I. Leukocytes, Granulocytes, the Monocyte-Macrophage System, and Inflammation
Our bodies are exposed continually to bacteria, viruses, fungi, and parasites, all of which occur normally and to varying degrees in the skin, the mouth, the respiratory passageways, the intestinal tract, the lining membranes of the eyes, and even the urinary tract. Many of these infectious agents are capable of causing serious abnormal physiologic function or even death if they invade the deeper tissues. In addition, we are exposed intermittently to other highly infectious bacteria and viruses besides those that are normally present, and these can cause acute lethal diseases such as pneumonia, streptococcal infection, and typhoid fever.
Our bodies have a special system for combating the different infectious and toxic agents. This system is composed of blood leukocytes (white blood cells) and tissue cells derived from leukocytes. These cells work together in two ways to prevent disease: (1) by actually destroying invading bacteria or viruses by phagocytosis and (2) by forming antibodies and sensitized lymphocytes, which may destroy or inactivate the invader. This chapter is concerned with the first of these methods, and Chapter 34 with the second.
Leukocytes (White Blood Cells)
The leukocytes, also called white blood cells, are the mobile units of the body’s protective system. They are formed partially in the bone marrow (granulocytes and monocytes and a few lymphocytes) and partially in the lymph tissue (lymphocytes and plasma cells). After formation, they are transported in the blood to different parts of the body where they are needed.
The real value of the white blood cells is that most of them are specifically transported to areas of serious infection and inflammation, thereby providing a rapid and potent defense against infectious agents. As we see later, the granulocytes and monocytes have a special ability to “seek out and destroy” a foreign invader.
General Characteristics of Leukocytes
Types of White Blood Cells
Six types of white blood cells are normally present in the blood. They are polymorphonuclear neutrophils, polymorphonuclear eosinophils, polymorphonuclear basophils, monocytes, lymphocytes, and, occasionally, plasma cells. In addition, there are large numbers of platelets, which are fragments of another type of cell similar to the white blood cells found in the bone marrow, the megakaryocyte. The first three types of cells, the polymorphonuclear cells, all have a granular appearance, as shown in cell numbers 7, 10, and 12 in Figure 33-1, and for this reason are called granulocytes, or, in clinical terminology, “polys,” because of the multiple nuclei.
Figure 33-1 Genesis of white blood cells. The different cells of the myelocyte series are 1, myeloblast; 2, promyelocyte; 3, megakaryocyte; 4, neutrophil myelocyte; 5, young neutrophil metamyelocyte; 6,“band” neutrophil metamyelocyte; 7, polymorphonuclear neutrophil; 8, eosinophil myelocyte; 9, eosinophil metamyelocyte; 10, polymorphonuclear eosinophil; 11, basophil myelocyte; 12, polymorphonuclear basophil; 13-16, stages of monocyte formation.
The granulocytes and monocytes protect the body against invading organisms mainly by ingesting them (i.e., by phagocytosis). The lymphocytes and plasma cells function mainly in connection with the immune system; this is discussed in Chapter 34. Finally, the function of platelets is specifically to activate the blood clotting mechanism, which is discussed in Chapter 36.
Concentrations of the Different White Blood Cells in the Blood
The adult human being has about 7000 white blood cells per microliter of blood (in comparison with 5 million red blood cells). Of the total white blood cells, the normal percentages of the different types are approximately the following:
The number of platelets, which are only cell fragments, in each microliter of blood is normally about 300,000.
Genesis of the White Blood Cells
Early differentiation of the pluripotential hematopoietic stem cell into the different types of committed stem cells is shown in Figure 32-2 in the previous chapter. Aside from those cells committed to form red blood cells, two major lineages of white blood cells are formed, the myelocytic and the lymphocytic lineages. The left side of Figure 33-1 shows the myelocytic lineage, beginning with the myeloblast; the right shows the lymphocytic lineage, beginning with the lymphoblast.
Figure 33-2 Movement of neutrophils by diapedesis through capillary pores and by chemotaxis toward an area of tissue damage.
The granulocytes and monocytes are formed only in the bone marrow. Lymphocytes and plasma cells are produced mainly in the various lymphogenous tissues—especially the lymph glands, spleen, thymus, tonsils, and various pockets of lymphoid tissue elsewhere in the body, such as in the bone marrow and in so-called Peyer’s patches underneath the epithelium in the gut wall.
The white blood cells formed in the bone marrow are stored within the marrow until they are needed in the circulatory system. Then, when the need arises, various factors cause them to be released (these factors are discussed later). Normally, about three times as many white blood cells are stored in the marrow as circulate in the entire blood. This represents about a 6-day supply of these cells.
The lymphocytes are mostly stored in the various lymphoid tissues, except for a small number that are temporarily being transported in the blood.
As shown in Figure 33-1, megakaryocytes (cell 3) are also formed in the bone marrow. These megakaryocytes fragment in the bone marrow; the small fragments, known as platelets (or thrombocytes), then pass into the blood. They are very important in the initiation of blood clotting.
Life Span of the White Blood Cells
The life of the granulocytes after being released from the bone marrow is normally 4 to 8 hours circulating in the blood and another 4 to 5 days in tissues where they are needed. In times of serious tissue infection, this total life span is often shortened to only a few hours because the granulocytes proceed even more rapidly to the infected area, perform their functions, and, in the process, are themselves destroyed.
The monocytes also have a short transit time, 10 to 20 hours in the blood, before wandering through the capillary membranes into the tissues. Once in the tissues, they swell to much larger sizes to become tissue macrophages, and, in this form, can live for months unless destroyed while performing phagocytic functions. These tissue macrophages are the basis of the tissue macrophage system, discussed in greater detail later, which provides continuing defense against infection.
Lymphocytes enter the circulatory system continually, along with drainage of lymph from the lymph nodes and other lymphoid tissue. After a few hours, they pass out of the blood back into the tissues by diapedesis. Then they re-enter the lymph and return to the blood again and again; thus, there is continual circulation of lymphocytes through the body. The lymphocytes have life spans of weeks or months, depending on the body’s need for these cells.
The platelets in the blood are replaced about once every 10 days; in other words, about 30,000 platelets are formed each day for each microliter of blood.
Neutrophils and Macrophages Defend Against Infections
It is mainly the neutrophils and tissue macrophages that attack and destroy invading bacteria, viruses, and other injurious agents. The neutrophils are mature cells that can attack and destroy bacteria even in the circulating blood. Conversely, the tissue macrophages begin life as blood monocytes, which are immature cells while still in the blood and have little ability to fight infectious agents at that time. However, once they enter the tissues, they begin to swell—sometimes increasing their diameters as much as fivefold—to as great as 60 to 80 micrometers, a size that can barely be seen with the naked eye. These cells are now called macrophages, and they are extremely capable of combating disease agents in the tissues.
White Blood Cells Enter the Tissue Spaces by Diapedesis
Neutrophils and monocytes can squeeze through the pores of the blood capillaries by diapedesis. That is, even though a pore is much smaller than a cell, a small portion of the cell slides through the pore at a time; the portion sliding through is momentarily constricted to the size of the pore, as shown in Figure 33-2 and 33-6.
Figure 33-6 Migration of neutrophil from the blood into inflamed tissue. Cytokines and other biochemical products of the inflamed tissue cause increased expression of selectins and intracellular adhesion molecule-1 (ICAM-1) in the surface of endothelial cells. These adhesion molecules bind to complementary molecules/receptors on the neutrophil, causing it to adhere to the wall of the capillary or venule. The neutrophil then migrates through the vessel wall by diapedesis toward the site of tissue injury.
White Blood Cells Move Through Tissue Spaces by Ameboid Motion
Both neutrophils and macrophages can move through the tissues by ameboid motion, described in Chapter 2. Some cells move at velocities as great as 40 μm/min, a distance as great as their own length each minute.
White Blood Cells Are Attracted to Inflamed Tissue Areas by Chemotaxis
Many different chemical substances in the tissues cause both neutrophils and macrophages to move toward the source of the chemical. This phenomenon, shown in Figure 33-2, is known as chemotaxis. When a tissue becomes inflamed, at least a dozen different products that can cause chemotaxis toward the inflamed area are formed. They include (1) some of the bacterial or viral toxins, (2) degenerative products of the inflamed tissues themselves, (3) several reaction products of the “complement complex” (discussed in Chapter 34) activated in inflamed tissues, and (4) several reaction products caused by plasma clotting in the inflamed area, as well as other substances.
As shown in Figure 33-2, chemotaxis depends on the concentration gradient of the chemotactic substance. The concentration is greatest near the source, which directs the unidirectional movement of the white cells. Chemotaxis is effective up to 100 micrometers away from an inflamed tissue. Therefore, because almost no tissue area is more than 50 micrometers away from a capillary, the chemotactic signal can easily move hordes of white cells from the capillaries into the inflamed area.
The most important function of the neutrophils and macrophages is phagocytosis, which means cellular ingestion of the offending agent. Phagocytes must be selective of the material that is phagocytized; otherwise, normal cells and structures of the body might be ingested. Whether phagocytosis will occur depends especially on three selective procedures.
First, most natural structures in the tissues have smooth surfaces, which resist phagocytosis. But if the surface is rough, the likelihood of phagocytosis is increased.
Second, most natural substances of the body have protective protein coats that repel the phagocytes. Conversely, most dead tissues and foreign particles have no protective coats, which makes them subject to phagocytosis.
Third, the immune system of the body (described in detail in Chapter 34) develops antibodies against infectious agents such as bacteria. The antibodies then adhere to the bacterial membranes and thereby make the bacteria especially susceptible to phagocytosis. To do this, the antibody molecule also combines with the C3 product of the complement cascade, which is an additional part of the immune system discussed in the next chapter. The C3 molecules, in turn, attach to receptors on the phagocyte membrane, thus initiating phagocytosis. This selection and phagocytosis process is called opsonization.
Phagocytosis by Neutrophils
The neutrophils entering the tissues are already mature cells that can immediately begin phagocytosis. On approaching a particle to be phagocytized, the neutrophil first attaches itself to the particle and then projects pseudopodia in all directions around the particle. The pseudopodia meet one another on the opposite side and fuse. This creates an enclosed chamber that contains the phagocytized particle. Then the chamber invaginates to the inside of the cytoplasmic cavity and breaks away from the outer cell membrane to form a free-floating phagocytic vesicle (also called a phagosome) inside the cytoplasm. A single neutrophil can usually phagocytize 3 to 20 bacteria before the neutrophil itself becomes inactivated and dies.
Phagocytosis by Macrophages
Macrophages are the end-stage product of monocytes that enter the tissues from the blood. When activated by the immune system, as described in Chapter 34, they are much more powerful phagocytes than neutrophils, often capable of phagocytizing as many as 100 bacteria. They also have the ability to engulf much larger particles, even whole red blood cells or, occasionally, malarial parasites, whereas neutrophils are not capable of phagocytizing particles much larger than bacteria. Also, after digesting particles, macrophages can extrude the residual products and often survive and function for many more months.
Once Phagocytized, Most Particles Are Digested by Intracellular Enzymes
Once a foreign particle has been phagocytized, lysosomes and other cytoplasmic granules in the neutrophil or macrophage immediately come in contact with the phagocytic vesicle, and their membranes fuse, thereby dumping many digestive enzymes and bactericidal agents into the vesicle. Thus, the phagocytic vesicle now becomes a digestive vesicle, and digestion of the phagocytized particle begins immediately.
Both neutrophils and macrophages contain an abundance of lysosomes filled with proteolytic enzymes especially geared for digesting bacteria and other foreign protein matter. The lysosomes of macrophages (but not of neutrophils) also contain large amounts of lipases, which digest the thick lipid membranes possessed by some bacteria such as the tuberculosis bacillus.
Both Neutrophils and Macrophages Can Kill Bacteria
In addition to the digestion of ingested bacteria in phagosomes, neutrophils and macrophages contain bactericidal agents that kill most bacteria even when the lysosomal enzymes fail to digest them. This is especially important because some bacteria have protective coats or other factors that prevent their destruction by digestive enzymes. Much of the killing effect results from several powerful oxidizing agentsformed by enzymes in the membrane of the phagosome or by a special organelle called the peroxisome. These oxidizing agents include large quantities of superoxide (O2−), hydrogen peroxide (H2O2), and hydroxyl ions (OH−), all of which are lethal to most bacteria, even in small quantities. Also, one of the lysosomal enzymes, myeloperoxidase, catalyzes the reaction between H2O2 and chloride ions to form hypochlorite, which is exceedingly bactericidal.
Some bacteria, notably the tuberculosis bacillus, have coats that are resistant to lysosomal digestion and also secrete substances that partially resist the killing effects of the neutrophils and macrophages. These bacteria are responsible for many of the chronic diseases, an example of which is tuberculosis.
Monocyte-Macrophage Cell System (Reticuloendothelial System)
In the preceding paragraphs, we described the macrophages mainly as mobile cells that are capable of wandering through the tissues. However, after entering the tissues and becoming macrophages, another large portion of monocytes becomes attached to the tissues and remains attached for months or even years until they are called on to perform specific local protective functions. They have the same capabilities as the mobile macrophages to phagocytize large quantities of bacteria, viruses, necrotic tissue, or other foreign particles in the tissue. And, when appropriately stimulated, they can break away from their attachments and once again become mobile macrophages that respond to chemotaxis and all the other stimuli related to the inflammatory process. Thus, the body has a widespread “monocyte-macrophage system” in virtually all tissue areas.
The total combination of monocytes, mobile macrophages, fixed tissue macrophages, and a few specialized endothelial cells in the bone marrow, spleen, and lymph nodes is called the reticuloendothelial system. However, all or almost all these cells originate from monocytic stem cells; therefore, the reticuloendothelial system is almost synonymous with the monocyte-macrophage system. Because the term reticuloendothelial system is much better known in medical literature than the term monocyte-macrophage system, it should be remembered as a generalized phagocytic system located in all tissues, especially in those tissue areas where large quantities of particles, toxins, and other unwanted substances must be destroyed.
Tissue Macrophages in the Skin and Subcutaneous Tissues (Histiocytes)
Although the skin is mainly impregnable to infectious agents, this is no longer true when the skin is broken. When infection begins in a subcutaneous tissue and local inflammation ensues, local tissue macrophages can divide in situ and form still more macrophages. Then they perform the usual functions of attacking and destroying the infectious agents, as described earlier.
Macrophages in the Lymph Nodes
Essentially no particulate matter that enters the tissues, such as bacteria, can be absorbed directly through the capillary membranes into the blood. Instead, if the particles are not destroyed locally in the tissues, they enter the lymph and flow to the lymph nodes located intermittently along the course of the lymph flow. The foreign particles are then trapped in these nodes in a meshwork of sinuses lined by tissue macrophages.
Figure 33-3 illustrates the general organization of the lymph node, showing lymph entering through the lymph node capsule by way of afferent lymphatics, then flowing through the nodal medullary sinuses,and finally passing out the hilus into efferent lymphatics that eventually empty into the venous blood.
Figure 33-3 Functional diagram of a lymph node.
(Redrawn from Ham AW: Histology, 6th ed. Philadelphia: JB Lippincott, 1969.) (Modified from Gartner LP, Hiatt JL: Color Textbook of Histology, 2nd ed. Philadelphia: WB Saunders, 2001.)
Large numbers of macrophages line the lymph sinuses, and if any particles enter the sinuses by way of the lymph, the macrophages phagocytize them and prevent general dissemination throughout the body.
Alveolar Macrophages in the Lungs
Another route by which invading organisms frequently enter the body is through the lungs. Large numbers of tissue macrophages are present as integral components of the alveolar walls. They can phagocytize particles that become entrapped in the alveoli. If the particles are digestible, the macrophages can also digest them and release the digestive products into the lymph. If the particle is not digestible, the macrophages often form a “giant cell” capsule around the particle until such time—if ever—that it can be slowly dissolved. Such capsules are frequently formed around tuberculosis bacilli, silica dust particles, and even carbon particles.
Macrophages (Kupffer Cells) in the Liver Sinusoids
Still another route by which bacteria invade the body is through the gastrointestinal tract. Large numbers of bacteria from ingested food constantly pass through the gastrointestinal mucosa into the portal blood. Before this blood enters the general circulation, it passes through the liver sinusoids, which are lined with tissue macrophages called Kupffer cells, shown in Figure 33-4. These cells form such an effective particulate filtration system that almost none of the bacteria from the gastrointestinal tract passes from the portal blood into the general systemic circulation. Indeed, motion pictures of phagocytosis by Kupffer cells have demonstrated phagocytosis of a single bacterium in less than of a second.
Figure 33-4 Kupffer cells lining the liver sinusoids, showing phagocytosis of India ink particles into the cytoplasm of the Kupffer cells.
(Redrawn from Copenhaver WM et al: Bailey’s Textbook of Histology, 10th ed. Baltimore: Williams & Wilkins, 1971.)
Macrophages of the Spleen and Bone Marrow
If an invading organism succeeds in entering the general circulation, there are other lines of defense by the tissue macrophage system, especially by macrophages of the spleen and bone marrow. In both these tissues, macrophages become entrapped by the reticular meshwork of the two organs and when foreign particles come in contact with these macrophages, they are phagocytized.
The spleen is similar to the lymph nodes, except that blood, instead of lymph, flows through the tissue spaces of the spleen. Figure 33-5 shows a small peripheral segment of spleen tissue. Note that a small artery penetrates from the splenic capsule into the splenic pulp and terminates in small capillaries. The capillaries are highly porous, allowing whole blood to pass out of the capillaries into cords of red pulp.The blood then gradually squeezes through the trabecular meshwork of these cords and eventually returns to the circulation through the endothelial walls of the venous sinuses. The trabeculae of the red pulp are lined with vast numbers of macrophages, and the venous sinuses are also lined with macrophages. This peculiar passage of blood through the cords of the red pulp provides an exceptional means of phagocytizing unwanted debris in the blood, including especially old and abnormal red blood cells.
Figure 33-5 Functional structures of the spleen.
(Modified from Bloom W, Fawcett DW: A Textbook of Histology, 10th ed. Philadelphia: WB Saunders, 1975.)
Inflammation: Role of Neutrophils and Macrophages
When tissue injury occurs, whether caused by bacteria, trauma, chemicals, heat, or any other phenomenon, multiple substances are released by the injured tissues and cause dramatic secondary changes in the surrounding uninjured tissues. This entire complex of tissue changes is called inflammation.
Inflammation is characterized by (1) vasodilation of the local blood vessels, with consequent excess local blood flow; (2) increased permeability of the capillaries, allowing leakage of large quantities of fluid into the interstitial spaces; (3) often clotting of the fluid in the interstitial spaces because of increased amounts of fibrinogen and other proteins leaking from the capillaries; (4) migration of large numbers of granulocytes and monocytes into the tissue; and (5) swelling of the tissue cells. Some of the many tissue products that cause these reactions are histamine, bradykinin, serotonin, prostaglandins, several different reaction products of the complement system (described in Chapter 34), reaction products of the blood clotting system, and multiple substances called lymphokines that are released by sensitized T cells (part of the immune system; also discussed in Chapter 34). Several of these substances strongly activate the macrophage system, and within a few hours, the macrophages begin to devour the destroyed tissues. But at times, the macrophages also further injure the still-living tissue cells.
“Walling-Off” Effect of Inflammation
One of the first results of inflammation is to “wall off” the area of injury from the remaining tissues. The tissue spaces and the lymphatics in the inflamed area are blocked by fibrinogen clots so that after a while, fluid barely flows through the spaces. This walling-off process delays the spread of bacteria or toxic products.
The intensity of the inflammatory process is usually proportional to the degree of tissue injury. For instance, when staphylococci invade tissues, they release extremely lethal cellular toxins. As a result, inflammation develops rapidly—indeed, much more rapidly than the staphylococci themselves can multiply and spread. Therefore, local staphylococcal infection is characteristically walled off rapidly and prevented from spreading through the body. Streptococci, in contrast, do not cause such intense local tissue destruction. Therefore, the walling-off process develops slowly over many hours, while many streptococci reproduce and migrate. As a result, streptococci often have a far greater tendency to spread through the body and cause death than do staphylococci, even though staphylococci are far more destructive to the tissues.
Macrophage and Neutrophil Responses During Inflammation
Tissue Macrophage Is a First Line of Defense Against Infection
Within minutes after inflammation begins, the macrophages already present in the tissues, whether histiocytes in the subcutaneous tissues, alveolar macrophages in the lungs, microglia in the brain, or others, immediately begin their phagocytic actions. When activated by the products of infection and inflammation, the first effect is rapid enlargement of each of these cells. Next, many of the previously sessile macrophages break loose from their attachments and become mobile, forming the first line of defense against infection during the first hour or so. The numbers of these early mobilized macrophages often are not great, but they are lifesaving.
Neutrophil Invasion of the Inflamed Area Is a Second Line of Defense
Within the first hour or so after inflammation begins, large numbers of neutrophils begin to invade the inflamed area from the blood. This is caused by inflammatory cytokines (e.g., TNF, IL-1) and other biochemical products produced by the inflamed tissues that initiate the following reactions:
1. They cause increased expression of adhesion molecules, such as selectins and intracellular adhesion molecule-1 (ICAM-1) on the surface of endothelial cells in the capillaries and venules. These adhesion molecules, reacting with complementary integrin molecules on the neutrophils, cause the neutrophils to stick to the capillary and venule walls in the inflamed area. This effect is called margination and is shown in Figure 33-2 and in more detail in Figure 33-6.
2. They also cause the intercellular attachments between the endothelial cells of the capillaries and small venules to loosen, allowing openings large enough for neutrophils to crawl through by diapedesis,directly from the blood into the tissue spaces.
3. They then cause chemotaxis of the neutrophils toward the injured tissues, as explained earlier.
Thus, within several hours after tissue damage begins, the area becomes well supplied with neutrophils. Because the blood neutrophils are already mature cells, they are ready to immediately begin their scavenger functions for killing bacteria and removing foreign matter.
Acute Increase in Number of Neutrophils in the Blood—“Neutrophilia.”
Also within a few hours after the onset of acute, severe inflammation, the number of neutrophils in the blood sometimes increases fourfold to fivefold—from a normal of 4000 to 5000 to 15,000 to 25,000 neutrophils per microliter. This is called neutrophilia, which means an increase in the number of neutrophils in the blood. Neutrophilia is caused by products of inflammation that enter the blood stream, are transported to the bone marrow, and there act on the stored neutrophils of the marrow to mobilize these into the circulating blood. This makes even more neutrophils available to the inflamed tissue area.
Second Macrophage Invasion into the Inflamed Tissue Is a Third Line of Defense
Along with the invasion of neutrophils, monocytes from the blood enter the inflamed tissue and enlarge to become macrophages. However, the number of monocytes in the circulating blood is low: Also, the storage pool of monocytes in the bone marrow is much less than that of neutrophils. Therefore, the buildup of macrophages in the inflamed tissue area is much slower than that of neutrophils, requiring several days to become effective. Furthermore, even after invading the inflamed tissue, monocytes are still immature cells, requiring 8 hours or more to swell to much larger sizes and develop tremendous quantities of lysosomes; only then do they acquire the full capacity of tissue macrophages for phagocytosis. Yet, after several days to several weeks, the macrophages finally come to dominate the phagocytic cells of the inflamed area because of greatly increased bone marrow production of new monocytes, as explained later.
As already pointed out, macrophages can phagocytize far more bacteria (about five times as many) and far larger particles, including even neutrophils themselves and large quantities of necrotic tissue, than can neutrophils. Also, the macrophages play an important role in initiating the development of antibodies, as we discuss in Chapter 34.
Increased Production of Granulocytes and Monocytes by the Bone Marrow Is a Fourth Line of Defense
The fourth line of defense is greatly increased production of both granulocytes and monocytes by the bone marrow. This results from stimulation of the granulocytic and monocytic progenitor cells of the marrow. However, it takes 3 to 4 days before newly formed granulocytes and monocytes reach the stage of leaving the bone marrow. If the stimulus from the inflamed tissue continues, the bone marrow can continue to produce these cells in tremendous quantities for months and even years, sometimes at a rate 20 to 50 times normal.
Feedback Control of the Macrophage and Neutrophil Responses
Although more than two dozen factors have been implicated in control of the macrophage response to inflammation, five of these are believed to play dominant roles. They are shown in Figure 33-7 and consist of (1) tumor necrosis factor (TNF), (2) interleukin-1 (IL-1), (3) granulocyte-monocyte colony-stimulating factor (GM-CSF), (4) granulocyte colony-stimulating factor (G-CSF), and (5) monocyte colony-stimulating factor (M-CSF). These factors are formed by activated macrophage cells in the inflamed tissues and in smaller quantities by other inflamed tissue cells.
Figure 33-7 Control of bone marrow production of granulocytes and monocyte-macrophages in response to multiple growth factors released from activated macrophages in an inflamed tissue. G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-monocyte colony-stimulating factor; IL-1, interleukin-1; M-CSF, monocyte colony-stimulating factor; TNF, tumor necrosis factor.
The cause of the increased production of granulocytes and monocytes by the bone marrow is mainly the three colony-stimulating factors, one of which, GM-CSF, stimulates both granulocyte and monocyte production; the other two, G-CSF and M-CSF, stimulate granulocyte and monocyte production, respectively. This combination of TNF, IL-1, and colony-stimulating factors provides a powerful feedback mechanism that begins with tissue inflammation and proceeds to formation of large numbers of defensive white blood cells that help remove the cause of the inflammation.
Formation of Pus
When neutrophils and macrophages engulf large numbers of bacteria and necrotic tissue, essentially all the neutrophils and many, if not most, of the macrophages eventually die. After several days, a cavity is often excavated in the inflamed tissues. It contains varying portions of necrotic tissue, dead neutrophils, dead macrophages, and tissue fluid. This mixture is commonly known as pus. After the infection has been suppressed, the dead cells and necrotic tissue in the pus gradually autolyze over a period of days, and the end products are eventually absorbed into the surrounding tissues and lymph until most of the evidence of tissue damage is gone.
The eosinophils normally constitute about 2 percent of all the blood leukocytes. Eosinophils are weak phagocytes, and they exhibit chemotaxis, but in comparison with the neutrophils, it is doubtful that the eosinophils are significant in protecting against the usual types of infection.
Eosinophils, however, are often produced in large numbers in people with parasitic infections, and they migrate in large numbers into tissues diseased by parasites. Although most parasites are too large to be phagocytized by eosinophils or any other phagocytic cells, eosinophils attach themselves to the parasites by way of special surface molecules and release substances that kill many of the parasites. For instance, one of the most widespread infections is schistosomiasis, a parasitic infection found in as many as one third of the population of some developing countries in Asia, Africa, and South America; the parasite can invade any part of the body. Eosinophils attach themselves to the juvenile forms of the parasite and kill many of them. They do so in several ways: (1) by releasing hydrolytic enzymes from their granules, which are modified lysosomes; (2) probably by also releasing highly reactive forms of oxygen that are especially lethal to parasites; and (3) by releasing from the granules a highly larvacidal polypeptide called major basic protein.
In a few areas of the world, another parasitic disease that causes eosinophilia is trichinosis. This results from invasion of the body’s muscles by the Trichinella parasite (“pork worm”) after a person eats undercooked infested pork.
Eosinophils also have a special propensity to collect in tissues in which allergic reactions occur, such as in the peribronchial tissues of the lungs in people with asthma and in the skin after allergic skin reactions. This is caused at least partly by the fact that many mast cells and basophils participate in allergic reactions, as we discuss in the next paragraph. The mast cells and basophils release an eosinophil chemotactic factor that causes eosinophils to migrate toward the inflamed allergic tissue. The eosinophils are believed to detoxify some of the inflammation-inducing substances released by the mast cells and basophils and probably also to phagocytize and destroy allergen-antibody complexes, thus preventing excess spread of the local inflammatory process.
The basophils in the circulating blood are similar to the large tissue mast cells located immediately outside many of the capillaries in the body. Both mast cells and basophils liberate heparin into the blood, a substance that can prevent blood coagulation.
The mast cells and basophils also release histamine, as well as smaller quantities of bradykinin and serotonin. Indeed, it is mainly the mast cells in inflamed tissues that release these substances during inflammation.
The mast cells and basophils play an important role in some types of allergic reactions because the type of antibody that causes allergic reactions, the immunoglobulin E (IgE) type, has a special propensity to become attached to mast cells and basophils. Then, when the specific antigen for the specific IgE antibody subsequently reacts with the antibody, the resulting attachment of antigen to antibody causes the mast cell or basophil to rupture and release large quantities of histamine, bradykinin, serotonin, heparin, slow-reacting substance of anaphylaxis, and a number of lysosomal enzymes. These cause local vascular and tissue reactions that cause many, if not most, of the allergic manifestations. These reactions are discussed in greater detail in Chapter 34.
A clinical condition known as leukopenia, in which the bone marrow produces very few white blood cells, occasionally occurs. This leaves the body unprotected against many bacteria and other agents that might invade the tissues.
Normally, the human body lives in symbiosis with many bacteria because all the mucous membranes of the body are constantly exposed to large numbers of bacteria. The mouth almost always contains various spirochetal, pneumococcal, and streptococcal bacteria, and these same bacteria are present to a lesser extent in the entire respiratory tract. The distal gastrointestinal tract is especially loaded with colon bacilli. Furthermore, one can always find bacteria on the surfaces of the eyes, urethra, and vagina. Any decrease in the number of white blood cells immediately allows invasion of adjacent tissues by bacteria that are already present.
Within 2 days after the bone marrow stops producing white blood cells, ulcers may appear in the mouth and colon, or the person might develop some form of severe respiratory infection. Bacteria from the ulcers rapidly invade surrounding tissues and the blood. Without treatment, death often ensues in less than a week after acute total leukopenia begins.
Irradiation of the body by x-rays or gamma rays, or exposure to drugs and chemicals that contain benzene or anthracene nuclei, is likely to cause aplasia of the bone marrow. Indeed, some common drugs, such as chloramphenicol (an antibiotic), thiouracil (used to treat thyrotoxicosis), and even various barbiturate hypnotics, on very rare occasions cause leukopenia, thus setting off the entire infectious sequence of this malady.
After moderate irradiation injury to the bone marrow, some stem cells, myeloblasts, and hemocytoblasts may remain undestroyed in the marrow and are capable of regenerating the bone marrow, provided sufficient time is available. A patient properly treated with transfusions, plus antibiotics and other drugs to ward off infection, usually develops enough new bone marrow within weeks to months for blood cell concentrations to return to normal.
Uncontrolled production of white blood cells can be caused by cancerous mutation of a myelogenous or lymphogenous cell. This causes leukemia, which is usually characterized by greatly increased numbers of abnormal white blood cells in the circulating blood.
Types of Leukemia
Leukemias are divided into two general types: lymphocytic leukemias and myelogenous leukemias. The lymphocytic leukemias are caused by cancerous production of lymphoid cells, usually beginning in a lymph node or other lymphocytic tissue and spreading to other areas of the body. The second type of leukemia, myelogenous leukemia, begins by cancerous production of young myelogenous cells in the bone marrow and then spreads throughout the body so that white blood cells are produced in many extramedullary tissues—especially in the lymph nodes, spleen, and liver.
In myelogenous leukemia, the cancerous process occasionally produces partially differentiated cells, resulting in what might be called neutrophilic leukemia, eosinophilic leukemia, basophilic leukemia, or monocytic leukemia. More frequently, however, the leukemia cells are bizarre and undifferentiated and not identical to any of the normal white blood cells. Usually, the more undifferentiated the cell, the more acute is the leukemia, often leading to death within a few months if untreated. With some of the more differentiated cells, the process can be chronic, sometimes developing slowly over 10 to 20 years. Leukemic cells, especially the very undifferentiated cells, are usually nonfunctional for providing the normal protection against infection.
Effects of Leukemia on the Body
The first effect of leukemia is metastatic growth of leukemic cells in abnormal areas of the body. Leukemic cells from the bone marrow may reproduce so greatly that they invade the surrounding bone, causing pain and, eventually, a tendency for bones to fracture easily.
Almost all leukemias eventually spread to the spleen, lymph nodes, liver, and other vascular regions, regardless of whether the origin of the leukemia is in the bone marrow or the lymph nodes. Common effects in leukemia are the development of infection, severe anemia, and a bleeding tendency caused by thrombocytopenia (lack of platelets). These effects result mainly from displacement of the normal bone marrow and lymphoid cells by the nonfunctional leukemic cells.
Finally, an important effect of leukemia on the body is excessive use of metabolic substrates by the growing cancerous cells. The leukemic tissues reproduce new cells so rapidly that tremendous demands are made on the body reserves for foodstuffs, specific amino acids, and vitamins. Consequently, the energy of the patient is greatly depleted, and excessive utilization of amino acids by the leukemic cells causes especially rapid deterioration of the normal protein tissues of the body. Thus, while the leukemic tissues grow, other tissues become debilitated. After metabolic starvation has continued long enough, this alone is sufficient to cause death.
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