innate immunity

II.  NON-SPECIFIC IMMUNITY

The elements of the non-specific (innate) immune system (Table 2) include anatomical barriers, secretory molecules and cellular components. Among the mechanical anatomical barriers are the skin and internal epithelial layers, the movement of the intestines and the oscillation of broncho-pulmonary cilia. Associated with these protective surfaces are chemical and biological agents.

A. Anatomical barriers to infections

1. Mechanical factors

The epithelial surfaces form a physical barrier that is very impermeable to most infectious agents. Thus, the skin acts as our first line of defense against invading organisms. The desquamation of skin epithelium also helps remove bacteria and other infectious agents that have adhered to the epithelial surfaces. Movement due to cilia or peristalsis helps to keep air passages and the gastrointestinal tract free from microorganisms. The flushing action of tears and saliva helps prevent infection of the eyes and mouth. The trapping effect of mucus that lines the respiratory and gastrointestinal tract helps protect the lungs and digestive systems from infection.

2. Chemical factors

Fatty acids in sweat inhibit the growth of bacteria. Lysozyme and phospholipase found in tears, saliva and nasal secretions can breakdown the cell wall of bacteria and destabilize bacterial membranes. The low pH of sweat and gastric secretions prevents growth of bacteria. Defensins (low molecular weight proteins) found in the lung and gastrointestinal tract have antimicrobial activity. Surfactants in the lung act as opsonins (substances that promote phagocytosis of particles by phagocytic cells).


3. Biological factors

The normal flora of the skin and in the gastrointestinal tract can prevent the colonization of pathogenic bacteria by secreting toxic substances or by competing with pathogenic bacteria for nutrients or attachment to cell surfaces.
 

B. Humoral barriers to infection

The anatomical barriers are very effective in preventing colonization of tissues by microorganisms. However, when there is damage to tissues the anatomical barriers are breached and infection may occur. Once infectious agents have penetrated tissues, another innate defense mechanism comes into play, namely acute inflammation. Humoral factors play an important role in inflammation, which is characterized by edema and the recruitment of phagocytic cells. These humoral factors are found in serum or they are formed at the site of infection.

1. Complement system – The complement system is the major humoral non-specific defense mechanism (see  complement chapter). Once activated complement can lead to increased vascular permeability, recruitment of phagocytic cells, and lysis and opsonization of bacteria.

2. Coagulation system – Depending on the severity of the tissue injury, the coagulation system may or may not be activated. Some products of the coagulation system can contribute to the non-specific defenses because of their ability to increase vascular permeability and act as chemotactic agents for phagocytic cells. In addition, some of the products of the coagulation system are directly antimicrobial. For example, beta-lysin, a protein produced by platelets during coagulation can lyse many Gram positive bacteria by acting as a cationic detergent.

3. Lactoferrin and transferrin – By binding iron, an essential nutrient for bacteria, these proteins limit bacterial growth.

4. Interferons – Interferons are proteins that can limit virus replication in cells.

5. Lysozyme – Lysozyme breaks down the cell wall of bacteria.

6. Interleukin-1 – Il-1 induces fever and the production of acute phase proteins, some of which are antimicrobial because they can opsonize bacteria.
 

PHAGOCYTOSIS AND INTRACELLULAR KILLING

A. Phagocytic cells

1. Neutrophiles/Polymorphonuclear cells
PMNs are motile phagocytic cells that have lobed nuclei. They can be identified by their characteristic nucleus or by an antigen present on the cell surface called CD66. They contain two kinds of granules the contents of which are involved in the antimicrobial properties of these cells. The primary or azurophilic granules, which are abundant in young newly formed PMNs, contain cationic proteins and defensins that can kill bacteria, proteolytic enzymes like elastase, and cathepsin G to breakdown proteins, lysozyme to break down bacterial cell walls, and characteristically, myeloperoxidase, which is involved in the generation of bacteriocidal compounds. The second type of granule found in more mature PMNs is the secondary or specific granule. These contain lysozyme, NADPH oxidase components, which are involved in the generation of toxic oxygen products, and characteristically lactoferrin, an iron chelating protein and B12-binding protein.

2. Monocytes/Macrophages - Macrophages are phagocytic cells that have a characteristic kidney-shaped nucleus. They can be identified morphologically or by the presence of the CD14 cell surface marker. Unlike PMNs they do not contain granules but they have numerous lysosomes which have contents similar to the PNM granules.

B. Response of phagocytes to infection

Circulating PMNs and monocytes respond to danger (SOS) signals generated at the site of an infection. SOS signals include N-formyl-methionine containing peptides released by bacteria, clotting system peptides, complement products and cytokines released from tissue macrophages that have encountered bacteria in tissue. Some of the SOS signals stimulate endothelial cells near the site of the infection to express cell adhesion molecules such as ICAM-1 and selectins which bind to components on the surface of phagocytic cells and cause the phagocytes to adhere to the endothelium. Vasodilators produced at the site of infection cause the junctions between endothelial cells to loosen and the phagocytes then cross the endothelial barrier by “squeezing” between the endothelial cells in a process called diapedesis (Figure 9). Once in the tissue spaces some of the SOS signals attract phagocytes to the infection site by chemotaxis (movement toward an increasing chemical gradient). The SOS signals also activate the phagocytes, which results in increased phagocytosis and intracellular killing of the invading organisms.