toll-like receptors (TLRs), differentiate between commensal and pathogenic microorganisms and mediate the generation of protective immunoinflammatory responses to potentially invading pathogens or promote immune tolerance to commensal microorganisms. Activation of Toll-like receptors is a signal for epithelial cells to produce cytokines, chemokines, and peptide antibiotics, primarily β-defensins. More than 45 different antimicrobial peptides have been identified in human saliva and gingival crevicular fluid. These peptides are produced by salivary glands and epithelial cells, forming a continuous layer on the mucosal surfaces. Defensins, cathelicidins (LL-37), calprotectins, and histatins are the primary antimicrobial peptides found in the oral cavity. Their main function is to prevent bacterial, fungal, or viral adhesion and infection. In addition to their antimicrobial activity, these peptides are involved in several other important processes in host tissues, such as wound healing, cell proliferation, and chemotaxis of immune cells.

The epithelium is constantly renewed by cell division in the deeper layers, and this turnover occurs more rapidly in the mucosa than in masticatory areas. The formation of cells in the deeper epithelial layers is balanced by the loss of cells from the surface. The rapid shedding of surface cells acts as a protective mechanism, limiting the colonization and invasion of microbes adhering to the mucosal surface. Thus, the oral epithelium provides the first line of defense against various environmental agents and microbes.

Role of Normal Microflora

The oral cavity hosts unique microflora that plays a key role in the natural defense of the mucous membranes against external microbes. These normal microorganisms (commensal bacteria) compete with external bacteria for nutrients, oxygen, and adhesion sites. Lipopolysaccharides produced by these endogenous microorganisms activate the immune system and stimulate antibody synthesis. If the normal microflora is depressed, for example, due to antibiotic or glucocorticoid use, it may lead to the excessive proliferation of potentially harmful bacteria and fungi on the mucous membranes.

Protective Role of Saliva

Saliva contains numerous antimicrobial components that protect the oral cavity against possible microbial colonization and subsequent infection. These factors include peroxidase, lysozyme, lactoferrin, cystatin, and SLPI (secretory leukocyte protease inhibitor). There are also specific peptides, such as histatins, cathelicidin (LL-37), and α- and β-defensins, which are secreted by the salivary glands and their ducts. These peptides not only provide antimicrobial protection but also enhance the mechanisms of both innate and adaptive immune responses.

Non-Specific Defense Factors in Saliva

Saliva contains several non-specific defense factors that are essential for protecting the oral cavity from microbial colonization and infection:

– Lysozyme: An enzyme that destroys bacterial cell walls.

– Lactoferrin: A protein that binds iron and possesses antimicrobial properties.

– Peroxidase: An enzyme that contributes to the destruction of microorganisms.

– Beta-lysins: Antimicrobial peptides.

– Tetrapeptide sialin: A compound with antimicrobial activity.

– Acidic glycoproteins: Proteins that prevent microorganisms from adhering to surfaces.

– Nucleases: Enzymes that cleave DNA and RNA.

– Mucin: A glycoprotein that provides viscosity of saliva and protects mucosal surfaces.

– Interferon: A protein with antiviral activity.

Mechanisms of Action

The enzymes acting on the bacterial cell walls, include lysozyme that affects Gram-positive bacteria, preventing their adhesion and growth. Peroxidase system of saliva including salivary peroxidase and myeloperoxidase is cytotoxic for bacteria and it inhibits their growth and production of acids, functioning synergistically with other molecules.

The primary target of lysozyme is peptidoglycan, a glycosidic polymer and a structural component of bacterial cell walls, which provides bacteria with shape and osmotic stability. Lysozyme can directly kill some bacteria by degrading this peptidoglycan layer. Although most bacteria do not die immediately, they become more susceptible to other antimicrobial agents and osmotic stress. Lysozyme damages microbes through at least three different mechanisms:

– Enzymatic cleavage: Lysozyme breaks down bacterial peptidoglycan.

– Cationic protein activity: Lysozyme acts as a small cationic protein, releasing autolytic enzymes from bacteria.

– Amphipathic properties: As a cationic and amphipathic protein (containing both hydrophobic and hydrophilic groups), lysozyme destroys bacterial membranes.

Although the bactericidal activity of lysozyme against many pathogenic bacteria is relatively weak, especially against Gram-negative bacteria, its effectiveness is significantly enhanced by other host defense substances, such as lactoferrin, antibody-complement complexes, or hydrogen peroxide-ascorbic acid. Presumably, these cofactors disrupt the outer membrane of Gram-negative bacteria, providing lysozyme with access to the sensitive peptidoglycan layer.

Glycoproteins, such as mucin, cover the epithelial surface, creating a protective barrier that prevents the penetration of various particles and infectious agents; they also protect the underlying epithelial layers. Mucins serve as a source for secretory IgA, contributing to immune defense.