Host-defense mechanisms

Biology

Anatomy or system affected: Blood, cells, gastrointestinal system, immune system, skin, urinary system

Definition: Immunological methods that the body uses to protect against external infectious agents and to maintain internal homeostasis, such as those rooted in the skin, sweat, urine, tears, phagocytes, and “helpful” bacteria

Structure and Functions

Humans exist in an environment that contains a wide variety of potentially infectious agents. These agents range in size from microscopic viruses—such as rhinoviruses, which cause the common cold—to a wide variety of bacteria and even macroscopic agents, such as parasitic worms. In the absence of a functioning immune system, as is observed in persons with acquired immunodeficiency syndrome (AIDS) or congenital immune deficiencies, a person will eventually succumb to overwhelming infections.

Host-defense mechanisms consist of two major components: an innate system that is not dependent on prior exposure to an infectious agent and an acquired immunity that is stimulated by exposure to an agent. In general, the innate system functions in a nonspecific manner, while the acquired immune responses are highly specific.

The first major lines of host defense are the physical barriers to infection. These include the intact skin and the mechanical or physical barriers that serve to protect body openings. Few infectious agents are capable of penetrating intact skin. Numerous sweat glands and follicles are also associated with skin, and their secretion of fatty acids or lactic acid serves to produce an acid environment that inhibits the growth of bacteria. In addition, the high salt content found on the surface of the body also serves to inhibit growth. Bacteria that can resist the high levels of salt and acid, such as Staphylococcus or Streptococcus, tend to cause skin-related problems such as acne or boils.

Openings of the body, such as the mouth, anus, and vagina, exhibit both the physical barrier of skin and a variety of other defense strategies. Secreted mucus serves to trap foreign particles, which can then be expelled, depending on the tissue, by the ciliary action of the cells, coughing or sneezing, or the washing action of saliva, urine, or tears. Many of these secretions also contain antibacterial or antiviral agents. Gastric juices contain hydrochloric acid, while the enzyme lysozyme, found in tears and saliva, serves to cause the breakdown of certain bacteria.

The normal flora of organisms found within the body also plays an important role in defense. Bacteria in the mouth and gut serve to suppress any external agents that may find their way to those regions. Removal of the innate flora with antibiotics may result in yeast infections of the mouth or vaginal tract, or ulceration by “opportunistic” organisms of the gut.

Penetration of the host by infectious agents initially brings into action other aspects of the innate immune system. This can take the form of a series of “professional” phagocytes, cells that literally eat foreign particles such as bacteria; also included are chemical agents found in tissue and blood.

Two major forms of phagocytes are found in blood and tissues: neutrophils and monocytes/macrophages. Neutrophils represent the most numerous white cells in blood, approximately 60 to 70 percent of the total. They can be recognized by their multilobed nuclei, which confer the ability to pass between the endothelial cells of capillaries into sites of tissue infections. When neutrophils locate a target, such as an infectious agent or a dead cell, they surround that target with membranous arms called pseudopods and ingest it. Once the particle is incorporated within this “phagosome,” it is ready for killing and digestion.

The killing of ingested organisms such as bacteria involves a series of complicated reactions, the major products of which are highly reactive oxidizing agents such as peroxides or metabolic by-products such as acid. At the same time, digestive organelles within the phagocyte, called lysosomes, fuse with the phagosome. Lysosomes contain numerous digestive enzymes, and these function to digest the engulfed particle. In effect, the particle now ceases to exist.

Monocytes, which are most often observed in their differentiated macrophage stage, function in a similar manner. Unlike circulating cells such as neutrophils, however, macrophages constitute the mononuclear phagocytic system that is associated with many tissues in the body. Examples of tissue-associated macrophages are the Kupffer cells of the liver, the microglia of the brain, and certain alveolar cells of the lungs. In addition to serving a nonspecific phagocytic function, macrophages serve as antigen-presenting cells (APCs) for specific immune responses.

A variety of blood chemicals also can be associated with innate immunity. Complement represents a series of some twenty blood proteins, activated in a cascade fashion, which exhibit a variety of pharmacologic activities. The complement pathway can be initiated upon exposure to certain bacteria. Components of the pathway can serve as chemoattractants for neutrophils. They can increase the efficiency of phagocytosis (opsonization), and they can form a membrane attack complex on the surface of a target, resulting in lysis.

Another type of blood cell may play a role in certain types of parasitic infections: the eosinophil. Granulocytes, like the neutrophils, eosinophils contain within their granules digestive enzymes capable of being released against targets such as parasitic worms. The binding of these enzymes on the surface of a target damages the parasite’s membrane, resulting ultimately in death of the parasite.

Acquired host defenses, while involving mechanisms similar to those of the innate systems, differ in one important way: they require prior exposure to the antigen. Acquired immunity consists of two major arms: humoral immunity, which represents substances soluble in the blood, and cellular immunity, which utilizes cells targeted against agents in a specific manner.

Humoral immunity centers primarily on proteins called antibodies. Exposure to foreign antigens triggers a series of reactions among three separate types of blood cells: antigen-presenting cells, T lymphocytes, and B lymphocytes. It is the B cell that secretes the antibodies.

The process starts when an APC encounters and phagocytizes an antigen. The antigen is digested, and pieces, or determinants, of the antigen are expressed on the surface of the cell. The most common APC is the macrophage, but antigen presentation can also be carried out by dendritic cells found in the dermis of the skin. This portion of the process is analogous to the series of events associated with innate immunity. At this point, however, the determinant is “presented” to appropriate T and B lymphocytes. Only those lymphocytes that possess specific receptors for that antigenic determinant can interact with the APC. It is this aspect that represents the specificity of the reaction. In association with a subclass of T lymphocytes called T helper cells (also known as CD4+ cells), the B cell is stimulated to begin the secretion of large quantities of antibodies. The antibodies recognize and bind only those antigens against which they were produced.

The formation of antigen-antibody complexes is the key to the humoral response. The result of the reaction depends upon the form taken by the antigen. The binding of antibodies to a bacterium or virus results in opsonization, a significantly enhanced ability of phagocytes to engulf the target. Antibody binding to a virus may also inhibit the agent’s binding to a target cell, rendering the virus inactive. If the antigen is a toxin, antibody binding will neutralize the molecule.

The other arm of acquired immunity directly utilizes cellular defenses. The key cell here is the T lymphocyte. T lymphocytes mature in an organ called the thymus, which is located in humans near the thyroid in the neck and which provides the basis for the cells’ name. One subset of T cells is often referred to as killer cells (or CD8+ cells) because of their function. They possess receptors on their surfaces that bind to specific target cells, which are generally cells infected with viruses, though T cells are also associated with rejection of foreign grafts. Once the T cell binds to the target, pharmacologically active granules are released that bind to and disrupt the membrane of the target. Thus, the humoral response is directed primarily against extracellular agents such as bacteria, while the cellular response is directed primarily against intracellular parasites.

Disorders and Diseases

In their most obvious form, the mechanisms of host defense protect against disease. Humans exist in an environment that is a sea of microorganisms. Most infections, while often uncomfortable, are not life-threatening. It is only when the immune system fails to function properly or is overwhelmed that illness results in the death of the individual. Ironically, the study of these circumstances has provided much knowledge of the functioning of the immune system.

Throughout history, diseases have periodically plagued humanity. Epidemics of viral diseases such as polio and bacterial infections such as bubonic plague or cholera have killed untold millions of people. Among the most important advances in medicine since the eighteenth century has been the development of vaccination as a means of preventing disease. In the case of passive immunity, host defenses are temporarily augmented, while active immunity, mimicking an actual infection, often provides lifelong protection.

Passive immunity involves the acquisition of preformed antibodies by an individual. Since colostrum, or milk from a nursing mother, contains a form of antibody, this is the most common form of passive immunization. Preformed antibodies may also be given to a person exposed to potentially lethal toxins under circumstances in which there may be insufficient time for a proper immune response. These can include persons exposed to snake venom or tetanus toxin. While temporarily providing protection, passively acquired antibodies survive in the individual only for a short period.

More commonly, vaccines are utilized to provide active immunization by stimulating the acquired host defenses. These vaccines generally utilize inactivated or attenuated parasites that stimulate specific cellular or humoral responses. The prototypes of active immunization are the polio vaccines developed by Jonas Salk and Albert Sabin in the 1950s. Salk’s vaccine utilizes a formalin-inactivated poliovirus, while Sabin’s consists of attenuated virus. While controversy exists regarding which is superior, both vaccines act in basically the same manner. Exposure to either vaccine results in the production of protective antibodies in the circulation of the individual. In the event of actual infection by poliovirus, the agent would be neutralized before it could reach its target in the central nervous system. Analogous vaccines have been developed against previously common viral diseases such as smallpox, measles, and mumps, and against bacterial diseases such as pertussis (whooping cough) and diphtheria.

The process by which the acquired immune process functions is in part defined by the nature of the antigen. It is also important to remember that the humoral and cellular defense systems are not self-exclusive; each functions in conjunction with the other. If the antigen in question is a bacterium, it is primarily the role of the humoral system to deal with the infection. This can take several forms. The antibody may bind to the surface of the cell, inactivating the cell wall or membrane enzymes, resulting in the death of the cell. The antibody-antigen (bacterium) complex may also activate the complement pathway, resulting in either opsonization or the formation of a membrane attack complex by complement components. Indeed, antibody binding by itself may result in opsonization.

If the antigen is a virus-infected cell, the cellular portion of the response comes into play. Cytotoxic T cells can bind to the target through specific receptors, causing the death of the virus-infected cell. If an antibody binds to viral receptors on the infected cell, cytotoxic cells with receptors for the antibody may show increased affinity for the target in a process called antibody-dependent cell-mediated cytotoxicity (ADCC). The result is the death of the target. The antibody may also serve to neutralize a cell-free virus before the particle can even infect the target cell. Certain bacteria, however, such as the mycobacteria associated with tuberculosis and leprosy, are found as intracellular parasites. In such cases, it is the cellular immune system that plays a major role in defense. In this manner, the humoral and cellular defense mechanisms complement each other.

Failure of the immune system to function is clearly illustrated in persons infected with the human immunodeficiency virus (HIV), the virus that causes AIDS. HIV infects the subclass of T lymphocytes called T helper cells. The eventual result is the death and depletion of this subclass of cells. As briefly described earlier, T helper cells are central to the function of both the humoral and the cellular arms of acquired immunity. The interaction of these cells with B lymphocytes is necessary for both antibody production by these cells and their proliferation. The T helper cell is also required for activation and proliferation of the CD8+ cytotoxic T cells.

As AIDS progresses in the individual, the T-helper subclass becomes increasingly depleted. As a result, both the cellular and humoral immune systems become progressively less functional. The person becomes more susceptible to opportunistic organisms in the environment and eventually succumbs to any of a wide variety of diseases.

In rare congenital cases, only certain aspects of the immune system are nonfunctional. These often tragic examples serve to illustrate the role of various cells within the host defense. For example, children with B-cell deficiencies suffer from repeated bacterial infections, while yeast and viral infections rarely result in problems. Children in whom the thymus fails to develop (DiGeorge or Nezelof syndromes), however, suffer from repeated viral infections but rarely from bacterial infections.

Severe combined immunodeficiency syndrome (SCID) affects approximately one of every 58,000 live births. This genetic disorder is the result of a lack of the enzyme adenosine deaminase (ADA), which ultimately causes a lack of functioning T cells. For years, patients with this disorder had been doomed to living in sterile bubble environments and would die at a young age because of their inability to fight even the mildest infection. Bone marrow transplants for patients with compatible donors can sometimes strengthen the immune system; however, this option is not available for everyone.

In 1990, two unrelated girls with SCID, four and nine years old, were the subject of the first clinical trial of gene therapy. T cells in their blood were isolated and cultured, and normal copies of the ADA gene were introduced into the cells. The genetically engineered T cells were then infused back into the patients over a period of approximately two years. Both girls showed remarkable improvement, with near normal levels of ADA and functioning immune systems, and were thereafter able to lead normal lives. These positive results remained several years after cessation of the actual gene therapy, indicating that this first clinical trial of gene therapy was a success. The door is now open for using gene therapy on other disorders, including those of the immune system.

Host defenses are also utilized within the homeostatic process, which can be defined as maintaining the status quo. An example of such a process is the role of the immune system in protecting humans against various forms of cancer. Although immunosuppressed individuals appear to be at no greater risk for most cancers than normal persons, certain types of skin cancers, as well as certain types of B-cell lymphomas, arise more frequently in these persons. Thus, it is likely that the immune system plays at least some role in protecting the individual from certain forms of cancer. Artificial stimulation of the immune system has, however, been utilized in an attempt to treat sundry forms of advanced cancers. The process involves the removal of immune cells from the patient and the incubation of those cells with a form of interferon generally secreted by T helper cells during their regulation of the immune response. The cells are then returned to the patient. The theory is that, by nonspecifically stimulating cytotoxic cells, some of those cells may serve to destroy the cancer. In some instances, patients have shown improvement.

Clearly, the immune system functions by means of a complex process of cellular interactions. The initial encounter with a foreign infectious agent utilizes an innate system that serves as a first line of defense. Then, through a type of learning process, a specific immune response is generated that provides a more rapid, more efficient means of generating protection.

Perspective and Prospects

Manipulating the host’s immune system to protect against disease dates back more than a thousand years. To protect themselves against smallpox, the Chinese carried out a practice called variolation, in which dried crusts obtained from the pocks of mild cases were inhaled. The practice was copied by early Arabic physicians and eventually made its way to eighteenth century Europe. In the late eighteenth century, an English country physician, Edward Jenner, observed that dairymaids who had recovered from a mild disease called cowpox rarely exhibited the scars associated with smallpox. Jenner reasoned that a person who had been exposed to the cowpox agent would be protected against smallpox. Jenner tested his theory and was proved correct. Smallpox became the first disease that could be prevented by vaccination.

Competition between French and German scientists during the late nineteenth century resulted in much of the existing basic knowledge of host defenses. A Russian, Élie Metchnikoff, working with Louis Pasteur in Paris during the 1880s, developed the views of cellular immunity that are still current. In that same period, the work of Emil von Behring and Paul Ehrlich in Berlin established the role of humoral immunity in protecting against disease.

Active immunization remains the primary method by which an individual may be protected from disease, but the process lends itself to a variety of problems. Not all antigenic determinants of the bacterium or parasite in question are equally important. A response to some antigens may hinder the immune response to more important determinants. Furthermore, some individuals react inappropriately to some vaccines, resulting in severe allergic reactions.

For these reasons, much research involves the attempt to isolate only the desired antigen for the vaccine. This has taken several approaches. Purified components, rather than the entire organism, have been used in some vaccines. In some cases, the gene that encodes the desired antigen has been isolated and spliced into the genetic material of a harmless organism. Such an approach has been used to produce a modified hepatitis B vaccine. The gene encoding the surface antigen of the virus has been spliced into the genome of vaccinia, long used for vaccination against smallpox. When the individual is vaccinated, the hepatitis gene is expressed (though no virus can be made), and the person becomes immune to the disease. In theory, whole cocktails of vaccines can be prepared in a similar manner.

New illnesses and other environmental hazards that affect host defenses continue to arise. AIDS may be unusually lethal, but as a previously unknown disease, it is by no means unique. Nevertheless, the ability of the host immune system to respond to new infectious agents remains a bulwark for maintaining the health of an individual.

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