The constancy of the composition of the blood is made possible by the circulation, which conveys blood through the organs that regulate the concentrations of its components. In the lungs, blood acquires oxygen and releases carbon dioxide transported from the tissues. The kidneys remove excess water and dissolved waste products. Nutrient substances derived from food reach the bloodstream after absorption by the gastrointestinal tract. Glands of the endocrine system release their secretions into the blood, which transports these hormones to the tissues in which they exert their effects. Many substances are recycled through the blood; for example, iron released during the destruction of old red cells is conveyed by the plasma to sites of new red cell production where it is reused. Each of the numerous components of the blood is kept within appropriate concentration limits by an effective regulatory mechanism. In many instances, feedback control systems are operative; thus, a declining level of blood sugar (glucose) leads to accelerated release of glucose into the blood so that a potentially hazardous depletion of glucose does not occur.
Unicellular organisms, primitive multicellular animals, and the early embryos of higher forms of life lack a circulatory system. Because of their small size, these organisms can absorb oxygen and nutrients and can discharge wastes directly into their surrounding medium by simple diffusion. Sponges and coelenterates (e.g., jellyfish and hydras) also lack a blood system; the means to transport foodstuffs and oxygen to all the cells of these larger multicellular animals is provided by water, sea or fresh, pumped through spaces inside the organisms. In larger and more-complex animals, transport of adequate amounts of oxygen and other substances requires some type of blood circulation. In most such animals the blood passes through a respiratory exchange membrane, which lies in the gills, lungs, or even the skin. There the blood picks up oxygen and disposes of carbon dioxide.
The cellular composition of blood varies from group to group in the animal kingdom. Most invertebrates have various large blood cells capable of amoeboid movement. Some of these aid in transporting substances; other are capable of surrounding and digesting foreign particles or debris (phagocytosis). Compared with vertebrate blood, however, that of the invertebrates has relatively few cells. Among the vertebrates, there are several classes of amoeboid cells (white blood cells, or leukocytes) and cells that help stop bleeding (platelets, or thrombocytes).
Oxygen requirements have played a major role in determining both the composition of blood and the architecture of the circulatory system. In some simple animals, including small worms and mollusks, transported oxygen is merely dissolved in the plasma. Larger and more-complex animals, which have greater oxygen needs, have pigments capable of transporting relatively large amounts of oxygen. The red pigment hemoglobin, which contains iron, is found in all vertebrates and in some invertebrates. In almost all vertebrates, including humans, hemoglobin is contained exclusively within the red cells (erythrocytes). The red cells of the lower vertebrates (e.g., birds) have a nucleus, whereas mammalian red cells lack a nucleus. Red cells vary markedly in size among mammals; those of the goat are much smaller than those of humans, but the goat compensates by having many more red cells per unit volume of blood. The concentration of hemoglobin inside the red cell varies little between species. Hemocyanin, a copper-containing protein chemically unlike hemoglobin, is found in some crustaceans. Hemocyanin is blue in colour when oxygenated and colourless when oxygen is removed. Some annelids have the iron-containing green pigment chlorocruorin, others the iron-containing red pigment hemerythrin. In many invertebrates the respiratory pigments are carried in solution in the plasma, but in higher animals, including all vertebrates, the pigments are enclosed in cells; if the pigments were freely in solution, the pigment concentrations required would cause the blood to be so viscous as to impede circulation.
This article focuses on the main components and functions of human blood. For full treatment of blood groups, see the article blood group. For information on the organ system that conveys blood to all organs of the body, see cardiovascular system. For additional information on blood in general and comparison of the blood and lymph of diverse organisms, see circulation.
In humans, blood is an opaque red fluid, freely flowing but denser and more viscous than water. The characteristic colour is imparted by hemoglobin, a unique iron-containing protein. Hemoglobin brightens in colour when saturated with oxygen (oxyhemoglobin) and darkens when oxygen is removed (deoxyhemoglobin). For this reason, the partially deoxygenated blood from a vein is darker than oxygenated blood from an artery. The red blood cells (erythrocytes) constitute about 45 percent of the volume of the blood, and the remaining cells (white blood cells, or leukocytes, and platelets, or thrombocytes) less than 1 percent. The fluid portion, plasma, is a clear, slightly sticky, yellowish liquid. After a fatty meal, plasma transiently appears turbid. Within the body the blood is permanently fluid, and turbulent flow assures that cells and plasma are fairly homogeneously mixed.
The total amount of blood in humans varies with age, sex, weight, body type, and other factors, but a rough average figure for adults is about 60 millilitres per kilogram of body weight. An average young male has a plasma volume of about 35 millilitres and a red cell volume of about 30 millilitres per kilogram of body weight. There is little variation in the blood volume of a healthy person over long periods, although each component of the blood is in a continuous state of flux. In particular, water rapidly moves in and out of the bloodstream, achieving a balance with the extravascular fluids (those outside the blood vessels) within minutes. The normal volume of blood provides such an adequate reserve that appreciable blood loss is well tolerated. Withdrawal of 500 millilitres (about a pint) of blood from normal blood donors is a harmless procedure. Blood volume is rapidly replaced after blood loss; within hours, plasma volume is restored by movement of extravascular fluid into the circulation. Replacement of red cells is completed within several weeks. The vast area of capillary membrane, through which water passes freely, would permit instantaneous loss of the plasma from the circulation were it not for the plasma proteins—in particular, serum albumin. Capillary membranes are impermeable to serum albumin, the smallest in weight and highest in concentration of the plasma proteins. The osmotic effect of serum albumin retains fluid within the circulation, opposing the hydrostatic forces that tend to drive the fluid outward into the tissues.
The liquid portion of the blood, the plasma, is a complex solution containing more than 90 percent water. The water of the plasma is freely exchangeable with that of body cells and other extracellular fluids and is available to maintain the normal state of hydration of all tissues. Water, the single largest constituent of the body, is essential to the existence of every living cell.
The major solute of plasma is a heterogeneous group of proteins constituting about 7 percent of the plasma by weight. The principal difference between the plasma and the extracellular fluid of the tissues is the high protein content of the plasma. Plasma protein exerts an osmotic effect by which water tends to move from other extracellular fluid to the plasma. When dietary protein is digested in the gastrointestinal tract, individual amino acids are released from the polypeptide chains and are absorbed. The amino acids are transported through the plasma to all parts of the body, where they are taken up by cells and are assembled in specific ways to form proteins of many types. These plasma proteins are released into the blood from the cells in which they were synthesized. Much of the protein of plasma is produced in the liver.
The major plasma protein is serum albumin, a relatively small molecule, the principal function of which is to retain water in the bloodstream by its osmotic effect. The amount of serum albumin in the blood is a determinant of the total volume of plasma. Depletion of serum albumin permits fluid to leave the circulation and to accumulate and cause swelling of soft tissues (edema). Serum albumin binds certain other substances that are transported in plasma and thus serves as a nonspecific carrier protein. Bilirubin, for example, is bound to serum albumin during its passage through the blood. Serum albumin has physical properties that permit its separation from other plasma proteins, which as a group are called globulins. In fact, the globulins are a heterogeneous array of proteins of widely varying structure and function, only a few of which will be mentioned here. The immunoglobulins, or antibodies, are produced in response to a specific foreign substance, or antigen. For example, administration of polio vaccine, which is made from killed or attenuated (weakened) poliovirus, is followed by the appearance in the plasma of antibodies that react with poliovirus and effectively prevent the onset of disease. Antibodies may be induced by many foreign substances in addition to microorganisms; immunoglobulins are involved in some hypersensitivity and allergic reactions. Other plasma proteins are concerned with the coagulation of the blood.
Many proteins are involved in highly specific ways with the transport function of the blood. Blood lipids are incorporated into protein molecules as lipoproteins, substances important in lipid transport. Iron and copper are transported in plasma by unique metal-binding proteins (transferrin and ceruloplasmin, respectively). Vitamin B12, an essential nutrient, is bound to a specific carrier protein. Although hemoglobin is not normally released into the plasma, a hemoglobin-binding protein (haptoglobin) is available to transport hemoglobin to the reticuloendothelial system should hemolysis (breakdown) of red cells occur. The serum haptoglobin level is raised during inflammation and certain other conditions; it is lowered in hemolytic disease and some types of liver disease.
Lipids are present in plasma in suspension and in solution. The concentration of lipids in plasma varies, particularly in relation to meals, but ordinarily does not exceed 1 gram per 100 millilitres. The largest fraction consists of phospholipids, complex molecules containing phosphoric acid and a nitrogen base in addition to fatty acids and glycerol. Triglycerides, or simple fats, are molecules composed only of fatty acids and glycerol. Free fatty acids, lower in concentration than triglycerides, are responsible for a much larger transport of fat. Other lipids include cholesterol, a major fraction of the total plasma lipids. These substances exist in plasma combined with proteins of several types as lipoproteins. The largest lipid particles in the blood are known as chylomicrons and consist largely of triglycerides; after absorption from the intestine, they pass through lymphatic channels and enter the bloodstream through the thoracic lymph duct. The other plasma lipids are derived from food or enter the plasma from tissue sites.
Some plasma constituents occur in plasma in low concentration but have a high turnover rate and great physiological importance. Among these is glucose, or blood sugar. Glucose is absorbed from the gastrointestinal tract or may be released into the circulation from the liver. It provides a source of energy for tissue cells and is the only source for some, including the red cells. Glucose is conserved and used and is not excreted. Amino acids also are so rapidly transported that the plasma level remains low, although they are required for all protein synthesis throughout the body. Urea, an end product of protein metabolism, is rapidly excreted by the kidneys. Other nitrogenous waste products—uric acid and creatinine—are similarly removed.
Several inorganic materials are essential constituents of plasma, and each has special functional attributes. The predominant cation (positively charged ion) of the plasma is sodium, an ion that occurs within cells at a much lower concentration. Because of the effect of sodium on osmotic pressure and fluid movements, the amount of sodium in the body is an influential determinant of the total volume of extracellular fluid. The amount of sodium in plasma is controlled by the kidneys under the influence of the hormone aldosterone, which is secreted by the adrenal gland. If dietary sodium exceeds requirements, the excess is excreted by the kidneys. Potassium, the principal intracellular cation, occurs in plasma at a much lower concentration than sodium. The renal excretion of potassium is influenced by aldosterone, which causes retention of sodium and loss of potassium. Calcium in plasma is in part bound to protein and in part ionized. Its concentration is under the control of two hormones: parathyroid hormone, which causes the level to rise, and calcitonin, which causes it to fall. Magnesium, like potassium, is a predominantly intracellular cation and occurs in plasma in low concentration. Variations in the concentrations of these cations may have profound effects on the nervous system, the muscles, and the heart, effects normally prevented by precise regulatory mechanisms. Iron, copper, and zinc are required in trace amounts for synthesis of essential enzymes; much more iron is needed in addition for production of hemoglobin and myoglobin, the oxygen-binding pigment of muscles. These metals occur in plasma in low concentrations. The principal anion (negatively charged ion) of plasma is chloride; sodium chloride is its major salt. Bicarbonate participates in the transport of carbon dioxide and in the regulation of pH. Phosphate also has a buffering effect on the pH of the blood and is vital for chemical reactions of cells and for the metabolism of calcium. Iodide is transported through plasma in trace amounts; it is avidly taken up by the thyroid gland, which incorporates it into thyroid hormone.
The hormones of all the endocrine glands are secreted into the plasma and transported to their target organs, the organs on which they exert their effects. The plasma levels of these agents often reflect the functional activity of the glands that secrete them; in some instances, measurements are possible though concentrations are extremely low. Among the many other constituents of plasma are numerous enzymes. Some of these appear simply to have escaped from tissue cells and have no functional significance in the blood.
There are four major types of blood cells: red blood cells (erythrocytes), platelets (thrombocytes), lymphocytes, and phagocytic cells. Collectively, the lymphocytes and phagocytic cells constitute the white blood cells (leukocytes). Each type of blood cell has a specialized function: red cells take up oxygen from the lungs and deliver it to the tissues; platelets participate in forming blood clots; lymphocytes are involved with immunity; and phagocytic cells occur in two varieties—granulocytes and monocytes—and ingest and break down microorganisms and foreign particles. The circulating blood functions as a conduit, bringing the various kinds of cells to the regions of the body in which they are needed: red cells to tissues requiring oxygen, platelets to sites of injury, lymphocytes to areas of infection, and phagocytic cells to sites of microbial invasion and inflammation. Each type of blood cell is described in detail below.
The continuous process of blood cell formation (hematopoiesis) takes place in hematopoietic tissue. In the developing embryo, the first site of blood formation is the yolk sac. Later in embryonic life, the liver becomes the most important red blood cell-forming organ, but it is soon succeeded by the bone marrow, which in adult life is the only source of both red cells and the granulocytes. In young children, hematopoietic bone marrow fills most of the skeleton, whereas in adults the marrow is located mainly in the central bones (ribs, sternum, vertebrae, and pelvic bones). Bone marrow is a rich mixture of developing and mature blood cells, as well as fat cells and other cells that provide nutrition and an architectural framework upon which the blood-forming elements arrange themselves. The weight of the marrow of a normal adult is 1,600 to 3,700 grams and contains over 1,000,000,000,000 hematopoietic cells (18 × 109 cells per kilogram). Nourishment of this large mass of cells comes from the blood itself. Arteries pierce the outer walls of the bones, enter the marrow, and divide into fine branches, which ultimately coalesce into large venous sacs (sinusoids) through which blood flows sluggishly. In the surrounding hematopoietic tissue, newly formed blood cells enter the general circulation by penetrating the walls of the sinusoids.
In the adult the bone marrow produces all of the red cells, 60 to 70 percent of the white cells (i.e., the granulocytes), and all of the platelets. The lymphatic tissues, particularly the thymus, the spleen, and the lymph nodes, produce the lymphocytes (comprising 20 to 30 percent of the white cells). The reticuloendothelial tissues of the spleen, liver, lymph nodes, and other organs produce the monocytes (4 to 8 percent of the white cells). The platelets are formed from bits of the cytoplasm of the giant cells (megakaryocytes) of the bone marrow.
Both the red and white cells arise through a series of complex transformations from primitive stem cells, which have the ability to form any of the precursors of a blood cell. Precursor cells are stem cells that have developed to the stage where they are committed to forming a particular type of new blood cell. By dividing and differentiating, precursor cells give rise to the four major blood cell lineages: red cells, phagocytic cells, megakaryocytes, and lymphocytes. The cells of the marrow are under complex controls that regulate their formation and adjust their production to the changing demands of the body. When marrow stem cells are cultured outside the body, they form tiny clusters of cells (colonies), which correspond to red cells, phagocytic cells, and megakaryocytes. The formation of these individual colonies depends on hormonal sugar-containing proteins (glycoproteins), referred to collectively as colony-stimulating factors (CSFs). These factors are produced throughout the body. Even in minute amounts, CSFs can stimulate the division and differentiation of precursor cells into mature blood cells and thus exert powerful regulatory influences over the production of blood cells. A master colony-stimulating factor (multi-CSF), also called interleukin-3, stimulates the most ancestral hematopoietic stem cell. Further differentiation of this stem cell into specialized descendants requires particular kinds of CSFs; for example, the CSF erythropoietin is needed for the maturation of red cells, and granulocyte CSF controls the production of granulocytes. These glycoproteins, as well as other CSFs, serve as signals from the tissues to the marrow. For instance, a decrease in the oxygen content of the blood stimulates the kidney to increase its production of erythropoietin, thus ultimately raising the number of oxygen-carrying red cells. Certain bacterial components accelerate the formation of granulocyte CSF, thereby leading to an increased production of phagocytic granulocytes by the bone marrow during infection.
In the normal adult the rate of blood cell formation varies depending on the individual, but a typical production might average 200 billion red cells per day, 10 billion white cells per day, and 400 billion platelets per day.
Production of red blood cells (erythropoiesis)
Red cells are produced continuously in the marrow of certain bones. As stated above, in adults the principal sites of red cell production, called erythropoiesis, are the marrow spaces of the vertebrae, ribs, breastbone, and pelvis. Within the bone marrow the red cell is derived from a primitive precursor, or erythroblast, a nucleated cell in which there is no hemoglobin. Proliferation occurs as a result of several successive cell divisions. During maturation, hemoglobin appears in the cell, and the nucleus becomes progressively smaller. After a few days the cell loses its nucleus and is then introduced into the bloodstream in the vascular channels of the marrow. Almost 1 percent of the red cells are generated each day, and the balance between red cell production and the removal of aging red cells from the circulation is precisely maintained. When blood is lost from the circulation, the erythropoietic activity of marrow increases until the normal number of circulating cells has been restored.
In a normal adult the red cells of about half a litre (almost one pint) of blood are produced by the bone marrow every week. A number of nutrient substances are required for this process. Some nutrients are the building blocks of which the red cells are composed. For example, amino acids are needed in abundance for the construction of the proteins of the red cell, in particular of hemoglobin. Iron also is a necessary component of hemoglobin. Approximately one-quarter of a gram of iron is needed for the production of a pint of blood. Other substances, required in trace amounts, are needed to catalyze the chemical reactions by which red cells are produced. Important among these are several vitamins such as riboflavin, vitamin B12, and folic acid, necessary for the maturation of the developing red cell; and vitamin B6 (pyridoxine), required for the synthesis of hemoglobin. The secretions of several endocrine glands influence red cell production. If there is an inadequate supply of thyroid hormone, erythropoiesis is retarded and anemia appears. The male sex hormone, testosterone, stimulates red cell production; for this reason, red cell counts of men are higher than those of women.
The capacity of the bone marrow to produce red cells is enormous. When stimulated to peak activity and when provided adequately with nutrient substances, the marrow can compensate for the loss of several pints of blood per week. Hemorrhage or accelerated destruction of red cells leads to enhanced marrow activity. The marrow can increase its production of red cells up to eight times the usual rate. After that, if blood loss continues, anemia develops. The rate of erythropoiesis is sensitive to the oxygen tension of the arterial blood. When oxygen tension falls, more red cells are produced and the red cell count rises. For this reason, persons who live at high altitude have higher red cell counts than those who live at sea level. For example, there is a small but significant difference between average red cell counts of persons living in New York City, at sea level pressure, and persons living in Denver, Colo., more than 1.5 km (1 mile) above sea level, where the atmospheric pressure is lower. Natives of the Andes, living nearly 5 km (3 miles) above sea level, have extremely high red cell counts.
The rate of production of erythrocytes is controlled by the hormone erythropoietin, which is produced largely in the kidneys. When the number of circulating red cells decreases or when the oxygen transported by the blood diminishes, an unidentified sensor detects the change and the production of erythropoietin is increased. This substance is then transported through the plasma to the bone marrow, where it accelerates the production of red cells. The erythropoietin mechanism operates like a thermostat, increasing or decreasing the rate of red cell production in accordance with need. When a person who has lived at high altitude moves to a sea level environment, production of erythropoietin is suppressed, the rate of red cell production declines, and the red cell count falls until the normal sea level value is achieved. With the loss of one pint of blood, the erythropoietin mechanism is activated, red cell production is enhanced, and within a few weeks the number of circulating red cells has been restored to the normal value. The precision of control is extraordinary so that the number of new red cells produced accurately compensates for the number of cells lost or destroyed. Erythropoietin has been produced in vitro (outside the body) by the technique of genetic engineering (recombinant DNA). The purified, recombinant hormone has promise for persons with chronic renal failure, who develop anemia because of a lack of erythropoietin.
Destruction of red blood cells
Survival of the red blood cell in the circulation depends upon the continuous utilization of glucose for the production of energy. Two chemical pathways are employed, and both are essential for the normal life of the red cell. An extraordinary number of enzyme systems participate in these reactions and direct the energy evolved into appropriate uses. Red cells contain neither a nucleus nor RNA (ribonucleic acid, necessary for protein synthesis), so that cell division (mitosis) and production of new protein are impossible. Energy is not necessary for oxygen and carbon dioxide transport, which depends principally on the properties of hemoglobin. Energy, however, is needed for another reason. Because of the tendency for extracellular sodium to leak into the red cell and for potassium to leak out, energy is required to operate a pumping mechanism in the red cell membrane to maintain the normal gradients (differences in concentrations) of these ions. Energy is also required to convert methemoglobin to oxyhemoglobin and to prevent the oxidation of other constituents of the red cell.
Red cells have an average life span of 120 days. Because red cells cannot synthesize protein, reparative processes are not possible. As red cells age, wear and tear leads to loss of some of their protein, and the activity of some of their essential enzymes decreases. Chemical reactions necessary for the survival of the cell are consequently impaired. As a result, water passes into the aging red cell, transforming its usual discoid shape into a sphere. These spherocytes are inelastic, and, as they sluggishly move through the circulation, they are engulfed by phagocytes. Phagocytic cells form a part of the lining of blood vessels, particularly in the spleen, liver, and bone marrow. These cells, called macrophages, are constituents of the reticuloendothelial system and are found in the lymph nodes, in the intestinal tract, and as free-wandering and fixed cells. As a group they have the ability to ingest not only other cells but also many other microscopic particles, including certain dyes and colloids. Within the reticuloendothelial cells, erythrocytes are rapidly destroyed. Protein, including that of the hemoglobin, is broken down, and the component amino acids are transported through the plasma to be used in the synthesis of new proteins. The iron removed from hemoglobin passes back into the plasma and is transported to the bone marrow, where it may be used in the synthesis of hemoglobin in newly forming red cells. Iron not necessary for this purpose is stored within the reticuloendothelial cells but is available for release and reuse whenever it is required. In the breakdown of red cells, there is no loss to the body of either protein or iron, virtually all of which is conserved and reused. In contrast, the porphyrin ring structure of hemoglobin, to which iron was attached, undergoes a chemical change that enables its excretion from the body. This reaction converts porphyrin, a red pigment, into bilirubin, a yellow pigment. Bilirubin released from reticuloendothelial cells after the destruction of erythrocytes is conveyed through the plasma to the liver, where it undergoes further changes that prepare it for secretion into the bile. The amount of bilirubin produced and secreted into the bile is determined by the amount of hemoglobin destroyed. When the rate of red cell destruction exceeds the capacity of the liver to handle bilirubin, the yellow pigment accumulates in the blood, causing jaundice. Jaundice can also occur if the liver is diseased (e.g., hepatitis) or if the egress of bile is blocked (e.g., by a gallstone).
White blood cells (leukocytes)
White blood cells (leukocytes), unlike red cells, are nucleated and independently motile. Highly differentiated for their specialized functions, they do not undergo cell division (mitosis) in the bloodstream, but some retain the capability of mitosis. As a group they are involved in the body’s defense mechanisms and reparative activity. The number of white cells in normal blood ranges between 4,500 and 11,000 per cubic millimetre. Fluctuations occur during the day; lower values are obtained during rest and higher values during exercise. Intense physical exertion may cause the count to exceed 20,000 per cubic millimetre. Most of the white cells are outside the circulation, and the few in the bloodstream are in transit from one site to another. As living cells, their survival depends on their continuous production of energy. The chemical pathways utilized are more complex than those of the red cells and are similar to those of other tissue cells. White cells, containing a nucleus and able to produce ribonucleic acid (RNA), can synthesize protein. They comprise three classes of cells, each unique as to structure and function, that are designated granulocytes, monocytes, and lymphocytes.
Granulocytes, the most numerous of the white cells, are larger than red cells (approximately 12–15 μm in diameter). They have a multilobed nucleus and contain large numbers of cytoplasmic granules (i.e., granules in the cell substance outside the nucleus). Granulocytes are important mediators of the inflammatory response. There are three types of granulocytes: neutrophils, eosinophils, and basophils. Each type of granulocyte is identified by the colour of the granules when the cells are stained with a compound dye. The granules of the neutrophil are pink, those of the eosinophil are red, and those of the basophil are blue-black. About 50 to 80 percent of the white cells are neutrophils, while the eosinophils and basophils together constitute no more than 3 percent.
The neutrophils are fairly uniform in size with a diameter between 12 and 15 μm. The nucleus consists of two to five lobes joined together by hairlike filaments. Neutrophils move with amoeboid motion. They extend long projections called pseudopodium into which their granules flow; this action is followed by contraction of filaments based in the cytoplasm, which draws the nucleus and rear of the cell forward. In this way neutrophils rapidly advance along a surface. The bone marrow of a normal adult produces about 100 billion neutrophils daily. It takes about one week to form a mature neutrophil from a precursor cell in the marrow; yet, once in the blood, the mature cells live only a few hours or perhaps a little longer after migrating to the tissues. To guard against rapid depletion of the short-lived neutrophils (for example, during infection), the bone marrow holds a large number of them in reserve to be mobilized in response to inflammation or infection. Within the body, the neutrophils migrate to areas of infection or tissue injury. The force of attraction that determines the direction in which neutrophils will move is known as chemotaxis and is attributed to substances liberated at sites of tissue damage. Of the 100 billion neutrophils circulating outside the bone marrow, half are in the tissues and half are in the blood vessels. Of those in the blood vessels, half are within the mainstream of rapidly circulating blood, and the other half move slowly along the inner walls of the blood vessels (marginal pool), ready to enter tissues on receiving a chemotactic signal from them.
Neutrophils are actively phagocytic; they engulf bacteria and other microorganisms and microscopic particles. The granules of the neutrophil are microscopic packets of potent enzymes capable of digesting many types of cellular materials. When a bacterium is engulfed by a neutrophil, it is encased in a vacuole lined by the invaginated membrane. The granules discharge their contents into the vacuole containing the organism. As this occurs, the granules of the neutrophil are depleted (degranulation). A metabolic process within the granules produces hydrogen peroxide and a highly active form of oxygen (superoxide), which destroy the ingested bacteria. Final digestion of the invading organism is accomplished by enzymes.
Eosinophils, like other granulocytes, are produced in the bone marrow until they are released into the circulation. Although about the same size as neutrophils, the eosinophil contains larger granules, and the chromatin is generally concentrated in only two nonsegmented lobes. Eosinophils leave the circulation within hours of release from the marrow and migrate into the tissues (usually those of the skin, lung, and respiratory tract) through the lymphatic channels. Like neutrophils, eosinophils respond to chemotactic signals released at the site of cell destruction. They are actively motile and phagocytic. Eosinophils are involved in defense against parasites, and they participate in hypersensitivity and inflammatory reactions, primarily by dampening their destructive effects.
Basophils are the least numerous of the granulocytes, and their large granules almost completely obscure the underlying double-lobed nucleus. Within hours of their release from the bone marrow, basophils migrate from the circulation to the barrier tissues (e.g., the skin and mucosa), where they synthesize and store histamine, a natural modulator of the inflammatory response. When aggravated, basophils release, along with histamine and other substances, leukotrienes, which cause bronchoconstriction during anaphylaxis (a hypersensitivity reaction). Basophils incite immediate hypersensitivity reactions in association with platelets, macrophages, and neutrophils.
Monocytes are the largest cells of the blood (averaging 15–18 μm in diameter), and they make up about 7 percent of the leukocytes. The nucleus is relatively big and tends to be indented or folded rather than multilobed. The cytoplasm contains large numbers of fine granules, which often appear to be more numerous near the cell membrane. Monocytes are actively motile and phagocytic. They are capable of ingesting infectious agents as well as red cells and other large particles, but they cannot replace the function of the neutrophils in the removal and destruction of bacteria. Monocytes usually enter areas of inflamed tissue later than the granulocytes. Often they are found at sites of chronic infections.
In the bone marrow, granulocytes and monocytes arise from a common precursor under the influence of the granulocyte-macrophage colony-stimulating factor. Monocytes leave the bone marrow and circulate in the blood. After a period of hours, the monocytes enter the tissues, where they develop into macrophages, the tissue phagocytes that constitute the reticuloendothelial system (or macrophage system). Macrophages occur in almost all tissues of the body. Those in the liver are called Kupffer cells, those in the skin Langerhans cells. Apart from their role as scavengers, macrophages play a key role in immunity by ingesting antigens and processing them so that they can be recognized as foreign substances by lymphocytes.
Lymphocytes constitute about 28–42 percent of the white cells of the blood, and they are part of the immune response to foreign substances in the body. Most lymphocytes are small, only slightly larger than erythrocytes, with a nucleus that occupies most of the cell. Some are larger and have more abundant cytoplasm that contains a few granules. Lymphocytes are sluggishly motile, and their paths of migration outside of the bloodstream are different from those of granulocytes and monocytes. Lymphocytes are found in large numbers in the lymph nodes, spleen, thymus, tonsils, and lymphoid tissue of the gastrointestinal tract. They enter the circulation through lymphatic channels that drain principally into the thoracic lymph duct, which has a connection with the venous system. Unlike other blood cells, some lymphocytes may leave and reenter the circulation, surviving for about one year or more. The principal paths of recirculating lymphocytes are through the spleen or lymph nodes. Lymphocytes freely leave the blood to enter lymphoid tissue, passing barriers that prevent the passage of other blood cells. When stimulated by antigen and certain other agents, some lymphocytes are activated and become capable of cell division (mitosis).
The lymphocytes regulate or participate in the acquired immunity to foreign cells and antigens. They are responsible for immunologic reactions to invading organisms, foreign cells such as those of a transplanted organ, and foreign proteins and other antigens not necessarily derived from living cells. The two classes of lymphocytes are not distinguished by the usual microscopic examination but rather by the type of immune response they elicit. The B lymphocytes (or B cells) are involved in what is called humoral immunity. Upon encountering a foreign substance (or antigen), the B lymphocyte differentiates into a plasma cell, which secretes immunoglobulin (antibodies). The second class of lymphocytes, the T lymphocytes (or T cells), are involved in regulating the antibody-forming function of B lymphocytes as well as in directly attacking foreign antigens. T lymphocytes participate in what is called the cell-mediated immune response. T lymphocytes also participate in the rejection of transplanted tissues and in certain types of allergic reactions.
All lymphocytes begin their development in the bone marrow. The B lymphocytes mature partly in the bone marrow until they are released into the circulation. Further differentiation of B lymphocytes occurs in lymphoid tissues (spleen or lymph nodes), most notably on stimulation by a foreign antigen. The precursors of the T lymphocytes migrate from the marrow to the thymus, where they differentiate under the influence of a hormonelike substance. (The thymus is a small organ lying just behind the breastbone in the upper portion of the chest. It is relatively large at birth, begins to regress after puberty, and may be represented only by a fibrous cord in the elderly. The thymus begins to exert its effects on the differentiation of lymphocytes before birth. The removal of the thymus from certain animals at birth prevents the normal development of immunologic responses.) Once they have matured, the T lymphocytes leave the thymus and circulate through the blood to the lymph nodes and the spleen. The two classes of lymphocytes originally derived their names from investigations in birds, in which it was found that differentiation of one class of lymphocyte was influenced by the bursa of Fabricius (an outpouching of the gastrointestinal tract) and thus was called the B lymphocytes, and the other was influenced by the thymus and was called the T lymphocytes.
A primary function of lymphocytes is to protect the body from foreign microbes. This essential task is carried out by both T lymphocytes and B lymphocytes, which often act in concert. The T lymphocytes can recognize and respond only to antigens that appear on cell membranes in association with other molecules called major histocompatibility complex (MHC) antigens. The latter are glycoproteins that present the antigen in a form that can be recognized by T lymphocytes. In effect, T lymphocytes are responsible for continuous surveillance of cell surfaces for the presence of foreign antigens. By contrast, the antibodies produced by B lymphocytes are not confined to recognizing antigens on cell membranes; they can bind to soluble antigens in the blood or in extravascular fluids. T lymphocytes typically recognize antigens of infectious organisms that must penetrate cells in order to multiply, such as viruses. During their intracellular life cycle, viruses produce antigens that appear on the cell membrane. Two classes of T lymphocytes can be involved in the response to those cell-associated viral antigens: cytotoxic T lymphocytes, which destroy the cells by a lytic mechanism, and helper T lymphocytes, which assist B cells to produce antibodies against the microbial antigens. Helper T lymphocytes exert their influence on B lymphocytes through several hormonelike peptides termed interleukins (IL). Five different T lymphocyte interleukins (IL-2, IL-3, IL-4, IL-5, and IL-6) have been discovered, each with different (and sometimes overlapping) effects on B lymphocytes and other blood cells. Interleukin-1, produced by macrophages, is a peptide that stimulates T lymphocytes and that also acts on the hypothalamus in the brain to produce fever. The ability to develop an immune response (i.e., the T cell-mediated and humoral immune responses) to foreign substances is called immunologic competence (immunocompetence). Immunologic competence, which begins to develop during embryonic life, is incomplete at the time of birth but is fully established soon after birth. If an antigen is introduced into a person’s body before immunologic competence has been established, an immune response will not result upon reinfection, and that person is said to be tolerant to that antigen.
Study of immunologic competence and immune tolerance has been accelerated by interest in organ transplantation. The success rates of organ transplantations have been improved by better knowledge about donor selection and improved techniques for suppressing the immune responses of the recipient. An important element in donor selection is tissue typing: the matching of the donor’s histocompatibility antigens (human leukocyte antigens) with those of the prospective recipient. The closer the match, the greater the probability that the graft will be accepted.