If an infectious agent is not successfully repelled by the chemical and physical barriers described above, it will encounter cells whose function is to eliminate foreign substances that enter the body. These cells are the nonspecific effector cells of the innate immune response. They include scavenger cells—i.e., various cells that attack infectious agents directly—and natural killer cells, which attack cells of the body that harbour infectious organisms. Some of these cells destroy infectious agents by engulfing and destroying them through the process of phagocytosis, while other cells resort to alternative means. As is true of other components of innate immunity, these cells interact with components of acquired immunity to fight infection.
All higher animals and many lower ones have scavenger cells—primarily leukocytes (white blood cells)—that destroy infectious agents. Most vertebrates, including all birds and mammals, possess two main kinds of scavenger cells. Their importance was first recognized in 1884 by Russian biologist Élie Metchnikoff, who named them microphages and macrophages, after Greek words meaning “little eaters” and “big eaters.”
Microphages are now called either granulocytes, because of the numerous chemical-containing granules found in their cytoplasm, or polymorphonuclear leukocytes, because of the oddly shaped nucleus these cells contain. Some granules contain digestive enzymes capable of breaking down proteins, while others contain bacteriocidal (bacteria-killing) proteins. There are three classes of granulocytes— neutrophils, eosinophils, and basophils—which are distinguished according to the shape of the nucleus and the way in which the granules in the cytoplasm are stained by dye. The differences in staining characteristics reflect differences in the chemical makeup of the granules. Neutrophils are the most common type of granulocyte, making up about 60 to 70 percent of all white blood cells. These granulocytes ingest and destroy microorganisms, especially bacteria. Less common are the eosinophils, which are particularly effective at damaging the cells that make up the cuticle (body wall) of larger parasites. Fewer still are the basophils, which release heparin (a substance that inhibits blood coagulation), histamine, and other substances that play a role in some allergic reactions (see immune system disorder: Allergies). Very similar in structure and function to basophils are the tissue cells called mast cells, which also contribute to immune responses.
Granulocytes, which have a life span of only a few days, are continuously produced from stem (i.e., precursor) cells in the bone marrow. They enter the bloodstream and circulate for a few hours, after which they leave the circulation and die. Granulocytes are mobile and are attracted to foreign materials by chemical signals, some of which are produced by the invading microorganisms themselves, others by damaged tissues, and still others by the interaction between microbes and proteins in the blood plasma. Some microorganisms produce toxins that poison granulocytes and thus escape phagocytosis; other microbes are indigestible and are not killed when ingested. By themselves, then, granulocytes are of limited effectiveness and require reinforcement by the mechanisms of specific immunity.
The other main type of scavenger cell is the macrophage, the mature form of the monocyte. Like granulocytes, monocytes are produced by stem cells in the bone marrow and circulate through the blood, though in lesser numbers. But, unlike granulocytes, monocytes undergo differentiation, becoming macrophages that settle in many tissues, especially the lymphoid tissues (e.g., spleen and lymph nodes) and the liver, which serve as filters for trapping microbes and other foreign particles that arrive through the blood or the lymph. Macrophages live longer than granulocytes and, although effective as scavengers, basically provide a different function. Compared with granulocytes, macrophages move relatively sluggishly. They are attracted by different stimuli and usually arrive at sites of invasion later than granulocytes. Macrophages recognize and ingest foreign particles by mechanisms that are basically similar to those of granulocytes, although the digestive process is slower and not as complete. This aspect is of great importance for the role that macrophages play in stimulating specific immune responses—something in which granulocytes play no part.
Natural killer cells do not attack invading organisms directly but instead destroy the body’s own cells that have either become cancerous or been infected with a virus. NK cells were first recognized in 1975, when researchers observed cells in the blood and lymphoid tissues that were neither the scavengers described above nor ordinary lymphocytes but which nevertheless were capable of killing cells. Although similar in outward appearance to lymphocytes, NK cells contain granules that harbour cytotoxic chemicals.
NK cells recognize dividing cells by a mechanism that does not depend on specific immunity. They then bind to these dividing cells and insert their granules through the outer membrane and into the cytoplasm. This causes the dividing cells to leak and die.
NK cells are the third most abundant type of lymphocyte in the body (B and T lymphocytes being present in the greatest numbers). They develop from hematopoietic stem cells and mature in the bone marrow and the liver.
The body has a number of nonspecific methods of fighting infection that are called early induced responses. They include the acute-phase response and the inflammation response, which can eliminate infection or hold it in check until specific, acquired immune responses have time to develop. Nonspecific immune responses occur more rapidly than acquired immune responses do, but they do not provide lasting immunity to specific pathogens.
Nonadaptive immune responses rely on a number of chemical signals, collectively called cytokines, to carry out their effects. These cytokines include members of the family of proteins called interleukins, which induce fever and the acute-phase response, and tumour necrosis factor-alpha, which initiates the inflammatory response.
When the body is invaded by a pathogen, macrophages release the protein signals interleukin-1 (IL-1) and interleukin-6 (IL-6) to help fight the infection. One of their effects is to raise the temperature of the body, causing the fever that often accompanies infection. (The interleukins increase body temperature by acting on the temperature-regulating hypothalamus in the brain and by affecting energy mobilization by fat and muscle cells.) Fever is believed to be helpful in eliminating infections because most bacteria grow optimally at temperatures lower than normal body temperature. But fever is only part of the more general innate defense mechanism called the acute-phase response. In addition to raising body temperature, the interleukins stimulate liver cells to secrete increased amounts of several different proteins into the bloodstream. These proteins, collectively called acute-phase proteins, bind to bacteria and, by doing so, activate complement proteins that destroy the pathogen. The acute-phase proteins act similarly to antibodies but are more democratic—that is, they do not distinguish between pathogens as antibodies do but instead attack a wide range of microorganisms equally. Another effect the interleukins have is to increase the number of circulating neutrophils and eosinophils, which help fight infection.
Infection often results in tissue damage, which may trigger an inflammatory response. The signs of inflammation include pain, swelling, redness, and fever, which are induced by chemicals released by macrophages. These substances promote blood flow to the area, increase the permeability of capillaries, and induce coagulation. The increased blood flow is responsible for redness, and the leakiness of the capillaries allows cells and fluids to enter tissues, causing pain and swelling. These effects bring more phagocytic cells to the area to help eliminate the pathogens. The first cells to arrive, usually within an hour, are neutrophils and eosinophils, followed a few hours later by macrophages. Macrophages not only engulf pathogens but also help the healing process by disposing of cellular debris which accumulates from destroyed tissue cells and neutrophils that self-destruct after ingesting microorganisms. If infection persists, components of specific immunity—antibodies and T cells—arrive at the site to fight the infection.
It has been known for centuries that persons who contract certain diseases and survive generally do not catch those illnesses again. Greek historian Thucydides recorded that, when the plague was raging in Athens during the 5th century bce, the sick and dying would have received no nursing at all had it not been for the devotion of those who had already recovered from the disease; it was known that no one ever caught the plague a second time. The same applies, with rare exceptions, to many other diseases, such as smallpox, chicken pox, measles, and mumps. Yet having had measles does not prevent a child from contracting chicken pox or vice versa. The protection acquired by experiencing one of these infections is specific to that infection; in other words, it is due to specific, acquired immunity, also called adaptive immunity.
There are other infectious conditions, such as the common cold, influenza, pneumonia, and diarrheal diseases, that can be caught again and again; these seem to contradict the notion of specific immunity. But the reason such illnesses can recur is that many different infectious agents produce similar symptoms (and thus the same disease). For example, more than 200 viruses can cause the cluster of symptoms known as the common cold. Consequently, even though infection with a particular agent does protect against reinfection by that same pathogen, it does not confer protection from other pathogens that have not been encountered.
Acquired immunity is dependent on the specialized white blood cells known as lymphocytes. This section describes the various ways in which lymphocytes operate to confer specific immunity. Although pioneer studies were begun in the late 19th century, most of the knowledge of specific immunity has been gained since the 1960s, and new insights are continually being obtained.
Lymphocytes are the cells responsible for the body’s ability to distinguish and react to an almost infinite number of different foreign substances, including those of which microbes are composed. Lymphocytes are mainly a dormant population, awaiting the appropriate signals to be stirred to action. The inactive lymphocytes are small, round cells filled largely by a nucleus. Although they have only a small amount of cytoplasm compared with other cells, each lymphocyte has sufficient cytoplasmic organelles (small functional units such as mitochondria, the endoplasmic reticulum, and a Golgi apparatus) to keep the cell alive. Lymphocytes move only sluggishly on their own, but they can travel swiftly around the body when carried along in the blood or lymph. At any one time an adult human has approximately 2 × 10 12 lymphocytes, about 1 percent of which are in the bloodstream. The majority are concentrated in various tissues scattered throughout the body, particularly the bone marrow, spleen, thymus, lymph nodes, tonsils, and lining of the intestines, which make up the lymphatic system. Organs or tissues containing such concentrations of lymphocytes are described as lymphoid. The lymphocytes in lymphoid structures are free to move, although they are not lying loose; rather, they are confined within a delicate network of lymph capillaries located in connective tissues that channel the lymphocytes so that they come into contact with other cells, especially macrophages, that line the meshes of the network. This ensures that the lymphocytes interact with each other and with foreign materials trapped by the macrophages in an ordered manner.
Lymphocytes originate from stem cells in the bone marrow; these stem cells divide continuously, releasing immature lymphocytes into the bloodstream. Some of these cells travel to the thymus, where they multiply and differentiate into T lymphocytes, or T cells. The T stands for thymus-derived, referring to the fact that these cells mature in the thymus. Once they have left the thymus, T cells enter the bloodstream and circulate to and within the rest of the lymphoid organs, where they can multiply further in response to appropriate stimulation. About half of all lymphocytes are T cells.
Some lymphocytes remain in the bone marrow, where they differentiate and then pass directly to the lymphoid organs. They are termed B lymphocytes, or B cells, and they, like T cells, can mature and multiply further in the lymphoid organs when suitably stimulated. Although it is appropriate to refer to them as B cells in humans and other mammals, because they are bone-marrow derived, the B actually stands for the bursa of Fabricius, a lymphoid organ found only in birds, the organisms in which B cells were first discovered.