Kathleen Scogna. The Gale Encyclopedia of Science. Editor: K Lee Lerner & Brenda Wilmoth Lerner, 4th Edition, Volume 3, Gale, 2008.
The immune system protects the body from disease-causing microorganisms. It consists of two levels of protection, the non-specific defenses and the specific defenses. The non-specific defenses, such as the skin and mucous membranes, prevent microorganisms from entering the body. The specific defenses are activated when microorganisms evade the non-specific defenses and invade the body. Only starting in the nineteenth century and continuing into the twentieth century have the components of the immune system and the ways in which it works been discovered. More remains to be clarified in the twenty-first century.
The human body is constantly bombarded with microorganisms, many of which can cause disease. Some of these microorganisms are viruses, such as those that cause colds and influenza; other microorganisms are bacteria, such as those that cause pneumonia and food poisoning. Still other microorganisms are parasites or fungi. Usually, the immune system is so efficient that most people are unaware of the battle that takes place almost everyday, as the immune system rids the body of harmful invaders. However, when the immune system is injured or destroyed, the consequences are severe. For instance, acquired immune deficiency syndrome (AIDS) is caused by a virus— human immunodeficiency virus (HIV)—that attacks a key immune system cell, the helper T-cell lymphocyte. Without these cells, the immune system cannot function. People with AIDS cannot fight off the microorganisms that constantly bombard their bodies, and eventually succumb to infections that a healthy immune system would effortlessly neutralize.
History
Since ancient times, medical observers had noticed that the body seemed to have powers to protect itself and resist disease. In particular, people who survived some infectious diseases did not suffer from those diseases again during their lifetime. This led to the practice of variolation in Asia, whereby people were injected with a mild case of smallpox to prevent the later development of a severe case of the disease. Lady Mary Wortley-Montague (1689-1762) introduced variolation to Britain from the Ottoman Empire in 1720. The procedure was rather dangerous, however, because the injected person could develop an acute rather than mild case of smallpox, which could lead to an epidemic.
The true roots of immunology-or the study of the immune system-date from 1796 when English physician Edward Jenner (1749-1823) discovered a method of smallpox vaccination. He noted that dairy workers who contracted cowpox from milking infected cows were thereafter resistant to smallpox. In 1796, Jenner injected a young boy with material from a milkmaid who had an active case of cowpox. After the boy recovered from his own resulting cowpox, Jenner inoculated him with smallpox; the boy was immune. After Jenner published the results of this and other cases in 1798, the practice of Jennerian vaccination spread rapidly.
It was French microbiologist Louis Pasteur (1822-1895) who established the cause of infectious diseases and the medical basis for immunization. First, Pasteur formulated his germ theory of disease-the concept that disease is caused by communicable microorganisms. In 1880, Pasteur discovered that aged cultures of fowl cholera bacteria lost their power to induce disease in chickens but still conferred immunity to the disease when injected. He went on to use attenuated (weakened) cultures of anthrax and rabies to vaccinate against those diseases. American scientists Theobald Smith (1859-1934) and Daniel Salmon (1850-1914) showed in 1886 that bacteria killed by heat could also confer immunity.
Why vaccination imparted immunity was not yet known. In 1888, Pierre-Paul-Emile Roux (1853-1933) and Alexandre Yersin (1863-1943) showed that diphtheria bacillus produced a toxin that the body responded to by producing an antitoxin. German bacteriologist Emil von Behring (1854-1917) and Japanese physician Shibasaburo Kitasato (1852-1931) found a similar toxin-antitoxin reaction in tetanus in 1890. They discovered that small doses of tetanus or diphtheria toxin produced immunity, and that this immunity could be transferred from animal to animal via serum. Von Behring concluded that the immunity was conferred by substances in the blood, which he called antitoxins, or antibodies. In 1894, Richard Pfeiffer (1858-1945) found that antibodies killed cholera bacteria (bacterioloysis). German bacteriologist Hans Buchner (1850-1902) in 1893 discovered another important blood substance called complement (Buchner’s term was alexin), and Belgian bacteriologist Jules Bordet (1870-1961) in 1898 found that it enabled the antibodies to combine with antigens (foreign substances) and destroy or eliminate them. It became clear that each antibody acted only against a specific antigen. Austrian American immunologist and pathologist Karl Landsteiner (1868-1943) was able to use this specific antigen-antibody reaction to distinguish the different blood groups.
A new element was introduced into the growing body of immune system knowledge during the 1880s by the Russian microbiologist Elie Metchnikoff (1845-1916). He discovered cell-based immunity: white blood cells (leucocytes), which Metchnikoff called phagocytes, ingested and destroyed foreign particles. Considerable controversy flourished between the proponents of cell-based and blood-based immunity until 1903, when British bacteriologist and immunologist Sir Almroth Edward Wright (1861-1947) brought them together by showing that certain blood substances were necessary for phagocytes to function as bacteria destroyers. A unifying theory of immunity was posited by German scientist Paul Ehrlich (1854-1915) in the 1890s; his side-chain theory explained that antigens and antibodies combine chemically in fixed ways, like a key fits into a lock. Until now, immune responses were seen as purely beneficial. In 1902, however, French physiologist Charles Richet (1850-1935) and French physiologist Paul Portier (1866-1962), demonstrated extreme immune reactions in test animals that had become sensitive to antigens by previous exposure. This phenomenon of hypersensitivity, called anaphylaxis, showed that immune responses could cause the body to damage itself. Hypersensitivity to antigens also explained allergies, a term coined by Austrian physician Clemens von Pirquet in 1906.
By the early 1900s immunology had become an established medical field with its own journals, first in Germany in 1909 and then in the United States in 1916 (the latter published by the world’s first immunology society, founded in 1913).
Much more was learned about antibodies in the mid-twentieth century, including the fact that they are proteins of the gamma globulin portion of plasma and are produced by plasma cells; their molecular structure was also worked out. An important advance in immunochemistry came in 1935 when Michael Heidelberger (1881-1991) and Edward Kendall (1886-1972) developed a method to detect and measure amounts of different antigens and antibodies in serum. Immunobiology also advanced. Australian biologist Sir Frank Macfarlane Burnet (1899-1985) suggested that animals did not produce antibodies to substances they had encountered very early in life; Brazilian-born British zoologist Peter Medawar (1915-1987) proved this idea in 1953 through experiments on mouse embryos.
In 1957, Burnet put forth his clonal selection theory to explain the biology of immune responses. On meeting an antigen, an immunologically responsive cell (shown by C.S. Gowans [1923-] in the 1960s to be a lymphocyte) responds by multiplying and producing an identical set of plasma cells, which in turn manufacture the specific antibody for that antigen. Further cellular research has shown that there are two types of lymphocytes (nondescript lymph cells): B-lymphocytes, which secrete antibody, and T-lymphocytes, which regulate the B-lymphocytes and either kill foreign substances directly (killer T cells) or stimulate macrophages to do so (helper T cells). Lymphocytes recognize antigens by characteristics on the surface of the antigen-carrying molecules. Researchers in the 1980s uncovered many more intricate biological and chemical details of the immune system components and the ways in which they interact.
Knowledge about the immune system’s role in rejection of transplanted tissue became extremely important as organ transplantation became surgically feasible. Peter Medawar’s work in the 1940s showed that such rejection was an immune reaction to antigens on the foreign tissue. Canadian neurologist Donald Calne (1936-) showed in 1960 that immunosuppressive drugs—drugs that suppress immune responses—reduced transplant rejection, and these drugs were first used on human patients in 1962. In the 1940s, American geneticist George D. Snell (1903-1996) discovered in mice a group of tissue-compatibility genes that played an important role in controlling acceptance or resistance to tissue grafts. French immunologist Jean Dausset (1916-) found human MHC (major histocompatability complex), a set of antigens to human leucocytes (white blood cells), called HLA (human leucocyte antigen). Matching of HLA in donor and recipient tissue is an important technique to predict compatibility in transplants. Venezuelan-born American immunologist Baruj Benacerraf (1920-) in 1969 showed that an animal’s ability to respond to an antigen was controlled by genes in the MHC complex.
In the late 1960s, Ion Gresser (1928-) discovered that the protein interferon acts against cancerous tumors. After the development of genetically engineered interferon in the mid-1980s finally made the substance available in practical amounts, research into its use against cancer accelerated. The invention of monoclonal antibodies in the mid-1970s was a major breakthrough. Increasingly sophisticated knowledge about the workings of the immune system holds out the hope of finding an effective method to combat one of the most serious immune system disorders, AIDS (acquired immune deficiency syndrome).
Organs of the Immune System
The organs of the immune system either make the cells that participate in the immune response or act as sites for immune function. These organs include the lymphatic vessels, lymph nodes, tonsils, thymus, Peyer’s patch, and spleen. The lymph nodes are small aggregations of tissues interspersed throughout the lymphatic system. White blood cells (lymphocytes) that function in the immune response are concentrated in the lymph nodes. Lymphatic fluid circulates through the lymph nodes via the lymphatic vessels. As the lymph filters through the lymph nodes, foreign cells of microorganisms are detected and overpowered.
The tonsils contain large numbers of lymphocytes. Located at the back of the throat and under the tongue, the tonsils filter out potentially harmful bacteria that may enter the body via the nose and mouth. Peyer’s patches are lymphatic tissues that perform this same function in the digestive system. Peyer’s patches are scattered throughout the small intestine and the appendix. They are also filled with lymphocytes that are activated when they encounter disease-causing microorganisms.
The thymus gland is another site of lymphocyte production. Located within the upper chest region, the thymus gland is most active during childhood when it makes large numbers of lymphocytes. The lymphocytes made here do not stay in the thymus, however; they migrate to other parts of the body and concentrate in the lymph nodes. The thymus gland continues to grow until puberty; during adulthood, however, the thymus shrinks in size until it is sometimes impossible to detect in x rays.
Bone marrow, found within the bones, also produces lymphocytes. These lymphocytes migrate out of the bone marrow to other sites in the body. Because bone marrow is an integral part of the immune system, certain bone cancer treatments that require the destruction of bone marrow are extremely risky, because without bone marrow, a person cannot make lymphocytes. People undergoing bone marrow replacement must be kept in strict isolation to prevent exposure to viruses or bacteria.
The spleen acts as a reservoir for blood and any rupture to the spleen can cause dangerous internal bleeding, a potentially fatal condition. The spleen also destroys worn-out red blood cells. Moreover, the spleen is also a site for immune function, since it contains lymphatic tissue and produces lymphocytes.
Overview of the Immune System
For the immune system to work properly, two things must happen: First, the body must recognize that it has been invaded by foreign microorganisms. Second, the immune response must be quickly activated before many body tissue cells are destroyed by the invaders.
How the immune system recognizes foreign invaders
The cell membrane of every cell is studded with various proteins that protrude from the surface of the membrane. These proteins are a kind of name tag called the major histocompatibility complex (MHC). They identify all the cells of the body as belonging to the self. An invading microorganism, such as a bacterium, does not have the self MHC on its surface. When an immune system cell encounters this non-self cell, it alerts the body that it has been invaded by a foreign cell. Every person has their own unique MHC. For this reason, organ transplants are often unsuccessful because the immune system interprets the transplanted organ as foreign, since the transplanted organ cells have a non-self MHC. Organ recipients usually take immuno-suppressant drugs to suppress the immune response, and every effort is made to transplant organs from close relatives, who have genetically similar MHCs.
In addition to a lack of the self MHC, cells that prompt an immune response have foreign molecules (called antigens) on their membrane surfaces. An antigen is usually a protein or polysaccharide complex on the outer layer of an invading microorganism. The antigen can be a viral coat, the cell wall of a bacterium, or the surface of other types of cells. Antigens are extremely important in the identification of foreign microorganisms. The specific immune response depends on the ability of the immune lymphocytes to identify the invader and create immune cells that specifically mark the invader for destruction.
How the two defenses work together
The immune system keeps out microorganisms with nonspecific defenses. Nonspecific defenses do not involve identification of the antigen of a microorganism; rather the nonspecific defenses simply react to the presence of a non-self cell. Oftentimes, these nonspecific defenses effectively destroy microorganisms. However, if they are not effective and the microorganisms manage to infect tissues, the specific defenses are activated. The specific defenses work by recognizing the specific antigen of a microorganism and mounting a response that targets the microorganism for destruction by components of the non-specific system. The major difference between the non-specific defenses and the specific defenses is that the former impart a general type of protection against all kinds of foreign invaders, while the specific defenses create protection that is tailored to match the particular antigen that has invaded the body.
The Nonspecific Defenses
The nonspecific defenses consist of the outer barriers, the lymphocytes, and the various responses that are designed to protect the body against invasion by any foreign microorganism.
Barriers: skin and mucous membranes
The skin and mucous membranes act as effective barriers against harmful invaders. The surface of the skin is slightly acidic, which makes it difficult for many microorganisms to survive. In addition, the enzyme lysozyme, which is present in sweat, tears, and saliva, kills many bacteria. Mucous membranes line many of the body’s entrances, such as those that open into the respiratory, digestive, and uro-genital tract. Bacteria become trapped in the thick mucous layers and are thus prevented from entering the body. In the upper respiratory tract, the hairs that line the nose also trap bacteria. Any bacteria that are inhaled deeper into the respiratory tract are swept back out again by the cilia-tiny hairs-that line the trachea and bronchii. One reason why smokers are more susceptible to respiratory infections is that hot cigarette smoke disables the cilia, slowing the movement of mucus and bacteria out of the respiratory tract. Within days of quitting smoking, the cilia regenerate and new non-smokers then cough and bring up large amounts of mucus, which eventually subsides.
Nonspecific immune cells
Nonspecific lymphocytes carry out search-and-destroy missions within the body. If these cells encounter a foreign microorganism, they will either engulf the foreign invader or destroy the invader with enzymes. The following is a list of non-specific lymphocytes:
Macrophages are large lymphocytes that engulf foreign cells. Because macrophages ingest other cells, they are also called phagocytes (phagein, to eat; kytos, cell).
Neutrophils are cells that migrate to areas where bacteria have invaded, such as entrances created by cuts in the skin. Neutrophils phagocytize microorganisms and release microorganism-killing enzymes. Neutrophils die quickly; pus is an accumulation of dead neutrophils.
Natural killer cells kill body cells infected with viruses, by punching a hole in the cell membrane, causing the cell to lyse, or break apart.
The inflammatory response
The inflammatory response is an immune response confined to a small area. When a finger is cut, the area becomes red, swollen, and warm. These signs are evidence of the inflammatory response. Injured tissues send out signals to immune system cells, which quickly migrate to the injured area. These immune cells perform different functions: some engulf bacteria, while others release bacteria-killing chemicals. Other immune cells release a substance called histamine, which causes blood vessels to become wider (dilate), thus increasing blood flow to the area. All of these activities promote healing in the injured tissue.
An inappropriate inflammatory response is the cause of allergic reactions. When a person is allergic to pollen, the body’s immune system is reacting to pollen (a harmless substance) as if it was a bacterium and an immune response is prompted. When pollen is inhaled it stimulates an inflammatory response in the nasal cavity and sinuses. Histamine is released that dilates blood vessels, and also causes large amounts of mucous to be produced, leading to a runny nose. In addition, histamine stimulates the release of tears and is responsible for the watery eyes and nasal congestion typical of allergies.
To combat these reactions, many people take drugs that deactivate histamine. These drugs, called antihistamines, are available over-the-counter and by prescription. Some allergic reactions, involve the production of large amounts of histamine that impairs breathing and necessitates prompt emergency care. People prone to these extreme allergic reactions must carry a special syringe with epinephrine (adrenalin), a drug that quickly counteracts this severe respiratory reaction.
Complement
The complement system is a group of more than 20 proteins that complement other immune responses. When activated, the complement proteins perform a variety of functions: they coat the outside of microorganisms, making them easier for immune cells to engulf; they stimulate the release of histamine in the inflammatory response; and they destroy virus-infected cells by puncturing the plasma membrane of the infected cell, causing the cell to burst open.
Specific Immune Defenses
The specific immune response is activated when microorganisms evade the nonspecific defenses. Two types of specific defenses destroy microorganisms in the human body: the cell-mediated response and the antibody response. The cell-mediated response attacks cells that have been infected by viruses. The antibody response attacks both free viruses that have not yet penetrated cells, and bacteria, most of which do not infect cells. However, some bacteria, such as the myco-bacteria that cause tuberculosis, do infect cells.
Specific immune cells
Two kinds of lymphocytes operate in the specific immune response: T lymphocytes and B lymphocytes, (T lymphocytes are made in the thymus gland, while B lymphocytes are made in bone marrow). The T and B lymphocytes migrate to other parts of the lymphatic system, such as the lymph nodes, Peyer’s patches, and tonsils. Non-specific lymphocytes attack any foreign cell, while B and T lymphocytes are individually configured to attack a specific antigen. In other words, the blood and lymph of humans have T-cell lymphocytes that specifically target the chickenpox virus, T-cell lymphocytes that target the diphtheria virus, and so on. When T-cell lymphocytes specific for the chickenpox virus encounter a body cell infected with this virus, the T cell multiplies rapidly and destroying the invading virus.
Memory cells
After the invader has been neutralized, some T cells remain behind. These cells, called memory cells, impart immunity to future attacks by the virus. Once a person has had chickenpox, memory cells quickly stave off subsequent infections. This secondary immune response, involving memory cells, is much faster than the primary immune response.
Some diseases, such as smallpox, are so dangerous that it is better to artificially induce immunity rather than to wait for a person to create memory cells after an infection. Vaccination injects whole or parts of killed viruses or bacteria into the bloodstream, prompting memory cells to be made without a person developing the disease.
Helper T-cells
Helper T-cells are a subset of T-cell lymphocytes that play a significant role in both the cell-mediated and antibody immune responses. Helper T cells are present in large numbers in the blood and lymphatic system, lymph nodes, and Peyer’s patches. When one of the body’s macrophage cells ingests a foreign invader, it displays the antigen on its membrane surface. These antigen-displaying-macrophages, or APCs, are the immune system’s distress signal. When a helper T cell encounters an APC, it immediately binds to the antigen on the macrophage. This binding unleashes several powerful chemicals called cytokines. Some cytokines, such as interleukin I, stimulate the growth and division of T cells. Other cytokines play a role in the fever response, another nonspecific immune defense. Still another cytokine, called interleukin II, stimulates the division of cytotoxic T cells, key components of the cell-mediated response. The binding also turns on the antibody response. In effect, the helper T cells stand at the center of both the cell-mediated and antibody responses.
Any disease that destroys helper T cells destroys the immune system. HIV infects and kills helper T cells, so disabling the immune system and leaving the body helpless to stave off infection.
B-cells and the antibody response
B-cell lymphocytes, or B cells, are the primary players in the antibody response. When an antigen-specific B cell is activated by the binding of an APC to a helper T cell, it begins to divide. These dividing B cells are called plasma cells. The plasma cells, in turn, secrete antibodies, proteins that attach to the antigen on bacteria or free viruses, marking them for destruction by macrophages or complement. After the infection has subsided, a few memory B cells persist that confer immunity.
A Closer Look at Antibodies
Antibodies are made when a B cell specific for the invading antigen is stimulated to divide by the binding of an APC to a helper T cell. The dividing B cells, called plasma cells, secrete proteins called antibodies. Antibodies are composed of a special type of protein called immunoglobin (Ig). An antibody molecule is Y-shaped and consists of two light chains joined to two heavy chains. These chains vary significantly between antibodies. The variable regions make antibodies antigen-specific. Constant regions, on the other hand, are relatively the same between antibodies. All antibody molecules, whether made in response to a chickenpox virus or to a Salmonella bacterium, have some regions that are similar.
How Antibodies Work to Destroy Invaders
An antibody does not itself destroy microorganisms. Instead, the antibody that has been made in response to a specific microorganism binds to the specific antigen on its surface. With the antibody molecule bound to its antigen, the microorganism is targeted by destructive immune cells like macrophages and NK cells. Antibody-tagged microorganisms can also be destroyed by the complement system.
T-Cells and the Cell-Mediated Response
T-cell lymphocytes are the primary players in the cell-mediated response. When an antigen-specific helper T cell is activated by the binding of an APC, the cell multiplies. The cells produced from this division are called cytotoxic T cells. Cytotoxic T cells target and kill cells that have been infected with a specific microorganism. After the infection has subsided, a few memory T cells persist, so conferring immunity.
How is the Immune Response ‘Turned Off?’
Chemical signals activate the immune response and other chemical signals must turn it off. When all the invading microorganisms have been neutralized, special T cells (called suppressor T cells) release cyto-kines that deactivate the cytotoxic T cells and the plasma cells.
Current Research
For many years it was believed that the immune system responded only to invading antigens and was not influenced by psychological events. However, building on research that began in the mid—1960s, scientists have determined that the immune system is also affected by a person’s psychological health, or state of mind. This branch of research is referred to as pscyho-immunology, or psychoneuroimmunology (the study of the relationship among psychology, neurology, and immunology). A complex network of nerves, hormones, and neuropeptides appear to link the immune system and an individual’s psyche. For example, extreme psychological stress has been shown to suppress the immune system and accelerate disease in people with HIV (human immunodeficiency virus). (Short-term stress is believed to have certain benefits to the body.) Other psychosocial factors—such as a fixation on dying, clinical depression, a lack of purpose in life, inability to be assertive, and lack of a supportive network of friends and family—may also affect the immune system. Research into pscyho-immunology focuses on treatments that can impact stress levels and other psychological factors.
Advances in immunological research indicate that the immune system may be made of more than 100 million highly specialized cells designed to combat specific antigens. While the task of identifying these cells and their functions may be daunting, headway is being made. By identifying these specific cells, researchers may be able to further advance another promising area of immunological research—the use of recombinant DNA technology, in which specific proteins can be mass produced. This approach has led to new cancer treatments that can stimulate the immune system by using synthetic versions of proteins released by interferons.