The action taken by the body to defend itself from pathogens or abnormalities is called the immune response. With the aid of the immune system, the body monitors constant exposure to harmful elements in the external and internal environment and provides a means of defense. Pathogens that are able to cause immune responses included bacteria, viruses, and parasites. The immune system must be able to determine what is a normal part of the body or "self," as opposed to that which is foreign or "non-self." The development of cancers, for example, represents a part of "self" that has been abnormally changed such that it is recognized as foreign to the immune system.
Description
The immune response can be roughly divided into two broad categories, innate (natural) immunity and adaptive (acquired) immunity. Innate immunity is the first line of defense against invasion by pathogens. This response is not directed against any one particular pathogen but is a capable of destroying many different invaders. If the pathogen is able to conquer this initial protection, an adaptive immune response will follow. In this response, lymphocytes arise that can specifically kill the invader and prevent re-infection. These lymphocytes recognize specific antigens on pathogens (substances that are foreign to the host cell and cause the production of antibodies to fight the disease).
Innate (natural) immunity
Innate immunity refers to those parts of the immune system that are normally present and do not given an elevated response upon a second exposure to a pathogen (without immunological memory). This immunity is non-specific and is not directed against one type of pathogen. It is more generalized to allow the recognition of common elements that may be shared among pathogenic microorganisms.
Anatomical or physical barriers provide innate protection. The skin provides a protective barrier and contains substances that are antimicrobial (against bacterial growth) such as lactic acid, ammonia, and uric acid. The bacteria (microflora) that normally inhabit the skin do not cause disease under normal conditions. These organisms also contribute to innate immunity. The competition of the microflora with pathogens for resources and nutrients limits the growth of pathogens. If the skin is broken due to wounds or burns, pathogenic bacteria may enter to cause disease. In the urinary and biliary tracts, the increased flow of secretions provides protection against the establishment of harmful organisms.
Physiologic barriers are also a part of the innate immune system. Stomach acid can kill and inhibit the growth of many microorganisms and degrade potentially harmful proteins. A rise in body temperature can create an environment that is no longer suitable for the growth of some bacteria. Saliva, nasal secretions, tears, and mucus also contain substances that block viruses and help in the destruction of harmful bacteria.
Some cells of the immune system are able to attack and engulf pathogens, molecules, or particles by a process known as phagocytosis. The Russian immunologist Eli Metchnikoff observed that some pathogenic microorganisms were destroyed by phagocytic cells he called macrophages. These phagocytic cells originate in the bone marrow, are called monocytes in the bloodstream, and become macrophages in the tissue. These phagocytic macrophages in the tissue are able to ingest and destroy some pathogens even though they have not previously encountered them. These cells are capable of migration and are found in many sites throughout the body, including the lymph nodes, spleen, liver, lungs, as well as the peritoneal lining that surrounds the organs and the lungs. Macrophages in the bone are called osteoclasts, in the central nervous system they are called microglia, and in the connective tissue they are known as histiocytes. The neutrophils (polymorphonuclear leukocytes or PMNs) are another type of phagocytic cell that is critically important for innate immunity. These cells are found in great numbers and are one of the most important types of white blood cells found in the bloodstream. They are quickly recruited to the site of infection to engulf pathogens. Both neutrophils and macrophages contain enzymes that break down the engulfed material.
Natural killer (NK) cells are a type of lymphocyte in the blood that can detect and destroy cells infected by certain viruses. Viruses attack host cells and use them to facilitate viral replication and production of more viruses. Infected host cells must be rapidly destroyed to prevent this replication and spread of disease. It has been observed that natural killer cells play an especially important role in the early defense against herpes viruses. They also are involved in the killing of some tumors. Natural killer cells may kill by activating a process called apoptosis, the programmed cell death that is present in all cells and is responsible for their self-destruction.
The plasma contains a group of proteins called complements that act in a coordinated manner to attack pathogens. When some pathogens bind with a complement protein called C3b, a series of reactions in the alternativecomplement pathway occur. The surface of the pathogen is changed so that phagocytic cells can ingest them, a process called opsinization.
If the pathogen is able to effectively cross the barriers of innate immunity, an early induced, non-adaptive response will occur. This response serves to stop pathogens or slow them down until the body can initiate an adaptive immune response. Additional phagocytic cells and molecules are summoned to the site of infection by cytokines, a group of proteins that affect the actions of other cells. Some cytokines can cause an increase in the number of neutrophils in the circulation and fever, an elevation in body temperature. As most pathogenic bacteria have optimal growth at lower temperatures, this temperature rise helps to inhibit their growth. The fever also enhances the adaptive immune responses that follow. Local effects from injury or infection give rise to inflammation as white blood cells, fluid, and plasma proteins gather at the site. This is evident clinically at the site by redness, pain, heat, and swelling. The blood vessels in the site of injury or infection increase in diameter and allow more blood to flow into the area at a slower rate. Immune cells arrive quickly to the site and move into the tissue from the bloodstream. Small proteins called chemokines assist in this process and enhance the migration and activation of cells. Other special proteins called interferons are produced by virally infected cells and may stop the virus from multiplying within other cells, preventing the spread of infection.
Adaptive (acquired) immunity
In adaptive immunity, the immune response is specific for a particular antigen, causes lymphocytes that recognize the antigen to multiply (clonal expansion), and imparts the quality of immunological memory of prior encounters with the antigen. Specificity is an essential component of adaptive immunity as many organisms have evolved to evade the innate immune system. A system of defense is needed to specifically eliminate these elusive invaders, of which there are countless numbers. Two parts of adaptive immunity meet this challenge: cellular-mediated immunity and humoral (antibody-mediated immunity).
CELL-MEDIATED IMMUNITY. Once a pathogen has evaded the innate immune system, the cellular immune response mechanisms are initiated. In the lymphoid tissues, naive lymphocytes that have not been exposed to the pathogen encounter pathogen antigens for the first time. Dendritic cells, macrophages, and B cells take up the antigens that have been trapped in the lymphoid tissue and present them to naïve T cells. These T cells become activated, recognizing specific antigens from the pathogen and become effector cells; helper T cells (TH1 or TH2) and cytotoxic T cells. The TH1 cells produce interferons and cytokines that assist in the activation of macrophages that have ingested pathogens. They also help B cells make antibodies that are used to opsinize pathogens and secrete cytokines that draw phagocytic cells to the site of infection. The TH2 cells produce B cell growth factors that activate the B cells, causing them to multiply and produce antibodies that give rise to a humoral (antibody) response. A delicate balance exists between the TH1 and TH2 cells and is directed by cytokines. Cytotoxic T cells are involved in the killing of pathogens that live inside host cells (cytosolic pathogens) such as viruses and some bacteria. These pathogens hide within cells, and cannot be reached with antibodies. Cytotoxic T cells cause infected cells to undergo programmed cell death or apoptosis and also secrete cytokines that assist in the immune response.
HUMORAL (ANTIBODY-MEDIATED) IMMUNITY. The humoral immune response uses antibodies produced by B cells to destroy pathogens. Pathogens travel in the extracellular fluid (outside of the cell) during the spread of infection. Antibodies specific for foreign pathogen antigens combine with them and neutralize the pathogen, preventing the spread of infection. Toxins secreted by bacteria, such as those from diphtheria and tetanus, are harmful to the body may also be neutralized by antibodies. Bacterial surfaces may be coated with antibody such that phagocytic cells can recognize them and ingest them (opsinization). When antibodies bind with pathogen antigens, the complement system of plasma proteins is activated. This results in opsinization and draws phagocytes to the site of infection.
The B cells are activated upon exposure to antigen, such as that which occurs in the lymphoid tissue. B cell surfaces contain immunoglobulin proteins (antibody) that bind with antigens from pathogens. With the aid of antigen-specific helper T cells, the B cells begin to multiply and produce cells that make antibody (plasma cells). This antibody is directed against the same specific antigen that was recognized by the helper T cell. Memory B cells are also produced and are involved in the protection of the body upon a second exposure to the pathogen at another time. Some pathogens can also cause the B cells to become activated without the help of T cells.
Role in human health
Pathogens have evolved over time such that they can avoid detection by the immune system. Bacteria may change their antigens to escape recognition by immune cells. Such mechanisms occur in the case of bacteria that cause pneumonia, food poisoning, and gonorrhea. Theinfluenzavirus may undergo a similar process, hence the reason that new flu vaccines are continually under development. The protozoans that cause malaria and sleeping sickness also use such methods to escape detection. Epstein-Barr and herpes simplexviruses enter a period of latency within the cells in which the virus does not multiply. The disease is "hidden" from immune surveillance, yet persists in the system to become active at a later time.
In opportunistic infections, a microorganism that is normally present as part of the microflora is no longer controlled by the host and seizes an opportunity to establish infection. This occurs in HIV infection due to suppressed immunity in the body. Opportunistic infections may arise following medical or surgical treatments. Such is the case with urinary tract infections when Esherichia coli that are normally found on the gut enter the urinary tract during catheterization or yeast infections following the administration of antibiotics.
Immune responses are particularly important during the process of organ transplantation where the recipient may perceive donor antigens as "non-self." Careful matching of donor and recipient tissues and the use of immunosuppressive agents that diminish the immune response minimize rejection. Graft-vs-host disease occurs during bone marrow transplants when the T cells of the donor recognize antigens in the recipient as "foreign."
Directions in immunotherapy
Humans have tried to understand the immune response and prevent the spread of disease throughout history. In ancient China and Asia Minor, attempts were made to inoculate against the smallpox virus by a process called variolization. In 1774 a farmer, Benjamin Jesty, used the cowpox virus to protect his children from smallpox. Edward Jenner began studies using cowpox virus in 1796 and demonstrated that immunization with cowpox protected a child from developing a smallpox infection. He published his results, calling this process vaccination. Efforts to refine this process ultimately lead to the declaration by the World Health Organization 1979 that the disease had been eradicated. Research directions for 2000 and beyond include vaccine development for HIV, tumors, schitosomiasis (a parasitic disease), and malaria.
Advances in cytokine therapy are another promising area of research and development. This approach involves boosting the body's own immune modulators to initiate an increased response. The use of cytokines has been explored in bone marrow transplantation, sepsis trials, and treatment of leprosy.
KEY TERMS
Adaptive immunity—The immune response is specific for a particular antigen, causes lymphocytes that recognize the antigen to multiply (clonal expansion), and imparts the quality of immunological memory of prior encounters with the antigen.
Apoptosis—The programmed cell death that is present in all cells and is responsible for their self-destruction.
Innate immunity—Parts of the immune system that are normally present, non-specific, and do not given an elevated response upon a second exposure.
Phagocytosis—The process whereby a cell engulfs particles or materials.
BOOKS
Anderson, William L. Immunology. Madison, CT: Fence Creek Publishing, 1999.
Janeway, Charles A., et al. Immunobiology: The Immune System in Health and Disease. London and New York: Elsevier Science London/Garland Publishing, 1999.
Levine, M., et al.,eds., New Generation Vaccines. New York: Marcel Dekker, 1997.
Roitt, Ivan, and Arthur Rabson. Really Essential Medical Immunology. Malden: Blackwell Science, 2000.
Sharon, Jacqueline. Basic Immunology. Baltimore, MD: Williams and Wilkins, 1998.
Widmann, Frances K., and Carol A. Itatani An Introduction to Clinical Immunology and Serology. Philadelphia, PA: F.A. Davis Company, 1998.
Wier, Donald M., and John Stewart. Immunology. New York: Churchchill Livingstone, Inc., 1997.
