• Chemical defenses

Various body fluids contain substances that contribute to our resistance to potential pathogens. Mucous secretions, tears, sweat, and saliva all contain lysozyme, an enzyme that destroys the cell walls of many gram-positive bacteria. Fatty acids in sweat and earwax have bacteristatic and fungistatic properties. The stomach contains a high concentration of hydrochloric acid, which rapidly kills most microbes, and in the small intestines bile destroys many of the survivors. The high acidity of the adult vagina protects its membranous surfaces against colonization by many types of pathogens. The digestive system produces mucin, a glycoprotein that coats microbes and prevents their attachment to intestinal epithelium. Several antimicrobial peptides and proteins have been isolated from cells of the skin and gastrointestinal tract of humans or animals.

Another protective factor released into the blood is beta-lysin. This protein attacks bacterial membranes.

Transferrins are iron-binding proteins that reduce the level of free iron in the blood. Lactoferrins perform the same function in milk, respiratory, intestinal, and genital secretions. The presence of free iron is necessary for the growth of most pathogenic microbes. Iron is also required by human cells, but it can be extracted from the iron-binding proteins as it is needed, whereas most bacteria cannot obtain protein-bound iron. Reducing free iron levels in the body therefore helps protect against microbial proliferation, This strategy is enhanced by mononuclear phagocytes that remove even more free iron from the blood during infection.

• Immunobiological defenses (humoral and cellular factors)

The main nonspecific humoral factors are as follows.

Interferons are a group of soluble proteins produced by host cells during infection by viruses and some other microbes. Uninfected cells in the area that are exposed to virus-induced interferon become resistant to viral infection. Interferons also stimulate the activity of our phagocytic and immunologic defenses.

Interleukin-I is a fever-inducing protein safely isolated in vacuoles of phagocytic cells, where it has no effect on the host. When stimulated by certain foreign substances such as bacterial endotoxin, phagocytes discharge the contents of these vacuoles, which circulate to the hypothalamic region of the brain and trigger an elevated body temperature.

NOTE: Although fever can itself damage human cells, it has several protective effects: it raises temperatures above that which is optimal for growth of some pathogens; it accelerates the mobilization and protective efficiency of the body's defenses; it stimulates lymphocyte activity in the immune response; and it increases the rate of iron storage, reducing iron availability to pathogens.

Complement is a complex group of serum proteins that act in concert with the immune system or with other serum proteins to facilitate bacterial lysis and phagocytosis. In the classical pathway of complement activation, an antibody-pathogen complex activates the complement system. The alternative pathway occurs in the absence of an immune response but requires a blood protein (called properdin) and other factors to combine with surface molecules of the bacterial cell wall, launching the cascade of events that has the same outcome as the classical pathway—activation of phagocytes and damage to the bacterial membrane. Either pathway can eliminate the foreign cell that triggered the response. (The immune-mediated complement system is discussed in details in LESSON 13).

The main cellular factors of nonspecific host defense are phagocytic cells, natural killers (NK-cells).

Phagocytic Defenses. When infectious agents penetrate the surface defenses of the body, they are usually devoured by leukocytes (white blood cells) or other phagocytic cells. These cells engulf and destroy foreign particles by phagocytosis .

Lysosomes are characteristic of a group of white blood cells called granulocytes. Of the three types of granulocytes found in normal blood, neutrophils are the most abundant. These cells are also called polymorphonuclear leukocytes (PMNs) because of their irregular multilobed nuclei. Neutrophils are actively phagocytic and are usually the first protective cells to arrive at the site of trauma or infection. They do their work rapidly and are fairly short-lived. Two other types of granulocytes—eosinophils and basophils—are not phagocytic but contribute to defense by producing substances that help regulate the host response to injury or infection.

The other group of leukocytes is made up of agranulocytes, so called because they have fewer dark-staining lysosomes. Nonetheless, lysosomes are present in numbers great enough to effect the destruction of engulfed particles during phagocytosis. Agranulocytes include lymphocytes and monocytes. Monocytes have a single large oval or horseshoe-shaped nucleus. Circulating monocytes migrate into tissue, where they enlarge and differentiate into actively phagocytic macrophages. Most macrophages are attached to tissues of the liver, spleen, lymph nodes, and bone marrow and to the walls of blood and lymph vessels. They engulf foreign particles and debris from blood and lymph that flow through these regions. These fixed macrophages therefore function as filters to clean debris from the blood and trap potential pathogens. Wandering macrophages migrate to the lungs, spleen, and other sites where microbes are likely to be encountered. Macrophages also travel to areas of trauma or infection to participate in the body's overall protective response. In addition, macrophages play an essential role in helping the immune system recognize antigens and respond to these foreign substances.

The monocytes and macrophages constitute the body's mononuclear phagocytic system (part of the reticuloendothelial system, which consists of all phagocytic cells and tissues to which fixed macrophages attach).

Most phagocytic cells in the circulation contain large numbers of lysosomes in their cytoplasm. Lysosomes contain a number of digestive enzymes—peptidoglycanases, lipases, and proteases—plus chemicals that oxidize and destroy engulfed cells. As a result of phagocytosis, an invading microbe is trapped within an intracytoplasmic vacuole called a phagosome. Lysosomes migrate to the vacuole membrane and discharge their contents into the phagosome. The phenomenon, called degranulation, occurs by fusion of lysosomal and vacuole membranes, and the phagocytic vacuole grows into a larger membranous sac called a phagolysosome. The chemicals in the phagolysosome kill and digest the engulfed microbe. Human tissue can also be damaged by the lysosomal contents. The vacuole membrane, however, usually prevents tissue injury by safely housing the discharged chemicals, preventing their sudden release into the cell’s cytoplasm or into the surrounding tissue. Phagocytes also kill microbes by converting oxygen to toxic products such as superoxide and hydrogen peroxide. Increased respiration, called the respiratory burst, initiated during the early stages of phagocytosis generates these toxic oxidants.

Outcome of phagocytosis. All types of phagocytic cells (granulocytes, macrophages in blood, and fixed macrophages of the reticuloendothelial system) may kill ingested microbes (complete phagocytosis), or may permit their prolonged survival or even their intracellular multiplication (incompleted phagocytosis). The outcome of pagocytosis is determined by a complex factors, including the specific nature of the microbe as well as the genetic and functional makeup and the preconditioning of the phagocytic cells.

• INFLAMMATION

Phagocytosis is an essential component of inflammation—a concentrated protective response to infection or tissue injury in which the body attempts to localize and destroy infectious microorganisms and repair damaged tissues. The cells of injured tissues release their contents and increase acidity at the site of injury. This activates local enzymes, called kinins, that increase the permeability of capillaries in the immediate region, promoting the escape of plasma from the vessels into the local tissues. Kinins also promote the release of histamine, prostaglandins, and other substances from surrounding cells. These chemicals further increase vascular permeability, so even more plasma accumulates, bringing complement, antibodies, and other protective chemicals to the site of injury. They also stimulate chemotaxis, the migration of white blood cells toward the source of injury or infection. These responses characteristically elicit four symptoms at the site of injury: swelling, pain, redness, and heat. The pain associated with inflammation is also due to the release of irritant chemicals that bind to nerve endings.

Inflammation protects the host by promoting phagocytosis of microbes, by localizing infection (microbes are often walled off in capsules of clotted plasma), and by producing an exudate (pus), which in some cases allows direct drainage of microbes and dead tissue out of the host's body (as from a pimple, for example). The symptoms of inflammation also alert us to the presence of infection, increasing the likelihood of early diagnoses and treatment.

• MICROBIAL DEFENSES

The body's resident or normal bacterial flora provide another important line of defense. The normal flora continually compete with potentially pathogenic microbes for the limited nutrients and space on the body's epithelial surfaces). Because the normal flora is already established, these beneficial microorganisms usually win the competition and prevent either initial infection or the unrestricted growth of pathogenic bacteria and fungi. Resident bacteria also have the ability to alter their local environment so that it is generally unfavorable for the growth of most pathogens.