Innate Immune Defense

 1. Oral Mucosa
  The epithelial lining and subepithelial tissues of the mouth provide a physical barrier against infection, but also create additional protection through chemical secretions and by communicating with the immune system.

A major physical and chemical barrier is the oral mucosa (Fabian, Hermann, Beck, Fejerdy, & Fabian, 2012). This mucosa has different characteristics in different regions of the mouth.
      In the gingival sulci, a variety of anti-microbial peptides are produced. These peptides are essentially endogenously produced antibiotics and have a wide range of targets and mechanisms of action.
    A subset of these peptides includes alpha-defensins and beta-defensins, which are produced by neutrophils and epithelial cells, respectively.
    These defensins, along with other antimicrobial peptides in the mucosa, are comprised of a high percentage of positively charged amino acids.
    This charge allows these peptides to bind to the negatively charged microbial membranes where they can act to open holes into the cell membranes. In the mucosa within the gingival sulci, neutrophils are present and are able to eat plaque-causing bacteria (Ji & Choi, 2013).
  2. Saliva
  Immune defense peptides are also present in the saliva, along with a host of enzymes that both assist with digestion and serve an antimicrobial purpose. Some of these defensive proteins include:
      Salivary immunoglobulins, which are also part of the adaptive immune system and will be discussed later.
     Other defenses include positively charged peptides such as lysozyme, a bactericidal permeability-increasing protein, amylase, mucins, and peroxidases, among many others (Fabian et al., 2012).
    While these proteins are kept at generally low concentrations in the saliva, their combined efforts exert a powerful antimicrobial effect that keeps the native flora in check.
    When an injury occurs to the mouth epithelium, or in gingival tissue, the concentration of these defensive peptides can be elevated to ward off opportunistic infections (Fabian et al., 2012).
  3. Histatins
  Histatin-5 is a specific fungicidal peptide secreted directly from the salivary glands (Salvatori, Puri, Tati, & Edgerton, 2016). This protein is able to bind to the HSP70/HSPA protein analogs on the cell surface of C.

Albicans, a species of fungi, where it is then internalized (Fabian et al., 2012). A few hypotheses for the fungicidal mechanism of histatin-5 have been proposed.
      One of these mechanisms is based on observations that histatins dysregulate the osmotic balance of the fungi cells, causing them to swell with water and burst.
    Other evidence has shown that histatins can directly dysregulate the mitochondria, causing metabolic stress and cell death (Puri & Edgerton, 2014).
  4. Lysozyme
  Lysozyme is another antimicrobial enzyme found in saliva and is also secreted directly from the salivary glands, with high levels found in sublingual saliva and within the gingival crevicular fluid.

Lysozyme’s enzymatic activity hydrolyzes the beta-1,4-glycosidic bonds that link N-acetylmuramic acid and N-acetyl-d-glucosamine, two sugar molecules found within the peptidoglycan structures of bacterial cell walls (Fabian et al., 2012).
      Gram-positive bacteria have a peptidoglycan layer connected to their outer membrane. Lysozyme is able to degrade the bacteria’s proteoglycan protective layer or permeabilize the bacterial membrane and surface lipopolysaccharides in the case of gram-negative bacteria.
    Following lysozyme breakdown of these defensive structures, other cationic antimicrobial peptides are able to gain entry to the microbe and destroy it. Gram-negative bacteria have an outer membrane made of lipopolysaccharides and proteins that shields their peptidoglycan structures from the environment.
      It has been proposed that cationic peptides are able to permeabilize this outer membrane, allowing lysozyme to access the underlying substrate (Fabian et al., 2012).
    These proposed mechanisms provide a glimpse at the complex interplay of antimicrobial compounds normally found in saliva.
  5. Antibodies
  Immune system B-cells are normally localized in the oral mucosal-associated lymphoid tissue (Fabian et al., 2012).
      
How Antibodies are Created
    
    Salivary immunoglobulins also referred to as antibodies, are secreted by B-cells following their activation within the lymphoid tissue. Antibodies are small proteins that are generated by B-cells that can recognize specific physical marks on the surfaces of microbes.

These immunoglobulins function by binding directly to bacteria, fungi, or viruses. Once bound, antibodies can either inactivate the microbe or target the microbe for eventual destruction by other components of the immune system.


    Benefits of Immunoglobins
    Immunoglobulins binding these microbes prevent them from adhering to mucous membranes in the oral cavity and upper GI tract. This promotes microbial clearance towards the stomach where the microbes are destroyed by the acidic environment.
    
    Immunoglobulins can also incorporate into the acquired pellicle of the teeth and act by binding specific microbial antigens, thereby anchoring the cells or viral capsids to the surface of the tooth (Fabian et al., 2012).
    
    Surface Immune Exclusion
    The microbes are then degraded by other oral defensive mechanisms. This approach, termed surface immune exclusion, is especially useful for defense against pathogens that are not necessarily dangerous within the oral cavity but can become dangerous if allowed to progress to the airways such as influenza virus or pneumonia-causing bacteria.
    
    It has been postulated that while surface immune exclusion is beneficial, it could also promote the buildup of plaques on the surface of the teeth, typically in the context of poor oral hygiene (Fabian et al., 2012).