|The Merck Manual of Medical Information--Home Edition
|Section 16. Immune Disorders
Biology of the Immune System
Just as the human mind allows a person to develop a concept of intellectual self, the immune system provides a concept of biologic self. The function of the immune system is to defend the body against invaders. Microbes (germs or microorganisms), cancer cells, and transplanted tissues or organs are all interpreted by the immune system as nonself against which the body must be defended.
Although the immune system is intricate, its basic strategy is simple: to recognize the enemy, mobilize forces, and attack. Understanding the anatomy and components of the immune system makes it possible to see how this strategy works.
Understanding the Immune System
Antibody: A protein, made by B lymphocytes, that reacts with a specific antigen; also called an immunoglobulin.
Antigen: Any molecule capable of stimulating an immune response.
Cell: The smallest living unit of tissue, composed of a nucleus and cytoplasm surrounded by a membrane. The nucleus houses DNA, and the cytoplasm contains structures (organelles) that carry out the cell's functions.
Chemotaxis: A process of attracting and recruiting cells in which a cell moves toward a higher concentration of a chemical substance.
Complement: A group of proteins that helps to attack antigens.
Cytokines: Soluble proteins, secreted by cells of the immune system, that act as messengers to help regulate an immune response.
Endocytosis: The process by which a cell engulfs (ingests) certain antigens.
Histocompatibility: Literally means compatible tissue. Used to determine whether a transplanted tissue or organ (for example, bone marrow or a kidney transplant) will be accepted by the recipient. Histocompatibility is determined by the major histocompatibility complex molecules.
Human leukocyte antigens (HLA): A synonym for human major histocompatibility complex.
Immune response: The response to an antigen by components of the immune system, either cells or antibodies.
Immunoglobulin: A synonym for antibody.
Interleukin: A type of cytokine that influences a variety of cells.
Leukocyte: A white blood cell. Lymphocytes and neutrophils, among others, are leukocytes.
Lymphocyte: The main cell of the lymphatic system, further categorized as B lymphocytes (which produce antibodies) and T lymphocytes (which help the body distinguish self from nonself).
Macrophage: A large cell that engulfs (ingests) microbes after they have been targeted for destruction by the immune system.
Major histocompatibility complex (MHC): A group of molecules important in helping the body distinguish self from nonself.
Molecule: A group (aggregation) of atoms chemically combined to form a unique chemical substance.
Natural killer cell: A type of lymphocyte that can kill certain microbes and cancer cells.
Neutrophil: A large white blood cell (leukocyte) that ingests antigens and other substances.
Peptide: Two or more amino acids chemically bonded to form a single molecule.
Protein: A large number of amino acids chemically bonded in a chain. Proteins are large peptides.
Receptor: A molecule on the cell surface or in the cytoplasm that fits another molecule like a lock and key.
The immune system maintains its own system of circulation--the lymphatic vessels--which permeates every organ in the body except the brain. The lymphatic vessels contain a pale, thick fluid (lymph) consisting of a fat-laden liquid and white blood cells.
Along the lymphatic vessels are special areas--the lymph nodes, tonsils, bone marrow, spleen, liver, lungs, and intestines--where lymphocytes can be recruited, mobilized, and deployed to appropriate sites as part of the immune response. The ingenious design of this system ensures the ready availability and quick assembly of an immune response anywhere it is needed. This system can be seen at work when a wound or an infection in a fingertip leads to an enlarged lymph node at the elbow, or when a throat infection causes the lymph nodes under the jaw to swell. The lymph nodes swell because the lymphatic vessels drain the infection by carrying it to the nearest area where an immune response can be organized.
Components of the Immune System
The immune system is composed of cells and soluble substances. The major cells of the immune system are the white blood cells. Macrophages, neutrophils, and lymphocytes are all types of white blood cells. Soluble substances are molecules that are not contained in cells but are dissolved in a liquid, such as plasma. (see page 734 in Chapter 152, Biology of Blood) The major soluble substances are antibodies, complement proteins, and cytokines. Some soluble substances act as messengers to attract and activate other cells. The major histocompatibility complex molecule is at the heart of the immune system and helps in the identification of self and nonself.
Macrophages are large white blood cells that ingest microbes, antigens, and other substances. An antigen is any substance that can stimulate an immune response. Bacteria, viruses, proteins, carbohydrates, cancer cells, and toxins all can serve as antigens.
The cytoplasm of macrophages contains granules, or packets, consisting of several chemicals and enzymes that are wrapped in a membrane. These enzymes and chemicals allow the macrophage to digest the ingested microbe, usually destroying it.
Macrophages are not found in the blood; rather, they reside strategically where body organs interface with the bloodstream or the outside world. For example, macrophages are found where the lungs receive outside air and where liver cells connect with blood vessels. Similar cells in the blood are called monocytes.
Like macrophages, neutrophils are large white blood cells that ingest microbes and other antigens and have granules that contain enzymes to destroy ingested antigens. However, unlike macrophages, neutrophils circulate in the blood; they need a specific stimulus to exit from the blood and enter tissues.
Macrophages and neutrophils often work together: Macrophages initiate an immune response and send signals to mobilize neutrophils to join them at a trouble spot. When the neutrophils arrive, they destroy the invaders by digesting them. The accumulation of neutrophils and the killing and digesting of microbes lead to the formation of pus.
Lymphocytes, the main cells of the lymphatic system, are relatively small compared to macrophages and neutrophils. Unlike neutrophils, which live no more than 7 to 10 days, lymphocytes can live for years or even decades. Most lymphocytes fall into three major categories:
- B lymphocytes are derived from a parent (stem) cell in the bone marrow and mature into plasma cells, which secrete antibodies.
- T lymphocytes are formed when stem cells migrate from the bone marrow to the thymus gland, where they undergo division and maturation. T lymphocytes learn how to differentiate self from nonself in the thymus gland. Mature T lymphocytes leave the thymus gland and enter the lymphatic system, where they function as part of the immune surveillance system.
- Natural killer cells, slightly larger than T and B lymphocytes, are so named because they kill certain microbes and cancer cells. The "natural" part of their name indicates that they are ready to kill a variety of target cells as soon as they are formed rather than requiring the maturation and education process that B and T lymphocytes need. Natural killer cells also produce some cytokines, messenger substances that regulate some of the functions of T lymphocytes, B lymphocytes, and macrophages.
When stimulated by an antigen, B lymphocytes mature into cells that make antibodies. Antibodies are proteins that interact with the antigen that initially stimulated the B lymphocytes. Antibodies are also called immunoglobulins.
Each antibody molecule has a unique part that binds to a specific antigen and a part whose structure determines the antibody class. There are five classes of antibodies: IgM, IgG, IgA, IgE, and IgD.
- IgM is the antibody that is produced upon initial exposure to an antigen. For example, when a child receives his first tetanus vaccination, antitetanus antibodies of the IgM class are produced 10 to 14 days later (the primary antibody response). IgM is abundant in the blood but is not normally present in organs or tissues.
- IgG, the most prevalent type of antibody, is produced upon subsequent exposure to an antigen. For example, after receiving a second tetanus shot (booster), a child produces IgG antibodies in 5 to 7 days. This secondary antibody response is faster and more abundant than the primary antibody response. IgG is present in both the blood and the tissues. It is the only antibody that is transferred across the placenta from the mother to the fetus. The mother's IgG protects the fetus and newborn until the infant's immune system can produce its own antibodies.
- IgA is the antibody that plays an important role in the body's defenses against the invasion of microorganisms through mucous membrane-lined surfaces, including the nose, eyes, lungs, and intestines. IgA is found in the blood and in secretions such as those in the gastrointestinal tract and in the nose, eyes, lungs, and breast milk.
- IgE is the antibody that causes acute (immediate) allergic reactions. In this regard, IgE is the only class of antibody that seemingly does more harm than good. However, IgE may be important in fighting against parasitic infections, such as river blindness and schistosomiasis, that are common in the developing world.
- IgD is an antibody present in very small amounts in circulating blood. Its function is not well understood.
The complement system comprises more than 18 proteins. These proteins act in a cascade, with one protein activating the next protein. The complement system can be activated by two distinct pathways. One pathway, called the alternative pathway, is activated by certain microbial products or antigens. The other pathway, called the classical pathway, is activated by specific antibodies bound to their antigens (immune complexes). The complement system functions to destroy foreign substances, either directly or in conjunction with other components of the immune system.
Cytokines function as the messengers of the immune system. They are secreted by cells of the immune system in response to stimulation. Cytokines amplify (or help) some aspects of the immune system and inhibit (or suppress) others. Many cytokines have been identified, and the list continues to grow.
Some cytokines can be given by injection as treatment of certain diseases. For example, interferon alfa is effective in treating certain cancers, such as hairy cell leukemia. Another cytokine, interferon beta, may be helpful in treating multiple sclerosis. A third cytokine, interleukin-2, may be beneficial in treating malignant melanoma and kidney cancer, although its use has adverse effects. Yet another cytokine, granulocyte colony-stimulating factor, which stimulates the production of neutrophils, can be given to cancer patients who have low numbers of neutrophils because of chemotherapy.
Major Histocompatibility Complex
All cells have molecules on their surface that are unique to a specific person. These molecules are called major histocompatibility complex molecules. Through its major histocompatibility complex molecules, the body is able to distinguish self from nonself. Any cell expressing identical major histocompatibility complex molecules is ignored; any cell expressing nonidentical major histocompatibility complex molecules is rejected.
There are two types of major histocompatibility complex molecule (also called human leukocyte antigens or HLA): class I and class II. Class I major histocompatibility complex molecules are present on all cells in the body except red blood cells. Class II major histocompatibility complex molecules are present on the surfaces only of macrophages and B lymphocytes and on T lymphocytes that have been stimulated by an antigen. A person's class I and class II major histocompatibility complex molecules are unique. Although identical twins have identical major histocompatibility molecules, the chance is low (one in four) that nonidentical twins will have identical molecules and extraordinarily low for nonsiblings.
The cells of the immune system learn to differentiate self from nonself in the thymus gland. When the immune system starts developing in the fetus, stem cells migrate to the thymus, where they divide and develop into T lymphocytes. While developing in the thymus gland, any T lymphocyte that reacts to the thymus' major histocompatibility complex molecules is eliminated. Any T lymphocyte that tolerates the thymus' major histocompatibility complex and learns to cooperate with cells expressing the body's unique major histocompatibility complex molecules is allowed to mature and leave the thymus.
The result is that mature T lymphocytes tolerate the body's own cells and organs and can cooperate with the body's other cells when called on to defend the body. If T lymphocytes were not made tolerant of the body's own major histocompatibility complex molecules, they could attack the body. However, sometimes T lymphocytes lose the ability to differentiate self from nonself, resulting in the development of autoimmune diseases such as systemic lupus erythematosus (lupus) or multiple sclerosis. (see page 816 in this chapter)
Immunity and the Immune Response
The immune system has evolved an intricate network of checks and balances that can be categorized as innate and learned immunity.
Everyone is born with innate immunity. The components of the immune system involved in innate immunity--macrophages, neutrophils, and complement--react similarly to all foreign substances, and the recognition of antigens does not vary from person to person.
As its name indicates, learned immunity is acquired. At birth, a person's immune system has not yet encountered the outside world or started to develop its memory files. The immune system learns to respond to every new antigen encountered. Learned immunity is, therefore, specific to the antigens encountered during a person's lifetime. The hallmark of specific immunity is its ability to learn, to adapt, and to remember.
The immune system carries a record or memory of every antigen a person encounters, whether through the lungs (by breathing), the intestine (by eating), or the skin. This is possible because lymphocytes are long-lived. When lymphocytes encounter an antigen for the second time, they mount a quick, vigorous, specific response to that antigen. This specific immune response is why people do not contract chickenpox or measles more than once and what makes vaccination successful in preventing disease. For example, to prevent polio, a person is given a vaccine made from a weakened form of the poliovirus. If the person is later exposed to the poliovirus, the immune system searches its memory files, finds the blueprint for poliovirus, and quickly activates the appropriate defenses. The result is that the poliovirus is eliminated by specific antibodies that neutralize the virus before it has a chance to multiply and invade the nervous system.
Innate immunity and learned immunity are not independent of each other. Each system interacts and influences the other, either directly or through the induction of cytokines (messengers). Rarely does a stimulus trigger a single response. Instead, several responses occur, some of which may act together or occasionally may conflict with each other. Yet all responses revolve around the three basic principles of recognition, mobilization, and attack.
Before the immune system can respond to an antigen, it must be able to recognize the antigen. It is able to do so through a process called antigen processing. Macrophages are the major antigen-processing cells, but other cells, including B lymphocytes, can also process antigens.
Antigen-processing cells ingest an antigen and chop it into small fragments. The fragments are then packaged within the major histocompatibility complex molecules and shuttled to the surface of the cell membrane. The area of the major histocompatibility complex that has the antigen fragment then binds (attaches) to a special molecule on the surface of the T lymphocyte called the T-cell receptor. The T-cell receptor is designed to fit--like a key in a lock--the part of the major histocompatibility complex bearing an antigen fragment.
T lymphocytes have two major subsets that differ in their ability to bind (attach) to one of the two classes of major histocompatibility complex molecules. The T-lymphocyte subset with a CD8 molecule on its surface can bind to class I major histocompatibility complex molecules. The T-lymphocyte subset with a CD4 molecule on its surface can bind to class II major histocompatibility complex molecules.
Once an antigen has been recognized by an antigen-processing cell and T lymphocyte, a series of events to mobilize the immune system follows. When an antigen-processing cell ingests an antigen, it releases cytokines--for example, interleukin-1, interleukin-8, or interleukin-12--that act on certain other cells. Interleukin-1 mobilizes other T lymphocytes; interleukin-12 stimulates natural killer cells to become more potent killers and to secrete interferon; interleukin-8 acts as a beacon, guiding neutrophils to the site where the antigen was spotted. This process of attracting and recruiting cells is called chemotaxis.
When T lymphocytes are triggered through their T-cell receptors, they produce several cytokines that help to recruit other lymphocytes, thus amplifying the immune response. Cytokines can also activate the nonspecific (innate) immune defenses. Cytokines therefore bridge innate and learned immunity.
Much of the immune system's machinery is geared toward killing or eliminating invading microbes once they have been recognized. Macrophages, neutrophils, and natural killer cells are able to eliminate many foreign invaders.
If an invader cannot be eliminated completely, walls can be built to imprison it. The prison wall is made of special cells and is called a granuloma. Tuberculosis is an example of an infection that is not totally eliminated; the bacteria that cause tuberculosis are imprisoned within a granuloma. Most healthy people who are exposed to these bacteria fend off the tuberculosis infection, but some bacteria survive indefinitely, usually in the lung, surrounded by a granuloma. If the immune system is weakened (even 50 or 60 years later), the prison walls crumble and the bacteria that cause tuberculosis start to multiply.
The body does not fight all invaders the same way. Invaders that stay outside the body's cells (extracellular organisms) are relatively easy to fight; the immune system mobilizes defenses to facilitate their ingestion by macrophages and other cells. How the immune system goes about this depends on whether the invaders are encapsulated (have a thick capsule around them) or are nonencapsulated. Invaders that gain access to the inside of cells (intracellular organisms) and remain viable (alive) and functional are fought in a different way altogether.
Encapsulated Extracellular Organisms
Some bacteria have a capsule that shields their cell wall, preventing macrophages from recognizing them. A common example of encapsulated bacteria are streptococci, which cause strep throat. The immune response is to have B lymphocytes produce antibodies against the capsule. Antibodies also neutralize the toxins that certain bacteria produce.
Once created, antibodies attach themselves to the capsules. The bacterium-antibody unit is called an immune complex. The immune complex attaches itself to a receptor on a macrophage. This engagement facilitates the ingestion of the whole complex by the macrophage, where the bacteria are digested. Immune complexes also activate the complement cascade. Attachment of products of the complement cascade to the immune complex makes it very easy for macrophages to identify immune complexes to ingest.
Nonencapsulated Extracellular Organisms
Some bacteria have only a cell wall; they do not have a capsule and are considered nonencapsulated. Escherichia coli, a common cause of food poisoning and urinary tract infections, is an example of a nonencapsulated bacterium. When nonencapsulated bacteria invade the body, macrophages, natural killer cells, cytokines, and the complement cascade spring into action.
Macrophages have sensors that recognize molecules on the surface of nonencapsulated bacteria. When these molecules and sensors are engaged, the bacterium is engulfed by the macrophage in a process called phagocytosis. Phagocytosis stimulates the macrophage to release several cytokines that attract neutrophils. The neutrophils then engulf and kill even more bacteria. Some of the cytokines released by the macrophages activate natural killer cells, which can then kill some of the bacteria directly or can help the neutrophils and macrophages kill more efficiently.
Nonencapsulated bacteria also activate the complement cascade. Complement helps destroy the bacteria and releases a product that serves as a signal to attract neutrophils, which then destroy the remaining bacteria.
Some microorganisms, such as tuberculosis bacteria, survive best inside a cell. Because these organisms must enter a cell to live, they have no particular defenses against being ingested. While being ingested, these organisms are sequestered within the cell in a protective structure called a vesicle or vacuole. The vesicles can fuse with other vesicles inside the cytoplasm, such as vesicles that assemble and package class II major histocompatibility complex molecules.
As these vesicles fuse, the major histocompatibility complex picks up some of the fragments of the bacteria. When the major histocompatibility complex is shuttled to the cell surface, it contains these foreign fragments. Major histocompatibility complex molecules are recognized by T lymphocytes, which respond to the antigen fragment by releasing cytokines. The cytokines activate macrophages. This activation results in the production of new chemicals within the cell. These chemicals now allow the macrophage to kill organisms inside the cell.
Some cytokines promote the production of antibodies. Antibodies are helpful in the defense against organisms outside the cell; however, they are ineffective against infections inside it.
Viruses are an example of another organism that must enter a cell in order to survive. However, viruses are processed not in vesicles but in special structures called proteosomes. Proteosomes break the virus into fragments that are transported to another structure within the cell, called the rough endoplasmic reticulum--the cell's factory for making proteins. Class I major histocompatibility complex molecules are also assembled within the rough endoplasmic reticulum. As the class I major histocompatibility complex molecules are assembled, they pick up virus fragments and take them along when they are shuttled to the cell surface.
Certain T lymphocytes recognize the class I molecules, which now contain the virus fragments, and bind to them. When the connection is completed, a signal sent through the cell membrane triggers the activation of antigen-specific T lymphocytes, most of which evolve into killer T cells. Unlike natural killer cells, however, killer T cells kill only the cells infected with the particular virus that stimulated their activation. For example, killer T cells help fight the influenza virus. The reason why most people need 7 to 10 days to recover from influenza is because that is how much time is needed to generate killer T cells that are specifically designed to fight the influenza virus.
Sometimes the immune system malfunctions, misinterprets the body's tissues as foreign, and attacks them, resulting in an autoimmune reaction. Autoimmune reactions can be triggered in several ways:
- A substance in the body that is normally strictly contained in a specific area (and thus is hidden from the immune system) is released into the general circulation. For example, the fluid in the eyeball is normally contained within the eyeball's chambers. If a blow to the eye releases this fluid into the bloodstream, the immune system may react against it.
- A normal body substance is altered. For example, viruses, drugs, sunlight, or radiation may change a protein's structure in a way that makes it seem foreign.
- The immune system responds to a foreign substance that is similar in appearance to a natural body substance and inadvertently targets the body substance as well as the foreign substance.
- Something malfunctions in the cells that control antibody production. For example, cancerous B lymphocytes may produce abnormal antibodies that attack red blood cells.
The results of an autoimmune reaction vary. Fever is common. Various tissues may be destroyed, such as blood vessels, cartilage, and skin. Virtually any organ can be attacked by the immune system, including the kidneys, lungs, heart, and brain. The resulting inflammation and tissue damage can cause kidney failure, breathing problems, abnormal heart function, pain, deformity, delirium, and death.
A large number of disorders almost certainly have an autoimmune cause, including lupus (systemic lupus erythematosus), myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, pemphigus, rheumatoid arthritis, scleroderma, Sjögren's syndrome, and pernicious anemia.