The term immunity indicates the condition of an individual who recovers from a disease and is no longer susceptible to that disease. A broader definition of immunity includes all of the physiological mechanisms that give an organism the ability to recognize foreign substances and neutralize or degrade them, with or without injury to the organism's own tissue. \Timmunology\t is the branch of medicine concerned with the body's response to foreign substances. HISTORY From the 15th century the Chinese practiced the custom of inhaling dried powders of smallpox crusts to gain protection from smallpox. The prevention of disease by inoculation of human smallpox material is hazardous, however. The first step in establishing a safer procedure was taken by Edward \TJenner\t, who observed that people who caught cowpox, as most milkmaids did, rarely contracted smallpox. In 1796, Jenner induced a mild dose of cowpox in a young boy. A few weeks later he extracted pus from another person's smallpox sores and tried to infect the boy with smallpox but found that the immunity provoked by the cowpox viruses apparently was also effective against smallpox organisms. This is now known to occur because these two viruses are structurally and chemically very closely related. Further development of protection from disease by immunization was accomplished by Louis \TPasteur\t, who discovered in 1879 that neglected cultures of the bacteria that cause chicken cholera lost much of their ability to cause the disease in chickens. Furthermore, fresh cultures failed to infect chickens previously inoculated with old cultures. The pathogenic organisms had become weakened or attenuated. The introduction of dead or weakened bacteria, called a vaccine, into the body to develop resistance to disease is called \Tvaccination\t (from the Latin vacca, "cow"). Today vaccination is used against such diseases as cholera, diphtheria, measles, mumps, whooping cough, rabies, tetanus, typhoid, yellow fever, and poliomyelitis. The work of Jenner and Pasteur marked the beginning of the field of immunology. Until 1900, the principal investigators in this field were French or German. Two different views emerged from their studies as to how the immune response functions. Paul \TEhrlich\t (1854-1915) proposed the humoral theory of immunity, which emphasized the role of chemical substances (\Lantibod\lies) produced by cells and released into the bloodstream as the major agents of immunity. Elie \TMetchnikoff\t developed the cellular theory of immunity, according to which phagocytes, the body's scavenger cells, are the major detectors of foreign material, as well as the primary defense system against infectious organisms. Today it is known that both theories are correct. FUNCTIONS OF THE IMMUNE SYSTEM In the early history of immunology, the term immunity referred primarily to the resistance of an individual to reinfection with bacteria, viruses, fungi, or parasites. Immune responses, however, are not always beneficial; the entrance of foreign substances into the body sometimes has severe effects, and may even lead to death. Under normal circumstances the immune system responds to foreign organisms by the production of antibodies and the stimulation of specialized cells, which destroy the organisms or neutralize their toxic products. When the immune system involved in this function becomes too active, however, the result may be undesirable features, such as hypersensitivity or allergic reactions. On the other hand, when the immune response is not working properly (immunodeficient), as in acquired immune deficiency syndrome (see \TAIDS\t), the individual may become more susceptible to repeated infections (see \Timmunodeficiency\t \Tdiseases\t). Another major function of the immune system is the removal of damaged or dying cells. This function may be misdirected, however, resulting in an immune response against the body's own cells or tissues, producing a condition known as an autoimmune disease (see \Tautoimmune diseases\t). The function of the immune system most recently discovered is the system's ability to recognize and eliminate the abnormal (mutant) cells that frequently arise within the body. These mutant, or cancer, cells may occur spontaneously, or they may be induced by certain viruses (oncogenic viruses) or chemicals (mutagens). An immune system that is functioning properly can usually recognize and dispose of such cancer cells by means of a process called immune surveillance. The malfunction of this process may result in the incidence of certain types of cancer. CELLS AND TISSUES IN THE IMMUNE RESPONSE The ability to recognize foreignness, specificity, and memory are the key characteristics of immune defense mechanisms. The immune system of the human body must be able to recognize bacteria, viruses, fungi, parasites, and foreign materials in order to locate and destroy them. Specificity means that immunity to one foreign substance or organism does not necessarily provide resistance to another foreign substance, even if the two are highly similar. Memory is the ability of an organism to develop an accelerated, enhanced, and long-lasting immunity after the initial attack by an infectious disease. These characteristics are invested in a single type of cell--the lymphocyte--which is one of several types of white blood cells (see LYMPH \Tsystem\t). Lymphocytes are carried by the circulatory and the lymphatic systems to the site of infection. Scattered along the lymphatic vessels are small swellings known as lymph nodes, which contain large numbers of lymphocytes. These nodes become hard when packed with lymphocytes that have been stimulated by the infectious organisms to divide and produce specific antibodies against specific organisms. A major milestone in modern immunology came when two distinct types of lymphocyte were discovered: the T lymphocytes, or T cells, and the B lymphocytes, or B cells. Immunity provided by antibody molecules in the circulatory system (this type of immunity is called humoral immunity) is provided by the B cells, which are produced in the bone and distributed to the various lymphoid tissues of the body, such as the lymph nodes, spleen, tonsils, and Peyer's patches, which line the small intestine. T cells are involved in the rejection of transplanted tissues, in attacking certain bacteria, viruses, and fungi, in some skin reactions resulting from contact with simple chemicals (contact dermatitis), and in immunity to cancer cells. Because the immunity associated with T cells does not involve the secretion of antibodies but requires direct physical contact with antigens, it is called cell-mediated immunity. T cells originate in the thymus and also become localized in lymphoid organs. The discovery was made in recent years that four kinds of T cells exist. Only one kind, the cytotoxic T cell, defends the body by destroying infected, foreign, or cancerous cells. The other three kinds regulate immune responses by secreting messenger proteins (lymphokines) or by direct contact with other cells. Helper T cells enable the other T cells and most B cells to perform their functions. It is this cell that is destroyed by the HIV, or HTLV-III, virus (see \Tretrovirus\t) in \TAIDS\t patients, resulting in a depressed immune response that allows infection by a variety of microorganisms and the growth of certain tumors. Suppressor T cells dampen the immune response of B and T cells. The fourth kind of T cell is involved in certain kinds of hypersensitivity reactions. In a normally healthy individual there is a balanced ratio of each of these four kinds of T cells to provide an efficient immune system for defense against all foreign substances. ANTIGENS An antigen is a substance that, when introduced into an organism, induces an immune response consisting of the production of a circulating antibody. This type of immunity is known as humoral immunity. Protein molecules are potent antigens. Within a few days after injection, an antigen elicits large amounts of the antibody capable of interacting with it. The interaction of an antigen with its specific antibody does not involve the entire antigen but only small areas on its surface; these areas are known as antigenic determinants. Protein molecules have several antigenic determinants, each of which can be recognized by an antibody. Because they have antigenic determinants, many carbohydrates are also antigenic; for example, carbohydrates located on the surface of red blood cells make up the blood group antigens. ANTIBODIES The molecules responsible for recognizing antigenic determinants on foreign molecules or on cell surfaces are called antibodies. Antibodies are members of a related group of gamma globulin molecules known as immunoglobulins (Ig). Each immunoglobulin molecule is made up of four distinct protein chains joined together in two pairs. One pair is small and is called a light (L) chain; the other pair is much larger and is known as a heavy (H) chain. These protein chains are unique, in that one segment at the end of each chain has essentially the same amino-acid sequence that is found in an entire range of antibodies having different specificities. This segment is called the constant (C) region. The arrangement of amino acids at the other end is different for every antibody molecule of a given specificity; therefore, this region is called the variable (V) region. The ability of antibody molecules to interact with many different antigens is associated with the variable regions that constitute the combining site. Five classes of immunoglobulins exist, based on structural differences in the constant regions of the heavy chains of human immunoglobulins. These differences in the heavy chains are identified by the Greek letters gamma, mu, alpha, delta, and epsilon, and the immunoglobulins that contain them are called IgG, IgM, IgA, IgD, and IgE, respectively. Each class has different biological and structural properties and is distributed throughout the body. IgG, the most abundant immunoglobulin, occurs primarily in serum, as well as throughout the internal body fluids. Produced in response to bacteria, viruses, and fungi that have gained access to the body, IgG is a major line of defense against such organisms. In humans it is the only immunoglobulin that can cross the placenta and this is important in the defense of newborns against bacterial and viral infections. IgM, the largest immunoglobulin, is a powerful activator of complement, protein molecules that, when activated in proper sequence, produce holes in the surface of a foreign cell, resulting in lysis, or death, of the cell. IgM, therefore, is highly efficient in destroying bacteria that have gained access to the blood. IgA acts as a barrier against pathogenic organisms that enter via the respiratory tract and the gut. Antibody-forming B cells located in these areas produce single molecules of IgA, which are then bound together in pairs as they are secreted into the mucus lining the respiratory and digestive tracts, thus preventing bacteria and viruses from getting past them and invading the rest of the body. IgE triggers allergic and asthmatic reactions. It binds to the surface of mast cells that line the respiratory and digestive tracts. These cells contain histamine and related molecules, which are released when particles such as pollen and cat or dog dander bind to the surface-bound IgE molecules. The molecules released by the mast cells cause asthma and allergic reactions. IgD, an immunoglobulin recently discovered in serum, is the least well understood. It may serve to bind antigen on B lymphocytes and thereby stimulate them to secrete antibodies specific for the antigens. ANTIBODIES IN DEFENSE The simplest and most prevalent means by which the immune system defends the body against bacteria and viruses is by the combination of a specific antibody with the antigenic determinants located on the surface of invading organisms. An aggregate of cells, called an agglutination, is formed by antibodies bound by one of their two combining sites to one cell, and to another cell by their other site. These aggregates are then engulfed and digested by the body's wandering scavenger cells, the macrophages. Antibodies also bind to toxic molecules, called toxins, given off by microorganisms, forming large, insoluble aggregates (precipitates) that are also removed by macrophages. Antibodies also cover up the attachment sites of viruses and thereby prevent their ability to infect cells. Precipitin and agglutination reactions are used as diagnostic tools for identifying and quantifying the antibodies of infectious organisms in blood samples and other body fluids. CELL-MEDIATED IMMUNITY Several immune response are mediated primarily or exclusively by cells through direct contact with their targets or by the effects of secreted molecules, lymphokines, from these cells. A variety of cells are capable of carrying out cell-mediated reactions. Because of their ability to engulf and digest particulate matter by the process of phagocytosis, macrophages and neutrophils are able to eliminate many foreign organisms and particulate materials that enter the body. Natural killer (NK) cells are cytotoxic to some tumor cells, particularly during early stages of tumor growth. Because the ability to kill tumor cells is enhanced by two lymphokines secreted by T cells, namely gamma \Tinterferon\t and \Tinterleukin\t-1 (IL-1), clinical trials are being conducted on these two molecules as potential anticancer substances. Another cell involved in CMI is the lymphokine-activated killer (\Tlak\t) cell, which is receiving widespread attention because of its ability to kill a variety of human tumors. \Tlak\t cells are stimulated to kill tumor cells by another lymphokine, interleukin-2 (IL-2), produced by T lymphocytes. Cytotoxid T lymphocytes are cells that destroy other cells by interacting specifically with antigens on the surface of cells, such as those on grafted tissues, viral antigens on infected cells, and chemicals that have entered the body and attached to cells. Another important lymphokine secreted by activated T cells is transfer factor, which is able to cause normal lymphocytes to release lymphokines or otherwise become activated and thus to destroy other cells. By using knowledge of the transfer ability thus gained, scientists have been able to treat individuals whose bodies cannot develop antibodies for certain bacteria, viruses, or fungi (Candida) because of a hereditary defect in the cell-mediated immunity of the cells. Transfer factor is prepared from the lymphocytes of a person with good immunity to a particular disease agent and is then injected into the body of someone who is deficient in the agent. Transfer factor stimulates the lymphocytes to develop normal immunity; the body is then able to defend itself against an organism to which it was once susceptible. Cell-mediated immunity is also involved in contact dermatitis, a reaction against small molecules such as urushiol, which is found in the sticky sap of poison ivy, poison sumac, and poison oak. Contact between urushiol and the skin causes a rash to develop within a few days. TRANSPLANTATION IMMUNITY When strips of skin are taken from a patient (called a donor) and grafted onto the skin of a recipient, the graft initially appears to "take"; within a few days, however, the graft becomes red, then blackens, and finally drops off or is rejected. In contrast, when skin is grafted to another part of the same patient's body, or from one identical twin to another, the graft is accepted; that is, it heals perfectly. The rejection of a graft is an immune reaction. Whether a transplant "takes" depends on preventing the organ from being rejected because of the recipient's immune response to the graft. Transplants are usually maintained by using a procedure called immunosuppression, in which the patient is given drugs designed to prevent the immune response that normally leads to rejection of the graft. The drug that provides the best results thus far is \Tcyclosporine\t. Other drugs include azathioprine (Imuran) and prednisone (a corticosteroid), which act to prevent cells from growing and dividing (processes that are essential to cells involved in the immune response). In recent years the success rate for organ transplants has been improved substantially by matching the tissue or histocompatibility antigens (known as the HLA system) of the donor with those of the recipient. Because of the thousands of combinations of HLA antigens on a person's cells, however, this procedure is expected to become more effective only when a large pool of potential donors is available and after the development of banks for the long-term storage of tissue. CANCER AND IMMUNITY Because organ transplants are closely related to \TCancer\t, researchers are attempting to encourage the body's immune defense system to accept the cells of transplants and to reject those of cancer. By the use of immunosuppressive procedures, surgeons have, in many cases, been able to prevent the rejection of transplanted organs while learning important clues to the relationship between cancer and immunity. If a connection exists between the failure of the immune system and the incidence of cancer, or its growth and spread, then any substance that stimulates the immune system is likely to help destroy or at least retard the spread of the cancer. One such substance is BCG (for bacillus Calmette-Guerin), a live bacterium related to the bacillus that causes tuberculosis. Using a procedure called immunotherapy, BCG has served to increase the immune response of patients suffering from various cancers. The advantage of such treatment is that it destroys every cancer cell, something no other method devised so far can do, and does not destroy normal body cells. When the tumor mass is fairly large at the time of diagnosis, however, the cancerous mass must often by removed by surgery, chemotherapy, or radiotherapy before immunotherapy can be used effectively. Other chemicals being tested as potential immunotherapeutic agents are gamma interferon, interleukin-1 and -2, tumor necrosis factor (TNF), and colony stimulatory factors (CSF). Clinical trials are under way to test each of these lymphokines as potential anticancer agents. MONOCLONAL ANTIBODIES A monoclonal \Tantibody\t is an antibody prepared in such a way that it reacts to a single antigen. The ability to produce monoclonal antibodies in great quantity is made possible by a technique that fuses a cancer cell with a lymphocyte to form a hybridoma. This hybridoma cell has the cancer cells's trait of dividing endlessly and lymphocyte's ability to produce an antibody to a specific antigen. If an antigen peculiar to a cancer cell is discovered, it can be used to produce a monoclonal antibody to it. If an anticancer drug or toxin, such as ricin, is attached to such an antibody, an immunotoxin is produced. Immunotoxins, when injected into a patient, will seek out the cancer cells and destroy them without damaging any normal cells or tissues. Peter Abramoff Bibliography: Golub, Edward S., Immunology: A Synthesis (1987); Kimball, J. W., Introduction to Immunology (1986); Roitt, Ivan, et al., Immunology (1985); Sell, Stewart, Basic Immunology (1987); Stites, Daniel, P., et al., Basic and Clinical Immunology (1984).