CHAPTER 19 : Lymphatic System and Immunity

Chapter 22:  The Lymphatic System and Immunity

An Overview of the Lymphatic System and Immunity

The lymphatic system includes the cells, tissues, and organs responsible for defending the body against both environmental hazards, such as various pathogens, and internal threats, such as cancer cells.

Lymphocytes are said to provide a specific defense , known as the immune response . The ability to resist infection and disease through the activation of specific defenses constitutes immunity .

Organization of the Lymphatic System

The lymphatic system consists of (1) lymph , a fluid that resembles plasma, but contains a much lower concentration of suspended proteins; (2) a network of lymphatic vessels , often called lymphatics , which begin in peripheral tissues and end at connections to veins; (3) an array of lymphoid tissues and lymphoid organs scattered throughout the body; and (4) lymphocytes and smaller numbers of supporting and phagocytic cells.

Functions of the Lymphatic System

Most of the body's lymphocytes are produced and stored within lymphoid tissues, such as the tonsils, and lymphoid organs, such as the spleen and thymus. However, lymphocytes are also produced in areas of red bone marrow, along with various supporting cells, such as monocytes and macrophages.

Lymphatic Vessels

Lymphatic vessels carry lymph from peripheral tissues to the venous system. The smallest lymphatic vessels are called lymphatic capillaries .

Lymphatic Capillaries. 

(a) The interwoven network formed by blood capillaries and lymphatic capillaries. Arrows show the movement of fluid out of blood vessels and the net flow of interstitial fluid and lymph. (b) A sectional view showing movement of fluid from the plasma through the interstitial fluid and into the lymphatic system.

The Relationship between the Lymphatic Ducts and the Venous System. 
(a) The thoracic duct carries lymph originating in tissues inferior to the diaphragm and from the left side of the upper body. The smaller right lymphatic duct services the rest of the body.

(b) The thoracic duct empties into the left subclavian vein. The right lymphatic duct drains into the right subclavian vein. (c) The lymphatic vessels of the trunk

Lymphedema

Blockage of the lymphatic drainage from a limb produces lymphedema, a condition in which interstitial fluids accumulate and the limb gradually becomes swollen and grossly distended. If the condition persists, the connective tissues lose their elasticity and the swelling becomes permanent.

In filariasis, larvae of a parasitic roundworm, generally Wuchereria bancrofti , are transmitted by mosquitoes or black flies. The adult worms form massive colonies within lymphatic vessels and lymph nodes. Repeated scarring of the passageways eventually blocks lymphatic drainage and produces extreme lymphedema with permanent distension of tissues. The limbs or external genitalia typically become grossly distended; this parasite–induced edema is called elephantiasis.

Lymphocytes account for 20–30 percent of the circulating white blood cell population. However, circulating lymphocytes are only a small fraction of the total lymphocyte population.. 

Types of Lymphocytes

Three classes of lymphocytes are in blood: (1) T ( t hymus–dependent) cells , (2) B ( b one marrow–derived) cells , and (3) NK ( n atural k iller) cells . Each type has distinctive biochemical and functional characteristics. 

Approximately 80 percent of circulating lymphocytes are classified as T cells. There are many types of T cells, including the following:

Cytotoxic T cells , which attack foreign cells or body cells infected by viruses. Their attack commonly involves direct contact. These lymphocytes are the primary cells involved in the production of cell–mediated immunity , or cellular immunity .

Helper T cells , which stimulate the activation and function of both T cells and B cells.

Suppressor T cells , which inhibit the activation and function of both T cells and B cells.

B cells account for 10–15 percent of circulating lymphocytes. When stimulated, B cells can differentiate into plasma cells , which are responsible for the production and secretion of antibodies –soluble proteins also known as immunoglobulins . These proteins bind to specific chemical targets called antigens

The remaining 5–10 percent of circulating lymphocytes are NK cells, also known as large granular lymphocytes . These lymphocytes attack foreign cells, normal cells infected with viruses, and cancer cells that appear in normal tissues. Their continuous policing of peripheral tissues has been called immunological surveillance .

Life Span and Circulation of Lymphocytes

.           All types of lymphocytes move throughout the body, wandering through tissues and then entering blood vessels or lymphatic vessels for transport. 

T cells move relatively quickly. For example, a wandering T cell may spend about 30 minutes in the blood, 5–6 hours in the spleen, and 15–20 hours in a lymph node. B cells, which are responsible for antibody production, move more slowly. A typical B cell spends about 30 hours in a lymph node before moving on. 

Lymphocytes have relatively long life spans. Roughly 80 percent survive for 4 years, and some last 20 years or more.

Lymphocyte Production

lymphocyte production, or lymphopoiesis, involves the bone marrow, thymus, and peripheral lymphoid tissues.

The Derivation and Distribution of Lymphocytes. 

Hemocytoblast divisions produce stem cells with two fates. (a) One group remains in the bone marrow, producing daughter cells that mature into B cells or NK cells. (b) The other group migrates to the thymus, where subsequent divisions produce daughter cells that mature into T cells. The mature B cells, NK cells, and T cells circulate throughout the body in the bloodstream and then (c) temporarily reside in peripheral tissues.

Lymphoid tissues are connective tissues dominated by lymphocytes. In a lymphoid nodule , or lymphatic nodule , the lymphocytes are densely packed in an area of areolar tissue

Lymphoid nodules occur in the connective tissue deep to the epithelia lining the respiratory, digestive, and urinary tracts.

The collection of lymphoid tissues linked with the digestive system is called the mucosa–associated lymphoid tissue (MALT) . Clusters of lymphoid nodules deep to the epithelial lining of the intestine are known as aggregated lymphoid nodules , orPeyer's patches. In addition, the walls of the appendix , or vermiform ("worm–shaped") appendix , a blind pouch that originates near the junction between the small and large intestines, contain a mass of fused lymphoid nodules.

Tonsils are large nodules in the walls of the pharynx. Most people have five tonsils. Left and right palatine tonsils are located at the posterior, inferior margin of the oral cavity, along the boundary with the pharynx. A single pharyngeal tonsil , often called the adenoids , lies in the posterior superior wall of the nasopharynx, and a pair of lingual tonsils lie deep to the mucous epithelium covering the base (pharyngeal portion) of the tongue. Because of their location, the latter are usually not visible unless they become infected and swollen.

The lymphocytes in a lymphoid nodule are not always able to destroy bacterial or viral invaders that have crossed the adjacent epithelium. If pathogens become established in a lymphoid nodule, an infection develops. Two examples are probably familiar to you: tonsillitis , an infection of one of the tonsils (generally the pharyngeal or palatine), and appendicitis , an infection of the appendix that begins in the lymphoid nodules.

Lymphoid Organs

A fibrous connective–tissue capsule separates the lymphoid organs–the lymph nodes , the thymus , and the spleen –from surrounding tissues.

Lymph nodes are small, oval lymphoid organs ranging in diameter from 1 to 25 mm (to about 1 in.). Figure 22–1 , p. 780, shows the general pattern of lymph node distribution in the body. Each lymph node is covered by a capsule of dense connective tissue

 Lymph Flow Lymph delivered by the afferent lymphatics flows through the lymph node within a network of sinuses, open passageways with incomplete walls

Lymph Node Function-  A lymph node functions like a kitchen water filter, purifying lymph before it reaches the venous circulation. As lymph flows through a lymph node, at least 99 percent of the antigens in the lymph are removed. Fixed macrophages in the walls of the lymphatic sinuses engulf debris or pathogens in lymph as it flows past. Antigens removed in this way are then processed by the macrophages and "presented" to nearby lymphocytes.

A minor injury commonly produces a slight enlargement of the nodes along the lymphatic vessels draining the region. This symptom, often called "swollen glands," typically indicates inflammation or infection of peripheral structures. The enlargement generally results from an increase in the number of lymphocytes and phagocytes in the node in response to a minor, localized infection. Chronic or excessive enlargement of lymph nodes constitutes lymphadenopathy, a condition that may occur in response to bacterial or viral infections, endocrine disorders, or cancer.

Lymphatic vessels are located in almost all portions of the body except the central nervous system, and lymphatic capillaries offer little resistance to the passage of cancer cells. As a result, metastasizing cancer cells commonly spread along lymphatic vessels. Under these circumstances, the lymph nodes serve as way stations for migrating cancer cells. Thus, an analysis of lymph nodes can provide information on the spread of the cancer cells, and such information helps determine the appropriate therapies.

The Thymus is located in the mediastinum, generally just posterior to the sternum. It is pink and has a grainy consistency. In newborn infants and young children, the thymus is relatively large, commonly extending from the base of the neck to the superior border of the heart. The thymus reaches its greatest size (relative to body size) in the first year or two after birth. Although the organ continues to increase in size throughout childhood, the body as a whole grows even faster, so the size of the thymus relative to that of the other organs in the mediastinum gradually decreases. The thymus reaches its maximum absolute size, at a weight of about 40 g (1.4 oz), just before puberty. After puberty, it gradually diminishes in size and becomes increasingly fibrous, a process called involution . By the time an individual reaches age 50, the thymus may weigh less than 12 g (0.3 oz). It has been suggested that the gradual decrease in the size and secretory abilities of the thymus may make the elderly more susceptible to disease.
The capsule that covers the thymus divides it into two thymic lobes.

Hormones of the Thymus The thymus produces several hormones that are important to the development and maintenance of normal immunological defenses. Thymosin  is the name originally given to an extract from the thymus that promotes the development and maturation of lymphocytes.

The Spleen  contains the largest collection of lymphoid tissue in the body. In essence, the spleen performs the same functions for blood that lymph nodes perform for lymph. Functions of the spleen can be summarized as (1) the removal of abnormal blood cells and other blood components by phagocytosis, (2) the storage of iron from recycled red blood cells, and (3) the initiation of immune responses by B cells and T cells in response to antigens in circulating blood. 

Anatomy of the Spleen The spleen is about 12 cm (5 in.) long and weighs, on average, nearly 160 g (5.6 oz). In gross dissection, the spleen is deep red, owing to the blood it contains. The spleen lies along the curving lateral border of the stomach, extending between the 9th and 11th ribs on the left side.

The Spleen. (a) A transverse section through the trunk, showing the typical position of the spleen within the abdominopelvic cavity. The shape of the spleen roughly conforms to the shapes of adjacent organs. (b) The external appearance of the intact spleen, showing major anatomical landmarks. Compare this view with that of part (a). (c) The histological appearance of the spleen. White pulp is dominated by lymphocytes; it appears blue because the nuclei of lymphocytes stain very darkly. Red pulp contains a preponderance of red blood cells.

The spleen has a soft consistency, so its shape primarily reflects its association with the structures around it.  The cellular components within constitute the pulp of the spleen. Red pulp contains large quantities of red blood cells, whereas white pulpresembles lymphoid nodules.

This circulatory arrangement gives the phagocytes of the spleen an opportunity to identify and engulf any damaged or infected cells in circulating blood. Lymphocytes are scattered throughout the red pulp, and the area surrounding the white pulp has a high concentration of macrophages and dendritic cells. Thus, any microorganism or other antigen in the blood will quickly come to the attention of the splenic lymphocytes.

Because the spleen is relatively fragile, it is very difficult to repair surgically. (Sutures typically tear out before they have been tensed enough to stop the bleeding.) A severely ruptured spleen is removed, a process called a splenectomy. A person without a spleen survives, but has a greater risk of bacterial infection, particularly involving pneumococcal bacteria than do individuals with a functional spleen.

The Lymphatic System and Body Defenses 
The human body has multiple defense mechanisms, which can be sorted into two general categories:

Nonspecific defenses do not distinguish one type of threat from another. Their response is the same, regardless of the type of invading agent. These defenses, which are present at birth, include physical barriers , phagocytic cells , immunological surveillance , interferons , complement , inflammation , and fever . They provide a defensive capability known as nonspecific resistance .

Specific defenses protect against particular threats. For example, a specific defense may protect against infection by one type of bacterium, but be ineffective against other bacteria and viruses. Many specific defenses develop after birth as a result of accidental or deliberate exposure to environmental hazards. Specific defenses depend on the activities of lymphocytes . The body's specific defenses produce a state of protection known as immunity, or specific resistance

22–3  Nonspecific Defenses

Nonspecific defenses prevent the approach, deny the entrance, or limit the spread of microorganisms or other environmental hazards.   Nonspecific defenses deny pathogens access to the body or destroy them without distinguishing among specific types.

 Physical barriers keep hazardous organisms and materials outside the body. For example, a mosquito that lands on your head may be unable to reach the surface of the scalp if you have a full head of hair.

Phagocytes are cells that engulf pathogens and cell debris. Examples of phagocytes are the macrophages of peripheral tissues and the microphages of blood.

Immunological surveillance is the destruction of abnormal cells by NK cells in peripheral tissues.

Interferons are chemical messengers that coordinate the defenses against viral infection.

Complement is a system of circulating proteins that assist antibodies in the destruction of pathogens.

The inflammatory response is a local response to injury or infection that is directed at the tissue level. Inflammation tends to restrict the spread of an injury as well as combat an infection.

Fever is an elevation of body temperature that accelerates tissue metabolism and defenses

Phagocytes perform janitorial and police services in peripheral tissues, removing cellular debris and responding to invasion by foreign compounds or pathogens.

Microphages are the neutrophils and eosinophils that normally circulate in the blood. These phagocytic cells leave the bloodstream and enter peripheral tissues that have been subjected to injury or infection.

Macrophages are large, actively phagocytic cells. Your body contains several types of macrophages, and most are derived from the monocytes of the circulating blood. Macrophages either are fixed permanently or move freely. Although no organs or tissues are purely phagocytic, almost every tissue in the body shelters resident or visiting macrophages. This relatively diffuse collection of phagocytic cells has been called the monocyte–macrophage system , or the reticuloendothelial system .

It may engulf a pathogen or other foreign object and destroy it with lysosomal enzymes.

It may bind to or remove a pathogen from the interstitial fluid, but be unable to destroy the invader until assisted by other cells.

It may destroy its target by releasing toxic chemicals, such as tumor necrosis factor , nitric oxide, or hydrogen peroxide, into the interstitial fluid.

Fixed macrophages , or histiocytes , are permanent residents of specific tissues and organs. These cells are normally incapable of movement, so the objects of their phagocytic attention must diffuse or otherwise move through the surrounding tissue until they are within range. Fixed macrophages are scattered among connective tissues, usually in close association with collagen or reticular fibers. Their presence has been noted in the papillary and reticular layers of the dermis, in the subarachnoid space of the meninges, and in bone marrow. In some organs, the fixed macrophages have special names:

Microglia are macrophages in the central nervous system, and Kupffer cells are macrophages located in and around the liver sinusoids. 

Free Macrophages Free macrophages , or mobile macrophages , travel throughout the body, arriving at the site of an injury by migration through adjacent tissues or by recruitment from the circulating blood. Some tissues contain free macrophages with distinctive characteristics; for example, the exchange surfaces of the lungs are patrolled by alveolar macrophages , also known as phagocytic dust cells

Movement and Phagocytosis 
Free macrophages and microphages share a number of functional characteristics:

Both can move through capillary walls by squeezing between adjacent endothelial cells, a process known as emigration , or diapedesis . The endothelial cells in an injured area develop membrane "markers" that let passing blood cells know that something is wrong. The cells then attach to the endothelial lining and migrate into the surrounding tissues.

Both may be attracted to or repelled by chemicals in the surrounding fluids, a phenomenon called chemotaxis . They are particularly sensitive to cytokines released by other body cells and to the chemicals released by pathogens.

For both, phagocytosis begins with adhesion , the attachment of the phagocyte to its target. In adhesion, receptors on the cell membrane of the phagocyte bind to the surface of the target. Adhesion is followed by the formation of a vesicle containing the bound target, as detailed in Figure 3–25 , p. 97. The contents of the vesicle are then digested when the vesicle fuses with lysosomes or peroxisomes.

Immunological Surveillance 
The immune system generally ignores the body's own cells unless they become abnormal in some way. Natural killer (NK) cells are responsible for recognizing and destroying abnormal cells when they appear in peripheral tissues. The constant monitoring of normal tissues by NK cells is called immunological surveillance . 

The cell membrane of an abnormal cell generally contains antigens that are not found on the membranes of normal cells. NK cells recognize an abnormal cell by detecting the presence of those antigens. The recognition mechanism differs from that used by T cells or B cells, which are activated only by exposure to a specific antigen at a specific site on a cell membrane. An NK cell responds to a variety of abnormal antigens that may appear anywhere on a cell membrane. NK cells are therefore much less selective about their targets than are other lymphocytes; if a membrane contains abnormal antigens, it will be attacked. As a result, NK cells are highly versatile: A single NK cell can attack bacteria in the interstitial fluid, body cells infected with virus, or cancer cells.

NK cells attack cancer cells and cells infected with viruses. Cancer cells probably appear throughout life, but their cell membranes generally contain unusual proteins called tumor–specific antigens , which NK cells recognize as abnormal. The affected cells are then destroyed, preserving tissue integrity.

Unfortunately, some cancer cells avoid detection, perhaps because they lack tumor–specific antigens or because these antigens are covered in some way. Other cancer cells are able to destroy the NK cells that detect them. This process of avoiding detection or neutralizing body defenses is called immunological escape . Once immunological escape has occurred, cancer cells can multiply and spread without interference by NK cells

NK cells are also important in fighting viral infections. Viruses reproduce inside cells, beyond the reach of circulating antibodies. However, infected cells incorporate viral antigens into their cell membranes, and NK cells recognize these infected cells as abnormal. By destroying them, NK cells can slow or prevent the spread of a viral infection.

Interferons are small proteins released by activated lymphocytes and macrophages and by tissue cells infected with viruses. On reaching the membrane of a normal cell, an interferon binds to surface receptors on the cell and, via second messengers, triggers the production of antiviral proteins in the cytoplasm. Antiviral proteins do not interfere with the entry of viruses, but they do interfere with viral replication inside the cell.

Complement 
Your plasma contains 11 special complement proteins (C) , which form the complement system . The term complement refers to the fact that this system complements the action of antibodies.
The complement proteins interact with one another in chain reactions, or cascades , comparable to those of the clotting system.

The Destruction of Target Cell Membranes. Five of the interacting complement proteins bind to the cell membrane, forming a functional unit called the membrane attack complex (MAC) . The MACs create pores in the membrane that are comparable to those produced by perforin, and that have the same effect: The target cell is soon destroyed.

The Stimulation of Inflammation. Activated complement proteins enhance the release of histamine by mast cells and basophils. Histamine increases the degree of local inflammation and accelerates blood flow to the region.

The Attraction of Phagocytes. Activated complement proteins attract neutrophils and macrophages to the area, improving the chances that phagocytic cells will be able to cope with the injury or infection.

The Enhancement of Phagocytosis. A coating of complement proteins and antibodies both attracts phagocytes and makes the target easier to engulf. Macrophage membranes contain receptors that can detect and bind to complement proteins and bound antibodies. After binding, the pathogens are easily engulfed. The antibodies involved are called opsonins , and the effect is called opsonization

Inflammation

The inflammatory response , is a localized tissue response to injury. Inflammation produces local sensations of swelling, redness, heat, and pain.

The changes in the interstitial environment trigger the complex process of inflammation. 

Inflammation has a number of effects:

The injury is temporarily repaired, and additional pathogens are prevented from entering the wound.

The spread of pathogens away from the injury is slowed.

Local, regional, and systemic defenses are mobilized to overcome the pathogens and facilitate permanent repairs. This repair process is called regeneration .

The Response to Injury 
Mast cells play a pivotal role in the inflammatory response. When stimulated by mechanical stress or chemical changes in the local environment, these cells release histamine, heparin, prostaglandins, and other chemicals into interstitial fluid. Events then proceed in a series of integrated steps:

The histamine that is released increases capillary permeability and accelerates blood flow through the area. The increased blood flow brings more cellular defenders to the site and carries away toxins and debris, diluting them and reducing their local impact.

Clotting factors and complement proteins leave the bloodstream and enter the injured or infected area. Clotting does not occur at the actual site of injury, due to the presence of heparin. However, a clot soon forms around the damaged area, and this clot both isolates the region and slows the spread of the chemical or pathogen into healthy tissues. Meanwhile, complement activation through the alternative pathway breaks down bacterial cell walls and attracts phagocytes.

The increased blood flow elevates the local temperature, increasing the rate of enzymatic reactions and accelerating the activity of phagocytes. The rise in temperature may also denature foreign proteins or vital enzymes of invading microorganisms.

Debris and bacteria are attacked by neutrophils drawn to the area by chemotaxis. As they circulate through a blood vessel in an injured area, neutrophils undergo activation , a process in which (1) they stick to the side of the vessel and move into the tissue by diapedesis; (2) their metabolic rate goes up dramatically, and while this respiratory burst continues, they generate reactive compounds, such as nitric oxide and hydrogen peroxide, that can destroy engulfed pathogens; and (3) they secrete cytokines that attract other neutrophils and macrophages to the area.

Fixed and free macrophages engulf pathogens and cell debris. At first, these cells are outnumbered by neutrophils, but as the macrophages and neutrophils continue to secrete cytokines, the number of macrophages increases rapidly. Eosinophils may get involved if the foreign materials become coated with antibodies.

Other cytokines released by active phagocytes stimulate fibroblasts to begin barricading the area with scar tissue, reinforcing the clot and further slowing the invasion of adjacent tissues.

The combination of abnormal tissue conditions and chemicals released by mast cells stimulates local sensory neurons, producing sensations of pain. The individual becomes consciously aware of these sensations and may take steps to limit the damage they signal, such as removing a splinter or cleaning a wound.

As inflammation is under way, the foreign proteins, toxins, microorganisms, and active phagocytes in the area activate the body's specific defenses.

The tissue degeneration that occurs after cells have been injured or destroyed is called necrosis . The process begins several hours after the initial event, and the damage is caused by lysosomal enzymes. Lysosomes break down by autolysis, releasing digestive enzymes that first destroy the injured cells and then attack surrounding tissues.

As local inflammation continues, debris, fluid, dead and dying cells, and necrotic tissue components accumulate at the injury site. This viscous fluid mixture is known as pus . An accumulation of pus in an enclosed tissue space is called an abscess .

Fever is the maintenance of a body temperature greater than 37.28C (998F). In Chapter 14 , we noted the presence of a temperature–regulating center in the preoptic area of the hypothalamus. Circulating proteins called pyrogens can reset this thermostat and raise body temperature. A variety of stimuli, including pathogens, bacterial toxins, and antigen– antibody complexes, either act as pyrogens themselves or stimulate the release of pyrogens by macrophages.

Within limits, a fever can be beneficial. High body temperatures may inhibit some viruses and bacteria, but the most likely beneficial effect is on body metabolism. For each rise in temperature, your metabolic rate jumps by 10 percent.

22–4  Specific Defenses:

Specific resistance, or immunity, is provided by the coordinated activities of T cells and B cells, which respond to the presence of specific antigens. The basic functional relationship can be summarized as follows:

T cells are responsible for cell–mediated immunity (or cellular immunity ), our defense against abnormal cells and pathogens inside cells.

B cells provide antibody–mediated immunity (or humoral immunity ), our defense against antigens and pathogens in body fluids.

Forms of Immunity 
Immunity is either innate or acquired

Types of Immunity

Innate immunity is genetically determined; it is present at birth and has no relationship to previous exposure to the antigen involved. For example, people do not get the same diseases that goldfish do. Innate immunity breaks down only in the case ofAIDS or other conditions that depress all aspects of specific resistance. 

Acquired immunity is not present at birth; you acquire immunity to a specific antigen only when you have been exposed to that antigen. Acquired immunity can be active or passive . 

Active immunity appears after exposure to an antigen, as a consequence of the immune response. The immune system is capable of defending against a large number of antigens. However, the appropriate defenses are mobilized only after you encounter a particular antigen. Active acquired immunity can develop as a result of natural exposure to an antigen in the environment ( naturally acquired immunity ) or from deliberate exposure to an antigen ( induced active immunity ).

Passive immunity is produced by the transfer of antibodies from another source.

Natural passive immunity results when a mother's antibodies protect her baby against infections during gestation (across the placenta) or in early infancy (through breast milk).

In induced passive immunity , antibodies are administered to fight infection or prevent disease. For example, antibodies that attack the rabies virus are injected into a person bitten by a rabid animal.

An Introduction to the Immune Response

T Cells and Cell–Mediated Immunity

T cells play a key role in the initiation, maintenance, and control of the immune response. We have already introduced three major types of T cells:

Cytotoxic T cells which are responsible for cell–mediated immunity. These cells enter peripheral tissues and directly attack antigens physically and chemically.

Helper T cells which stimulate the responses of both T cells and B cells. Helper T cells are absolutely vital to the immune response, because B cells must be activated by helper T cells before the B cells can produce antibodies. The reduction in the helper T cell population that occurs in AIDS is largely responsible for the loss of immunity.

Suppressor T cells which inhibit T cell and B cell activities and moderate the immune response.

Antigen presentation occurs when an antigen–glycoprotein combination capable of activating T cells appears in a cell membrane. The structure of these glycoproteins is genetically determined. The genes controlling their synthesis are located along one portion of chromosome 6, in a region called the major histocompatibility complex (MHC) . These membrane glycoproteins are called MHC proteins , or human leukocyte antigens (HLAs) .

Antigen Recognition

Inactive T cells have receptors that recognize Class I or Class II MHC proteins. The receptors also have binding sites that detect the presence of specific bound antigens. If an MHC protein contains any antigen other than the specific target of a particular kind of T cell, the T cell remains inactive. If the MHC protein contains the antigen that the T cell is programmed to detect, binding will occur. This process is called antigen recognition , because the T cell recognizes that it has found an appropriate target.

Cytotoxic T cells , also called cells or killer T cells , seek out and destroy abnormal and infected cells. Killer T cells are highly mobile cells that roam throughout injured tissues. When a cytotoxic T cell encounters its target antigens bound to Class I MHC proteins of another cell, it immediately destroys that cell. Three different methods may be used to destroy the target cell

Antigen Recognition and the Activation of Cytotoxic T Cells. 
An inactive cytotoxic T cell not only must encounter an appropriate antigen bound to Class I MHC proteins, but also must receive costimulation from the membrane it contacts. It is then activated and undergoes divisions that produce memory cells and active cells. When one of the active cells encounters a membrane displaying the target antigen, it will use one of several methods to destroy the cell

The T cell may (1) destroy the antigenic cell membrane through the release of perforin, (2) kill the target cell by secreting a poisonous lymphotoxin, or (3) activate genes in the target cell's nucleus that tell that cell to die

Memory Tc cells are produced by the same cell divisions that produce cytotoxic T cells. Memory Tc cells ensure that there will be no delay in the response if the antigen reappears. These cells do not differentiate further the first time the antigen triggers an immune response, although thousands of them are produced. Instead, they remain in reserve. If the same antigen appears a second time, memory T cells will immediately differentiate into cytotoxic T cells, producing a swift, effective cellular response that can overwhelm an invading organism before it becomes well established in the tissues.

Suppressor T cells suppress the responses of other T cells and of B cells by secreting suppression factors.

As a result, suppressor T cells act after the initial immune response. In effect, these cells put on the brakes and limit the degree of immune system activation from a single stimulus.

Activation of CD4 T Cells 
Upon activation, CD4 T cells undergo a series of divisions that produce helper T cells and memory

Antigen Recognition and Activation of Helper T Cells. 
Inactive CD4 T cells ( cells) must be exposed to appropriate antigens bound to Class II MHC proteins. The cells then undergo activation, dividing to produce active cells and memory cells. Active cells secrete cytokines that stimulate cell–mediated and antibody–mediated immunities. They also interact with sensitized B cells, as Figure 22–20 shows.

The memory cells remain in reserve, whereas the helper T cells secrete a variety of cytokines that coordinate specific and nonspecific defenses and stimulate cell–mediated and antibody–mediated immunities. For example, activated helper T cells secrete cytokines that:

Stimulate the T cell divisions that produce memory T cells and accelerate the maturation of cytotoxic T cells.

Enhance nonspecific defenses by attracting macrophages to the affected area, preventing their departure, and stimulating their phagocytic activity and effectiveness;

Attract and stimulate the activity of NK cells, providing another mechanism for the destruction of abnormal cells and pathogens; and

Promote the activation of B cells, leading to B cell division, plasma cell maturation, and antibody production.

 A Summary of the Pathways of T Cell Activation

B Cells and Antibody–Mediated Immunity

B cell membranes contain Class II MHC proteins. During sensitization, antigens are brought into the cell by endocytosis. The antigens subsequently appear on the surface of the B cell, bound to Class II MHC proteins. (The mechanism is comparable to that shown in Figure 22–16b , p. 802). Once this happens, the sensitized B cell is ready to go, but it generally will not undergo activation unless it receives the "OK" from a helper T cell

Next, a sensitized B cell encounters a helper T cell already activated by antigen presentation. The helper T cell binds to the MHC complex, recognizes the presence of an antigen, and begins secreting cytokines that promote B cell activation. After activation has occurred, these same cytokines stimulate B cell division, accelerate plasma cell formation, and enhance antibody production. 

The Sensitization and Activation of B Cells. 
A B cell is sensitized by exposure to antigens that bind to antibodies in the B cell membrane. The B cell then displays those antigens in its cell membrane. Activated helper T cells encountering the antigens release cytokines that trigger the activation of the B cell. The activated B cell then divides, producing memory B cells and plasma cells that secrete antibodies

When stimulated by cytokines from helper T cells, a plasma cell can secrete up to 100 million antibody molecules each hour. 

Memory B cells perform the same role for antibody–mediated immunity that memory T cells perform for cell–mediated immunity. Memory B cells do not respond to a threat on first exposure. Instead, they remain in reserve to deal with subsequent injuries or infections that involve the same antigens. On subsequent exposure, the memory B cells respond by dividing and differentiating into plasma cells that secrete antibodies in massive quantities.

Antibody Structure. 
(a) A diagrammatic view of the structure of an antibody. (b) A computer–generated image of a typical antibody. (c) Antigen–antibody binding. (d) A hapten, or partial antigen, can become a complete antigen by binding to a carrier molecule.

An antibody consists of two parallel pairs of polypeptide chains: one pair of heavy chains and one pair of light chains . Each chain contains both constant segments and variable segments .

B cells produce only five types of constant segments. These form the basis of a classification scheme that identifies antibodies as IgG, IgE, IgD, IgM , or IgA

Classes and Actions of Antibodies 
Body fluids have five classes of antibodies, or immunoglobulins (Igs) : IgG, IgE, IgD, IgM , and IgA

The formation of an antigen–antibody complex may cause the elimination of the antigen in seven ways:

Neutralization. Both viruses and bacterial toxins have specific sites that must bind to target regions on body cells in order to enter or injure those cells. Antibodies may bind to those sites, making the virus or toxin incapable of attaching itself to a cell. This mechanism is known as neutralization .

Agglutination and Precipitation. 

The three–dimensional structure created by such binding is known as an immune complex . When the antigen is a soluble molecule, such as a toxin, this process may create complexes that are too large to remain in solution. The formation of insoluble immune complexes is called precipitation . When the target antigen is on the surface of a cell or virus, the formation of large complexes is called agglutination . The clumping of red blood cells that occurs when incompatible blood types are mixed is an agglutination reaction.

The Activation of Complement. On binding to an antigen, portions of the antibody molecule change shape, exposing areas that bind complement proteins. The bound complement molecules then activate the complement system, destroying the antigen (as discussed previously).

The Attraction of Phagocytes. Antigens covered with antibodies attract eosinophils, neutrophils, and macrophages–cells that phagocytize pathogens and destroy foreign or abnormal cell membranes.

Opsonization. A coating of antibodies and complement proteins increases the effectiveness of phagocytosis.

The Stimulation of Inflammation. Antibodies may promote inflammation through the stimulation of basophils and mast cells.

The Prevention of Bacterial and Viral Adhesion. Antibodies dissolved in saliva, mucus, and perspiration coat epithelia and provide them with an additional layer of defense. A covering of antibodies makes it difficult for pathogens to attach to body surfaces and penetrate their defenses.

Primary and Secondary Responses to Antigen Exposure

The initial response to exposure to an antigen is called the primary response . When the antigen appears again, it triggers a more extensive and prolonged secondary response .

The Primary Response 
Because the antigen must activate the appropriate B cells, which must then differentiate into plasma cells, the primary response does not appear immediately

The Primary and Secondary Immune Responses. 
(a) The primary response takes about two weeks to develop peak antibody titers, and IgM and IgG antibody concentrations do not remain elevated. (b) The secondary response is characterized by a very rapid increase in IgG antibody titer, to levels much higher than those of the primary response. Antibody activity remains elevated for an extended period after the second exposure to the antigen.

As the plasma cells differentiate and begin secreting, the concentration of circulating antibodies undergoes a gradual, sustained rise.
During the primary response, the antibody titer ("standard"), or level of antibody activity, in the plasma does not peak until one to two weeks after the initial exposure.

Two types of antibodies are involved in the primary response. Molecules of immunoglobulin M , or IgM , are the first to appear in the bloodstream. IgM is secreted by the plasma cells that form immediately after B cell activation. These lymphocytes do not pause to produce memory cells. Levels of immunoglobulin G, or IgG , rise more slowly, because the stimulated lymphocytes undergo repeated cell divisions and generate large numbers of memory cells as well as plasma cells. In effect, IgM provides an immediate but limited defense that fights the infection until massive quantities of IgG can be produced.

The Secondary Response 
Unless they are exposed to the same antigen a second time, memory B cells do not differentiate into plasma cells. If and when that exposure occurs, the memory B cells respond immediately–faster than the B cells stimulated during the initial exposure

The effectiveness of the secondary response is one of the basic principles behind the use of immunization to prevent disease.

Summary: The Immune Response 
We have now described the basic chemical and cellular interactions that follow the appearance of a foreign antigen in the body.

An Integrated Summary of the Immune Response

The Course of the Body's Response to Bacterial Infection. 
An outline of the basic sequence of events that begins with the appearance of bacteria in peripheral tissues

In the early stages of bacterial infection, before antigen processing has occurred, neutrophils and NK cells migrate into the threatened area and destroy bacteria. Over time, cytokines draw increasing numbers of phagocytes to the region. Cytotoxic T cells appear as arriving T cells are activated by antigen presentation. Last of all, the population of plasma cells rises as activated B cells differentiate. This rise is followed by a gradual, sustained increase in the level of circulating antibodies. 
The basic sequence of events is similar when a viral infection occurs. The initial steps are different, however, because cytotoxic T cells and NK cells can be activated by contact with infected cells.

Defenses against Bacterial and Viral Pathogens. 
(a) Defenses against bacteria are usually initiated by active macrophages. (b) Defenses against viruses are usually activated after the infection of normal cells.

Hormones of the Immune System

One example of physical interaction is antigen presentation by activated macrophages and helper T cells. An example of the release of chemical messengers is the secretion of cytokines by many of the cells involved in the immune response.

Cytokines are classified according to their origins: Lymphokines are produced by lymphocytes, monokines by active macrophages and other antigen–presenting cells.

Interleukins may be the most diverse and important chemical messengers in the immune system. Nearly 20 types of interleukins have been identified;. Lymphocytes and macrophages are the primary sources of interleukins, but specific interleukins, such as interleukin–1 (IL–1), are also produced by endothelial cells, fibroblasts, and astrocytes. Interleukins have the following general functions:

Increasing T Cell Sensitivity to Antigens Exposed on Macrophage Membranes .

Stimulating B Cell Activity, Plasma Cell Formation, and Antibody production

Enhancing Nonspecific Defenses . Known effects of interleukin production include (1) the stimulation of inflammation, (2) the formation of scar tissue by fibroblasts, (3) the elevation of body temperature via the preoptic nucleus of the central nervous system, (4) the stimulation of mast cell formation, and (5) the promotion of adrenocorticotropic hormone (ACTH) secretion by the anterior lobe of the pituitary gland.

Moderating the Immune Response . Some interleukins help suppress immune function and shorten the duration of an immune response.

If the regulatory process sometimes breaks down, and massive production of interleukins can cause problems at least as severe as those of the primary infection. For example, in Lyme disease the release of IL–1 by activated macrophages in response to a localized bacterial infection produces symptoms of fever, pain, skin rash, and arthritis that affect the entire body.

Interferons stimulate NK cell activity, interferons can be used to fight some cancers. For example, alpha–interferons have been used in the treatment of malignant melanoma, bladder cancer, ovarian cancer, and two forms of leukemia, while alpha– or gamma–interferons may be used to treat Kaposi's sarcoma, a cancer that typically develops in individuals with AIDS.

Tumor necrosis factors (TNFs) slow the growth of a tumor and kill sensitive tumor cells. Activated macrophages secrete one type of TNF and carry the molecules in their cell membranes. Cytotoxic T cells produce a different type of TNF. In addition to their effects on tumor cells, tumor necrosis factors stimulate granular leukocyte production, promote eosinophil activity, cause fever, and increase T cell sensitivity to interleukins

Chemicals Regulating Phagocytic Activities 
Several cytokines coordinate immune defenses by adjusting the activities of phagocytic cells. These cytokines include factors that attract free macrophages and microphages and prevent their premature departure from the site of an injury.

Colony–Stimulating Factors 
We introduced colony–stimulating factors (CSFs) in Chapter 19 . These factors are produced by active T cells, cells of the monocyte–macrophage group, endothelial cells, and fibroblasts. CSFs stimulate the production of blood cells in bone marrow and lymphocytes in lymphoid tissues and organs.

Normal and Abnormal Resistance

The ability to produce an immune response after exposure to an antigen is called immunological competence . Cell–mediated immunity can be demonstrated as early as the third month of fetal development, but active antibody–mediated immunity appears later.

The Development of Immunological Competence

The natural immunity provided by maternal IgG may not be enough to protect the fetus if the maternal defenses are overrun by a bacterial or viral infection. For example, the microorganisms responsible for syphilis and rubella ("German measles") can cross from the maternal to the fetal bloodstream, producing a congenital infection that leads to the production of fetal antibodies. IgM provides only a partial defense, and these infections can result in severe developmental problems for the fetus. 

Delivery eliminates the maternal supply of IgG. Although the mother provides IgA antibodies in her breast milk, the infant gradually loses its passive immunity. The amount of maternal IgG in the infant's bloodstream declines rapidly over the first two months after birth. During this period, the infant becomes vulnerable to infection by bacteria or viruses that were previously overcome by maternal antibodies. The infant also begins producing its own IgG, as its immune system begins to respond to infections, environmental antigens, and vaccinations. It has been estimated that, from birth to age 12, children encounter a "new" antigen every six weeks. (This fact explains why most parents, exposed to the same antigens when they were children, remain healthy, while their children develop runny noses and colds.) Over this period, the concentration of circulating antibodies gradually rises toward normal adult levels, and the populations of memory B cells and T cells continue to increase.

Autoimmune disorders develop when the immune response mistakenly targets normal body cells and tissues. In an immunodeficiency disease , either the immune system fails to develop normally or the immune response is blocked in some way. Autoimmune disorders and immunodeficiency diseases are relatively rare–clear evidence of the effectiveness of the immune system's control mechanisms. A far more common, and generally far less dangerous, class of immune disorders is the allergies.

The recognition system can malfunction, however. When it does, the activated B cells make antibodies against other body cells and tissues. These misguided antibodies are called autoantibodies . The trigger may be a reduction in suppressor T cell activity, the excessive stimulation of helper T cells, tissue damage that releases large quantities of antigenic fragments, haptens bound to compounds normally ignored, viral or bacterial toxins, or a combination of factors. 

The symptoms produced depend on the specific antigen attacked by autoantibodies. For example,

The inflammation of thyroiditis results from the release of autoantibodies against thyroglobulin;

Rheumatoid arthritis occurs when autoantibodies form immune complexes within connective tissues, especially around the joints; and

Insulin–dependent diabetes mellitus (IDDM) is generally caused by autoantibodies that attack cells in the pancreatic islets.

Many autoimmune disorders appear to be cases of mistaken identity. For example, proteins associated with the measles, Epstein–Barr, influenza, and other viruses contain amino acid sequences that are similar to those of myelin proteins. As a result, antibodies that target these viruses may also attack myelin sheaths. This mechanism accounts for the neurological complications that sometimes follow a vaccination or a viral infection. It is also the mechanism that is likely responsible for multiple sclerosis .

Immunodeficiency Diseases 
Immunodeficiency diseases result from (1) problems with the embryological development of lymphoid organs and tissues; (2) an infection with a virus, such as HIV, that depresses the immune function; or (3) treatment with, or exposure to, immunosuppressive agents, such as radiation or drugs.
Individuals born with severe combined immunodeficiency disease (SCID) fail to develop either cellular or antibody–mediated immunity. Their lymphocyte populations are low, and normal B and T cells are absent. Such infants cannot produce an immune response, and even a mild infection can prove fatal. Total isolation offers protection at great cost, with severe restrictions on lifestyle. Bone marrow transplants from compatible donors, normally a close relative, have been used to colonize lymphoid tissues with functional lymphocytes. Gene–splicing techniques have led to therapies that can treat at least one form of SCID. 

AIDS, an immunodeficiency disease that we consider on page 820, is the result of a viral infection that targets primarily helper T cells. As the number of T cells declines, the normal immune control mechanism breaks down. When an infection occurs, suppressor factors released by suppressor T cells inhibit an immune response before the few surviving helper T cells can stimulate the formation of cytotoxic T cells or plasma cells in adequate numbers. 

Immunosuppressive drugs have been used for many years to prevent graft rejection after transplant surgery. But immunosuppressive agents can destroy stem cells and lymphocytes, leading to a complete immunological failure. This outcome is one of the potentially fatal consequences of radiation exposure.

Allergies are inappropriate or excessive immune responses to antigens. The sudden increase in cellular activity or antibody titers can have a number of unpleasant side effects. For example, neutrophils or cytotoxic T cells may destroy normal cells while attacking the antigen, or the antigen–antibody complex may trigger a massive inflammatory response. Antigens that trigger allergic reactions are often called allergens . 

There are several types of allergies. A complete classification recognizes four categories: immediate hypersensitivity (Type I), cytotoxic reactions (Type II), immune complex disorders (Type III) , and delayed hypersensitivity (Type IV) . Here we will consider only immediate hypersensitivity, probably the most common form of allergy. One form, allergic rhinitis , includes hay fever and environmental allergies that may affect 15 percent of the U.S. population.

In anaphylaxis, a circulating allergen affects mast cells throughout the body .

The Mechanism of Anaphylaxis

The entire range of symptoms can develop within minutes. Changes in capillary permeabilities produce swelling and edema in the dermis, and raised welts, or hives , appear on the surface of the skin. Smooth muscles along the respiratory passageways contract; the narrowed passages make breathing extremely difficult. In severe cases, an extensive peripheral vasodilation occurs, producing a fall in blood pressure that can lead to a circulatory collapse. This response is anaphylactic shock

Many of the symptoms of immediate hypersensitivity can be prevented by the prompt administration of antihistamines –drugs that block the action of histamine. (diphenhydramine hydrochloride) is a popular antihistamine that is available over the counter. The treatment of severe anaphylaxis involves antihistamine, corticosteroid, and epinephrine injections