Immunology is the study of the genetic, biological, chemical, and physical characteristics of the immune system. It describes the actions of cells, tissues, and organs that are specialized to protect the body from microorganisms and other foreign substances (Figure 20.1). In essence, immunology is concerned with how the body uses protective mechanisms to recognize self from nonself-molecules. Self and nonself are determined by specific receptors on the surface of cell membranes that recognize and differentiate among antigens. These receptors, specific to a cell or particle, are called self-antigens or cell surface markers. In response to foreign antigens, cells of the immune system produce specific antibodies that bind to specific antigens. An antigen–antibody complex is formed, which is then destroyed by the immune system. Another immune reaction to protect the body is cell-mediated immunity. This is an immune response that does not include antibodies but involves the activation of macrophages, natural killer (NK) cells, and cytotoxic T lymphocytes, and the release of various cytokines.

FIGURE 20.1 Overview of the lymphatic system.
The lymphatic system consists of lymphatic vessels, lymphoid tissue and cells, and lymphatic organs.

Immunity

Immunity is the body’s ability to respond to the presence of any foreign substance. The immune response that begins after exposure to invading organisms or substances is controlled by two immune system response mechanisms: (1) the innate (nonspecific) immune response and (2) the adaptive (specific) immune response. The immune system of a person is considered to be immunocompetent when it functions properly, and immunosuppressed (immunodepressed, immunocompromised) if part or all of the system cannot respond appropriately to a challenge by antigens.

Antigens

An antigen is any agent that is capable of binding specifically to components of the immune system such as lymphocytes, macrophages, and antibodies. Usually, only a part of an antigen triggers the immune response. The smallest part of an antigen molecule that can bind with an antibody is called an epitope or antigenic determinant. All antigens have one or more epitopes (Figure 20.2). Proteins, carbohydrates, lipids, and nucleic acids can all be antigens under certain circumstances.

• Proteins are the most immunogenic molecules and often have several epitopes for antibody recognition.

• Carbohydrates are potentially immunogenic when bound to a protein, forming complex glycoprotein molecules. These are located in the cell membrane and can cause an immune response. Examples of the antigenicity of carbohydrates are the polysaccharides on the surface of red blood cells (see ABO blood typing discussed in the Antigens section, later in this chapter).

• Lipids also can cause an immune response if conjugated with a protein carrier.

• Nucleic acids are poor immunogens themselves, but when bound to a carrier protein they can become immunogenic. A clinical example is the presence of anti-DNA antibodies in patients with systemic lupus erythematosus (see the section Autoimmune Diseases later in this chapter).

Moreover, a distinction between antigens is required because many of them are incapable of inducing an immune response. On the basis of the reaction of the immune system to a given antigen, antigens can be classified as immunogens, tolerogens, allergens, autoantigens, and tumor antigens.

• Immunogens are substances that stimulate the production of specific antibodies by the immune system. All immunogens are antigens but not all antigens are necessarily immunogens. Pathogenic organisms such as bacteria and viruses are immunogens.

• Tolerogens, like self-antigens, are tolerated by the immune system. However, if the molecular weight or form of a tolerogen changes, it can become an immunogen. For example, low molecular weight compounds, including some antibiotics and other drugs, are incapable of eliciting an immune response themselves, but become immunogens when conjugated with a high molecular weight molecule. The low molecular weight compound is called a hapten (Figure 20.3) and the high molecular weight compound is referred to as a carrier.

FIGURE 20.3 Haptens.
Haptens are small molecules and cannot stimulate the immune system. When a hapten combines with a carrier molecule it can result in an immune response and antibodies will bind to the hapten–carrier conjugate.

• Allergens are substances causing allergic reactions. They can be ingested, inhaled, injected, or come into contact with the skin to evoke an allergic response. Substances such as pollen, egg white, honey, and many others can cause such reactions in some individuals and therefore are referred to as allergens.

• Autoantigens are molecules, usually proteins, that are interpreted by the immune system as nonself-antigens, such as in the case of autoimmune diseases. Autoantigens are frequently components of multimolecular, subcellular particles that are involved in a variety of cell functions. Under normal circumstances these antigens would be accepted (tolerated) as self-antigens and not targeted by the immune system.

• Tumor antigens are always presented by tumor cells and never by normal cells of the body. In this case the antigens are tumor specific and typically result from tumor-specific mutations. Lymphocytes that recognize these antigens as nonself destroy these tumor cells before they can proliferate and metastasize. Examples of the origin of these tumor antigens include new genetic information introduced by a virus such as the human papillomavirus of cervical cancer, or the alteration of oncogenes by carcinogens.

A microbe or parts of a microbe such as flagella, capsules, portions of the bacterial cell wall, bacterial and viral toxins, spike proteins in the coat of viruses, and external structures of fungi and protozoans all can be antigenic. Nonmicrobial antigens include components of pollen, egg white, beeswax, cat dandruff, dog hair, foreign blood cells, as well as tissue and organ transplants (see Allergy–Hypersensitivity Reactions later in this chapter).

An organism’s self-antigens are located on the cell membrane and are unique for each individual, with the exception of identical twins, who carry the same genetic code. These antigen molecules are coded by a group of genes located on chromosome 6 and form the major histocompatibility complex (MHC). Antigens resulting from the MHC are glycoproteins and are found on all cells except red blood cells (see later in this section). These antigens were originally identified on the surface of white blood cells and therefore the MHC is sometimes referred to as the human leukocyte antigen (HLA) system. The MHC plays a major role in an individual’s immune system by recognizing and tolerating self-antigens and rejecting foreign antigens. This phenomenon of self-recognition is referred to as immunological tolerance. A healthy immune system can distinguish between the body’s self-antigens and nonself-antigens. However, in the case of an autoimmune disease, the immune system has lost its tolerance to the self-antigens and attacks the body’s own cells or cell structures.

Moreover, the MHC genes are clustered to form a multigene complex made of three subgroups called class I, class II, and class III. The class I genes encode the unique self-antigen characteristics and aid in the recognition of self-antigen molecules, and the class II genes encode receptors that recognize foreign antigens. These regulatory receptors are located mainly on macrophages and B cells and are involved in presenting antigens to the T cells during the immune response. Class III genes, in contrast to class I and class II MHC genes, which encode cell surface molecules, encode secreted complement components such as C2 and C4 (see Complement System later in this chapter).

Transplantation is a solution for replacement of damaged tissues or organs. However, for a transplant to be successful, matching as many MHC molecules (self-antigens) as possible is essential to avoid a serious immune reaction called rejection. Transplants are classified according to donor characteristics as autografts, isografts, allografts, and xenografts.

• Autografts are tissues transplanted from one site in an individual to another site. An example is the removal of a portion of a blood vessel from one site and transplanted to another, in order to provide a healthy blood vessel for a dialysis stent.

• Isografts are tissues or organs transplanted between genetically identical entities such as identical twins, for whom tissue or organ rejection is not an issue. For example, a kidney or part of the liver can be transplanted from one identical twin to the other without resulting in major transplant rejection.

• Allografts are transplants between genetically different individuals from the same species (e.g., humans) but with different genomes (genetic information). In other words, the MHC molecules are different and rejection of the transplant can occur.

• Xenografts are transplants between individuals of different species such as pigs and humans. Although xenografts are often less successful than same-species grafts, pig heart valves have been used extensively and with great success for human cardiac valve replacement.

Normally the most successful transplants are ranked in order as autografts followed by isografts, allografts, and xenografts. Rejections may occur immediately after transplantation, or after several weeks, months, or years. To reduce the immune response and prevent transplant rejection, immunosuppressive drugs such as cyclosporine and prednisone are used. However, the resulting compromised immune system puts the recipient of the transplant at a higher risk of infection and is a major concern when immunosuppressive drugs are used.

Blood typing, for compatibility before blood transfusion, is also based on genetically determined surface antigens on red blood cells (RBCs). Although more than 20 blood group systems are known today the ABO and Rh systems are used most often. The ABO system is based on the presence of type A or B antigens on the surface of RBCs. The RBCs of blood type A have A antigens, blood type B cells have B antigens, blood type AB cells have both antigens, and blood type O cells have neither A nor B antigens. The immune system does not normally produce antibodies against its own RBC antigens, but antibodies against another blood type are present in the blood plasma (Table 20.1). Type A blood contains antibodies against type B blood (anti-B) and type B blood contains antibodies against type A blood (anti-A). Type O blood contains both anti-A and anti-B, whereas type AB blood does not contain either.

TABLE 20.1

ABO Blood Typing

Blood Type	Antigen	Antibody
A	A	Anti-B
B	B	Anti-A
AB	A, B	None
O	None	Anti-A, anti-B

Because of the presence or absence of antigens and antibodies, people with type AB blood can donate only to persons with type AB blood, but can receive blood from all other ABO groups, thus they are often referred to as universal recipients. A person with blood type O does not have any antigens and therefore can donate to anyone. This group is often referred to as the universal donor group.

Because of the different antigens, not all blood groups are compatible with each other and mixing incompatible blood groups leads to agglutination [see Cytotoxic Hypersensitivity Reactions (Type II) later in this chapter].

In addition, many people have an additional antigen, the Rh factor (or D antigen), on the surface of their RBCs. This antigen was first discovered during experiments in rhesus monkeys and is therefore called the Rh factor. A person with the D antigen is called Rh positive (Rh⁺) and someone without D antigen is referred to as Rh negative (Rh⁻). Although a person with Rh⁻ blood does not normally contain Rh antibodies in the serum, exposure to Rh⁺ blood will trigger the production of Rh antibodies. An example of this is erythroblastosis fetalis, or hemolytic disease, which occurs when an Rh⁻ mother begins to develop antibodies because she is carrying an Rh⁺ fetus (for more information, please refer to the Medical Highlights box).

MEDICAL HIGHLIGHTS

Erythroblastosis Fetalis

Hemolytic disease of the newborn (erythroblastosis fetalis) occurs if an Rh-negative (Rh⁻) mother carries an Rh-positive (Rh⁺) fetus. The mother’s immune system develops antibodies against Rh⁺ blood when red blood cells (RBCs) of the fetus cross the placenta and enter the mother’s circulation. This can occur during childbirth. The mother’s immune system maintains the antibodies in case foreign blood cells enter her system again, such as in a future pregnancy. The mother’s body is now considered to be Rh sensitized. During the first pregnancy, Rh sensitization is not likely but does become a problem in subsequent pregnancies with another Rh⁺ fetus. In this instance, the mother’s antibodies cross the placenta and attack the fetus’s RBCs. The destruction of the fetus’s RBCs can result in a worst-case scenario in which the fetus is at great risk of erythroblastosis fetalis and can be stillborn. Prevention of this condition can be achieved by injecting the mother with anti-Rh immune globulin to prevent the sensitization of her immune system during the first pregnancy with an Rh⁺ fetus.

A fetus born with erythroblastosis fetalis is said to have hemolytic disease of the newborn and its treatment will be determined by the physician, based on the severity of the disease and the overall health of the infant.

Antibodies

One of the major functions of the immune system is to produce freely circulating soluble proteins that contribute specifically to the protection against foreign substances. These proteins are called antibodies and due to their globular structure are also known as immunoglobulins (Igs) or gamma (γ) globulins. In addition to acting as antibodies in the circulation, immunoglobulins serve as specific receptors on B cells. Produced by B lymphocytes, they recognize and bind to foreign antigens, forming an antigen–antibody complex, marking the antigen for destruction.

Structurally, antibodies are fork- or Y-shaped molecules composed of a pair of two identical long polypeptide chains (heavy chains) and a pair of identical short (light) polypeptide chains (Figure 20.4). At the end of the Y shape, formed by the heavy and light chains, are specific antigen-binding sites that differ from antibody to antibody. Because of the high variability of this region, it is referred to as the variable (V) region of the antibody. This variable region is composed of 110 to 130 amino acids, which gives the antibody its specificity for the antigen through its antigen-binding site. The remainder of the molecule is the constant (C) region that does not vary significantly from antibody to antibody. It is the variable region of antibodies that meets the enormous variety of antigenic challenges. The tips of the Y-shaped molecule consisting of the V and C regions are referred to as the Fab (fragment, antigen-binding) region, and the stem of the molecule is called the crystallized fragment or Fc fragment and plays a role in modulating immune cell activity. The Fc region can bind to various cell receptors including Fc receptors and complement proteins. This binding mediates different physiological effects, including opsonization (the action of making bacteric and other cells easier to phagocytize by marking or “tagging” them chemically), cell lysis, and degranulation of mast cells, basophils, and eosinophils.

FIGURE 20.4 Basic antibody (immunoglobulin) structure.
Antibodies are Y-shaped structures with two heavy chains and two light chains with specific antigen-binding sites.

Although all immunoglobulins share common features, different classes of antibodies trigger different responses when combining with the same epitope (antigenic determinant). Five classes of immunoglobulins have been identified (Table 20.2).

TABLE 20.2

Summary of Immunoglobulin Classes

Characteristic	IgG	IgD	IgE	IgA	IgM
Structure	Monomer	Monomer	Monomer	Monomer, dimer	Pentamer
Number of antigen-binding sites	2	2	2	2 (monomer), 4 (dimer)	10
Percentage of total serum antibody	80%	0.2%	0.002%	10–15%	5–10%
Average life span in serum	23 d	3 d	2–2.5 d	6 d	5 d
Function	Major antibody in circulation; long-term immunity	Receptor on B cells	Antibody in allergies and worm infections	Secretory antibody	First response to antigen; can serve as B-cell receptor

1. IgG, a monomer produced by B cells, is the major antibody in the blood and lymphatic circulation. This class of antibody can cross the placenta and provide passive immunity to the newborn.

2. IgA, a monomer in blood and a dimer in secretions such as tears, saliva, and secretions of the respiratory and digestive tracts, provides local protection against bacteria and viruses. IgA is also found in colostrum and mother’s milk, providing additional passive immunity to the newborn.

3. IgM is a pentamer and the largest of the immunoglobulins. Because of its large molecular size, it does not diffuse readily from the bloodstream, where it remains and is efficient in reacting with bacteria and foreign cells. IgMs provide the first immunoglobulin activity in an immune response. These antibodies are also mainly responsible for the clumping of red blood cells in transfusion reactions.

4. IgD is a monomer bound to the surface of B cells and plays a role in B-cell activation. Although IgD is present in small amounts in serum its function in the circulation is unknown.

5. IgE is a monomer that binds to receptors on mast cells and basophils. It is the least abundant antibody type in serum. Functionally, it is implicated in allergic reactions and stimulates basophils to release histamines. Research indicates that IgE production can occur locally in the nasal mucosa of patients with allergic rhinitis. IgEs also provide protection against parasites and a 10- to 100-fold increase in serum IgE levels has been detected in patients with parasitic infections.

Components of the Immune System

Tissues and Organs of the Immune System

Lymphatic Vessels

Lymphatic vessels anatomically communicate with the vessels of the cardiovascular system. They originate as microscopic blind-ended vessels in the capillary beds of tissues (Figure 20.5). The function of lymph capillaries is to absorb excess extracellular (interstitial) fluid generated by the hydrostatic pressure of blood capillaries in these areas. As soon as the interstitial fluid enters the lymph capillaries it is called lymph. The plasma-like, watery lymph contains white blood cells, which are important in the immune response, and also transports dietary lipids from the small intestine to the liver.

FIGURE 20.5 Origin of lymph capillaries.
Lymph capillaries are microscopic blind-ended vessels originating in the capillary beds of tissues.

The lymph capillaries drain the lymph into larger lymphatic vessels, which resemble veins of the cardiovascular system in their structure but have thinner walls and more valves. At various intervals throughout the body’s lymph vessels, lymph passes through lymph nodes (where lymphocytes first interact with a specific antigen) and then is collected by lymphatic trunks, which carry the lymph to the largest lymphatic vessels, the lymphatic ducts. The thoracic or left lymphatic duct is the main collecting duct of the lymphatic system. It receives lymph from the left side of the head, neck, and chest, left upper limb, and the entire body inferior to the ribs. The thoracic duct then drains the lymph into the cardiovascular system via the left subclavian vein. The right lymphatic duct drains lymph from the upper right side of the body into the right subclavian vein (Figure 20.6).

FIGURE 20.6 Drainage of lymph capillaries.
Lymph capillaries drain into larger lymphatic vessels that drain into lymphatic trunks and then into the thoracic and right lymphatic ducts. The thoracic and right lymphatic ducts deliver the lymph into the left and right subclavian veins.

Notably, the central nervous system is the only organ system in the body that does not contain lymph, lymphatic vessels, lymphatic tissue, or lymphatic organs. It does, however, have a blood–brain barrier that, when intact, impedes the entry of proteins and other harmful substances into the brain.

Symptoms	Cause	Treatment
Red, swollen tonsils, sometimes white patches on the tonsils, severe sore throat, painful swallowing, headache, fever, enlarged tender glands, loss of voice	Viral or bacterial infection	Viral infections: Warm liquids, gargling with salt water, acetaminophen or ibuprofen to reduce fever and pain Bacterial infections: Antibiotics in addition to treatments for viral infection; surgical removal (tonsillectomy) in case of recurrent tonsillitis and/or severe obstruction of airways

Lymph Nodes

Approximately 600 lymph nodes are located along the lymphatic vessels, with clusters in various areas of the body. Lymph enters the lymph nodes via afferent lymphatic vessels and exits through efferent lymphatic vessels. Before the lymph is returned to the cardiovascular system, it is filtered through the lymph nodes. In addition to phagocytosis to remove pathogens and other foreign substances, B lymphocytes and T lymphocytes are activated in the lymph nodes in response to an antigenic challenge.

Lymph nodes are small bean-shaped lymphatic organs, surrounded by a fibrous connective tissue capsule and ranging in diameter from 1 to 25 mm. The connective tissue capsule extends into the lymph node in the form of trabeculae, a meshwork of supporting reticular fibers. The parenchyma of the lymph nodes is divided into an outer cortex and an inner medulla. The cortex contains lymphoid nodules, some of which are referred to as primary nodules because they consist mainly of small lymphocytes. Secondary nodules contain a pale central region called the germinal center. A germinal center is formed when a B lymphocyte recognizes an antigen and proliferates into plasma cells for antibody production. The medulla consists of medullary cords that are separated by the medullary sinuses (Figure 20.8).

FIGURE 20.8 Lymph nodes are bean-shaped organs surrounded by a connective tissue capsule that forms trabeculae to provide the framework for the node. Afferent lymphatic vessels enter the node and efferent lymphatic vessels leave the node.

HEALTHCARE APPLICATION
Lymphoma

Term	Symptoms	Cause	Treatment
Non-Hodgkin’s lymphoma	Enlarged lymph nodes, fever, excessive sweating with night sweats, unintentional weight loss, abdominal pain or swelling	Production of abnormal lymphocytes that continue to divide and grow uncontrollably; crowding of these lymphocytes into the lymph nodes, causing them to swell; exact cause is unknown	Chemotherapy, radiation, stem cell transplantation, observation for slow-growing lymphomas, biologic therapy, radioimmunotherapy
Hodgkin’s lymphoma	Painless swelling of lymph nodes in neck, armpits, or groin; persistent fatigue; fever and chills; night sweats; unexplained weight loss; loss of appetite; itching	Exact cause unknown, commonly begins in the lymph nodes; development of abnormal B lymphocytes (Reed-Sternberg cells)	Depends on disease stage; radiation, chemotherapy, bone marrow transplant

Spleen

The spleen is the largest lymphatic organ of the body and is located in the upper left abdominal cavity between the stomach and diaphragm (Figure 20.9). The cellular components of the spleen consist of the red pulp, containing large quantities of blood, and the white pulp, which contains lymphoid tissue resembling lymphoid nodules. Approximately 25% of the body’s lymphocytes are located in the spleen. The spleen filters the blood, removing damaged blood cells and other cells with nonself-antigens. In response to circulating antigens, B cells, T cells, and macrophages are activated to eliminate any pathogens.

HEALTHCARE APPLICATION
Spleen Disorders

Term	Symptoms	Cause	Treatment
Trauma (damage or rupture)	Painful and tender abdomen, abdominal muscles contract and feel rigid, low blood pressure, light-headedness, blurred vision, confusion, loss of consciousness	Severe blow to the stomach, abdominal injury (e.g., car accidents), athletic mishaps	Immediate blood transfusions, followed by removal of the spleen (splenectomy), if required by the severity of tissue damage
Splenomegaly	Abdominal pain, early satiety (fullness) due to splenic encroachment, anemia	Mononucleosis caused by the Epstein-Barr virus, other viral infections, bacterial infections, parasitic infections; diseases involving the liver, hemolytic anemias, cancer, sarcoidosis	No treatment for the disease; treatment of the underlying conditions; treatment of symptoms

Thymus Gland

The thymus gland is a bilobate organ located in the mediastinum (Figure 20.10). The cells of the thymus produce thymosins, which are hormones essential for the maturation of the T lymphocytes. The thymus is large after birth and is essential in the development of the immune system in newborns. Although large in childhood, it gradually atrophies throughout adulthood. Functionally, after being active during the first years of life, its capacity slows down during puberty. By age 60 years the thymus gland is small and many of its cells have been replaced by adipose (fat) cells. As a result, the production of thymosin may have stopped, which negatively influences the maturation of T lymphocytes.

Red Bone Marrow (Myeloid Tissue)

Red bone marrow is found in flat and irregularly shaped bones and is considered the primary lymphoid organ. All blood cells, including the cells of the immune system, originate from hematopoietic stem cells, the hemocytoblasts located in the red bone marrow. The process of blood cell formation is called hemopoiesis or hematopoiesis and includes the following processes (Figure 20.11):

FIGURE 20.11 Development of blood cells.
Blood cell production is called *hemopoiesis* and occurs in the red bone marrow. The stem cell of all blood cells is the hemocytoblast, which undergoes differentiation to form the cell lines for all blood cells.

• Erythropoiesis is the formation of erythrocytes (red blood cells) and is stimulated by the hormone erythropoietin, which is produced in the kidneys.

• Leukopoiesis is the formation of leukocytes (white blood cells) from the hematopoietic stem cells of the red bone marrow. Two pathways or processes are responsible for the production of leukocytes: lymphopoiesis and myelopoiesis.

• Lymphopoiesis is the production of lymphocytes. Immature B cells and natural killer (NK) cells are produced in red bone marrow and are transported by circulating blood to the secondary lymphoid organs, located throughout the body. Immature T cells are also produced in red bone marrow but migrate to the thymus for maturation.

• Myelopoiesis generally refers to the production of monocytes and granulocytes. This process also generates precursor cells for macrophages and dendritic cells. These cells are also transported by the circulating blood to the secondary lymphoid organs.

HEALTHCARE APPLICATION
Leukemia

Symptoms	Causes	Treatment
Lymphocytosis; increased production of white blood cells; large atypical lymphocytes; cutaneous T-cell lymphoma; dermatitis	Genetic factors; mutagenic chemicals and viruses	Bone marrow transplants, various drug treatments, radiation

Cells of the Immune System

Leukocytes: White Blood Cells

Leukocytes are divided into two main subdivisions: granulocytes and agranulocytes. Granulocytes are characterized by intracellular granules and on the basis of their special staining properties, differently shaped nuclei, and specific functions. They are further subdivided into basophils, eosinophils, and neutrophils (Figure 20.12). Agranulocytes are devoid of granules and are subdivided into lymphocytes and monocytes (Figure 20.13).

Granulocytes

Polymorphonuclear leukocytes or neutrophils are the most abundant of actively motile phagocytes. They contain large numbers of small lysosomes and migrate to the site of infection to phagocytose invading organisms, after which they die. The death of neutrophils releases the digestive enzymes from their lysosomes, dissolves cellular debris, and prepares the site for healing.

Eosinophils are distinguished from other granulocytes by their large reddish-staining granules. They have phagocytotic capability but are less effective in this action than are neutrophils. Eosinophils increase in numbers during hypersensitivity (allergic) reactions and stimulate the release of histamines by basophils and macrophages. They also provide defense against parasitic infestation by increasing their numbers.

Basophils are the least common of the five leukocyte types. They have dark, bluish purple granules that contain chemical mediators promoting inflammation. These chemicals include histamine, proteoglycans, bradykinin, serotonin, and the anticoagulant heparin. Basophils leave the blood and accumulate at the site of infection. Discharge of the granular contents releases chemical mediators resulting in an increase in blood flow to the affected area. Basophils play a major role in allergic responses, particularly in type I hypersensitivity reactions, and also in the inflammatory response (see later in this chapter).

Agranulocytes

Monocytes are large circulating phagocytotic cells that develop into macrophages as they leave blood vessels during an inflammatory reaction. Both monocytes and macrophages are highly efficient in the engulfment and destruction of bacteria and of cellular debris at the site of an infection as well as in response to an invasion of foreign substances into various organs.

Macrophages ingest immunogens, break them down into smaller components, and then present these antigens to lymphocytes so that the immune response can begin. They are part of the innate defense because they defend against various kinds of agents, but they also play a role in the adaptive defense as they present the antigen to the lymphocytes. Cells presenting antigens to lymphocytes are called antigen-presenting cells. They are classified as wandering macrophages or fixed macrophages depending on their location and function.

Wandering macrophages develop from circulating monocytes that leave the bloodstream during the inflammatory response and act at the infected site. These macrophages usually have a short life span.

Fixed macrophages migrate to specific areas and remain in the specific organs and tissues, where they trap foreign substances and debris. In contrast to wandering macrophages, fixed macrophages can be active for months or years. Examples of fixed macrophages include Kupffer cells, alveolar macrophages, osteoclasts, microglial cells, and macrophages in the lining of the spleen and lymph nodes:

• Kupffer cells belong to the class of sinusoidal lining cells and are fixed macrophages located in the sinusoids of the liver (Figure 20.14, A).

FIGURE 20.14 A, Kupffer cells in the sinusoids of the liver; B, alveolar macrophage, drawing and electron micrograph; C, microglia.

• Alveolar macrophages are found in the alveoli of the lungs (Figure 20.14, B).

• Mesangial cells are macrophages located around blood vessels in the kidneys.

• Osteoclasts are macrophages in bone that break down the bone matrix when calcium is needed in the bloodstream.

• Microglial cells are the only phagocytotic cells in the brain, moving to areas where cell debris must be removed (Figure 20.14, C).

Like macrophages, dendritic cells (DCs) are antigen-presenting cells that arise from monocytes and then migrate through the blood and lymph to almost every tissue. Dendritic cells have class II MHC molecules as surface components and are characterized by long extensions that look like the dendrites of neurons, hence their name (Figure 20.15). In general, they are concentrated at sites where antigen-bearing microorganisms seek their portal of entry, such as the skin and mucous membranes. Dendritic cells check their environment for microorganisms, and when they encounter a pathogen they ingest the organism, break it down, and transport protein fragments to their cell membrane, where these cell fragments are presented to other immune system cells. The different types of DCs include thymic dendritic cells, Langerhans cells, interstitial dendritic cells, and interdigitating dendritic cells.

FIGURE 20.15 Dendritic (Langerhans) cells in the epidermis.

• Thymic dendritic cells produce thymosins, hormones that are believed to aid in the maturation process of T cells.

• Langerhans cells are located in the basal layer of the epidermis and engulf antigens by the process of pinocytosis. The antigens are broken down into polypeptides and moved to the cell surface. This process evokes the activation of T lymphocytes.

• Interstitial dendritic cells are part of a network in the gastrointestinal tract that monitors and interacts with the intestinal environment. These cells may induce the production of IgAs to protect the mucosal lining from pathogen attachment and invasion.

• Interdigitating dendritic cells are found in lymph nodes and play a major role in antigen presentation to the lymphocytes in these lymphatic organs.

Lymphocytes (mononuclear leukocytes) make up 30% to 40% of the white blood cells and they are the primary cells of the immune response. B lymphocytes (B cells) complete the first stage of development in the bone marrow before they enter the blood circulation and migrate to the secondary lymphoid organs. They are ultimately responsible for antigen interaction, the production of antibodies, and immune memory. The naive (inactive) B cells are small lymphocytes with antibodies located in the cell membrane. These surface antibody molecules serve as receptors for specific antigens (antigen-binding sites). One set of these surface immunoglobulins is responsible for antigen recognition and another molecule, a class II MHC molecule, is responsible for antigen presentation. Once an antigen binds to the antibody on the B cell, the B cell rapidly divides and forms plasma cells and memory B cells (see Antibody-mediated Immunity, later in this chapter).

T lymphocytes (T cells) mature in the thymus gland and are necessary for B-cell proliferation as well as cell-mediated immunity (discussed later in this chapter). B cells and T cells have unique surface antigens that distinguish them from each other and subdivide each group into subsets. The international naming system of surface antigens in blood cells is the CD system, which is of clinical importance (i.e., in the diagnosis of AIDS involving the CD4 and CD8 T-cell subsets).

Host Defense

Host defense mechanisms protect against foreign substances and microbes. Certain defense mechanisms are always present (innate) and often are sufficient to impede the replication and spreading of infectious agents. The function of the innate immune defense is to prevent the development of disease by mechanisms of the first and second lines of defense. Innate defense mechanisms are nonspecific because they challenge all invaders via general defense mechanisms. If the innate immune defense is insufficient to stop the invasion of the infectious agent, the adaptive immune system is activated. This process takes time to attain maximal strength. The adaptive immune system response is specific to a specific antigen and is therefore also referred to as specific defense. It represents the third line of defense (Figure 20.16).

First Line of Defense

The first line of defense includes physical and chemical barriers to prevent microbes from entering the body.

Physical Barriers

The intact skin and mucous membranes lining the respiratory, digestive, gastrointestinal, urinary, and reproductive systems provide physical protection against microbial invasion. The smallest of injuries to these physical barriers can provide a portal of entry for pathogens. The mucus of mucous membranes traps particles, which are then removed by the mechanical actions of cilia, called the ciliary escalator (Figure 20.17). The term ciliary escalator describes the process by which the ciliary action moves the mucus from the apical surface of the mucous membrane of the trachea to the oral cavity. The mucus, together with the trapped particles, is then swallowed together with the trapped particles and moved to the stomach, where the particles and microbes are destroyed by the acidity (pH 2) of the stomach’s environment. Sneezing and coughing assist in the removal of mucus from the upper respiratory tract. In smokers, the cilia of the respiratory tract are damaged and the ciliary action is impaired or absent; therefore the mucus is not easily transported to the oral cavity and must be removed by coughing actions (smoker’s cough).

FIGURE 20.17 Ciliary escalator.
The mucus on the apical surface of tracheal epithelial cells traps foreign particles and by ciliary motion the mucus is moved into the oral cavity.

Perspiration mechanically flushes organisms from pores of the sweat glands and also washes the surface of the skin. Tears, saliva, and the flow of urine produce flushing actions against invaders. Infrequent urination, for example, promotes urinary tract infection due to bacterial invasion.

Chemical Barriers

The pH 4.5 to 6 of the skin inhibits the colonization of many pathogens. Sebum produced by sebaceous (oil) glands contains fatty acids and lactic acids that are toxic to many pathogens. Sweat glands also produce fatty acids and lactic acids, which prevent undesirable bacterial colonization on the skin. Mucus produced by the mucous membranes of epithelial tissue contains lysozyme, lactoferrin, and lactoperoxidase, all of which are either bacteriostatic or bactericidal.

Lysozymes, enzymes that attack the peptidoglycan layer of the bacterial cell wall, are present in perspiration, nasal secretions, saliva, and tears. In addition, the acidity of the stomach, the alkalinity of the intestines, and the digestive enzymes all help to protect the digestive tract from unwanted, pathogenic bacterial colonization.

Second Line of Defense

Pathogens that penetrate the first line of defense usually are eliminated by a combination of nonspecific cellular and chemical responses provided by the second line of defense. These responses include phagocytosis, inflammation, fever, production of interferons, and activation of the complement system.

Phagocytosis and Phagocytes

Phagocytosis is a process by which invading foreign substances are destroyed by phagocytes. There are many cells of the immune system that are capable of phagocytosis. Phagocytes approach a microorganism or other particle and extend pseudopods (footlike projections) to engulf the organism. The complete encircling of the organism forms a sac called the phagosome, which fuses with lysosomes containing bactericidal chemicals. After destroying the invader, the phagocyte processes the proteins and presents parts of the antigen protein at the cell surface for lymphocyte recognition.

Steps in phagocytosis (Figure 20.18):

FIGURE 20.18 Process of phagocytosis.
Phagocytosis is part of the second line of defense and involves chemotaxis, the movement of phagocytes to the invaded site; adhesion; ingestion; and digestion.

• Chemotaxis is the guided movement of phagocytes to the invaded site. It is the result of a chemical attraction caused by chemotactic agents. In general, this is achieved through the action of chemokines produced during the complement cascade (see Complement System later in this chapter).

• Adhesion is the process by which phagocytes attach to foreign substances before their ingestion.

• Ingestion is the process by which the membrane of the phagocyte extends pseudopods, surrounding the particle to be ingested.

• Digestion occurs when the phagosome merges with lysosomes within the phagocytotic cell to produce a phagolysosome. The digestive enzymes of lysosomes break down and dissolve the invaders, followed by the release of these digested materials from the phagocyte into the extracellular fluid compartment.

Inflammatory Response

The inflammatory reaction is a protective mechanism, which under certain circumstances may be harmful. Initiating events of an inflammation can be either injury or the presence of antigens, but also extremes of temperature, chemicals, and radiation. If the inflammatory reaction begins when the skin is broken due to a minor injury, it is often strong enough to prevent disease by stopping pathogenic microbes from entering other tissues (Figure 20.19).

FIGURE 20.19 Steps of inflammation.
Inflammation occurs when microbes enter damaged tissue. In response to tissue damage blood vessels also dilate, bradykinin is released by the damaged endothelial cells, and monocytes/macrophages and neutrophils leave the blood vessels in an effort to destroy the invaders.

Steps of inflammation include the following:

1. An injury to capillaries and tissue cells is followed by the release of bradykinin from the injured cells.

2. Bradykinin activates sensory nerve impulses, which initiate pain.

3. The sensation of pain stimulates mast cells and basophils to release histamine.

4. Both bradykinin and histamine cause capillary dilation, increase blood flow, and increase capillary permeability in the infected area.

5. The break in the skin allows bacteria to enter the tissue, which results in the migration of neutrophils and monocytes to the site of injury.

6. Neutrophils phagocytize bacteria and destroy them via the hydrolytic enzymes of their lysosomes.

7. Monocytes that matured into macrophages leave the bloodstream and quickly phagocytize microbes.

The symptoms of inflammation (Box 20.1) include redness (rubor), increased temperature (calor), swelling (tumor), and pain (dolor) in the inflamed area. The redness and increased temperature are caused by the dilation of capillaries and increased blood flow in the region. The increased temperature increases the metabolic rate of the cells to increase the speed of healing. Heat also increases the activities of phagocytotic and other defensive cells. The sensation of pain results from stimulation of nociceptors (sensory receptors) caused by edema (excessive tissue fluid), and the release of prostaglandins by injured cells or bacterial toxins. Swelling (edema) is due to increased permeability of the capillaries and results in seeping of blood plasma components into the tissues. This capillary leakage provides a path to the site of infection for rapid action of infection-fighting cells and clotting factors.

BOX 20.1 Signs of Inflammation

Calor: Increased temperature of the inflamed area due to increased blood flow

Rubor: Redness caused by capillary dilation and increased blood flow to the area

Tumor: Swelling (edema) due to increased capillary permeability

Dolor: Pain that can be due to stimulation of pain receptors (nociceptors) by prostaglandin release, microbial toxins, and edema

Fever

Fever or pyrexia is a systemic response to extensive inflammation or microbial invasion (Box 20.2). A body temperature above 37.8° C (100° F) is generally considered to be a slight (mild) fever and helps the body to eliminate pathogenic organisms. Although high fever is dangerous, within limits it can also be beneficial if it reduces or eliminates the growth and reproduction of the invading microorganisms. The increase in body temperature is regulated by the hypothalamus in response to pyrogens, which are fever-producing substances released from white blood cells in response to microbial invasion. Also, microbial toxins released into the bloodstream can act as pyrogens. Pyrogens are transported by the bloodstream to the hypothalamus, where they stimulate specific neurons that release prostaglandins. Prostaglandins raise the physiological set point of the body temperature, which results in shivering (chills), a physiological response that initiates a rise in body temperature. Shivering involves increased muscle contraction, generating the heat necessary to increase body temperature. When the pathogens are eliminated the set point of the body temperature is lowered to pre-fever levels by evoking the physiological response of perspiration to cool off the body (the fever breaks).

BOX 20.2 Benefits of Fever

• Inhibits multiplication of microorganisms sensitive to higher temperatures

• Reduces the availability of iron to bacteria, resulting in a decline in their nutrition

• Stimulates the immune reaction by increasing the metabolism of the cells responsible to fight infection

• Speeds up hematopoiesis, phagocytosis, and other specific immune reactions

Interferons

Interferons are glycoproteins produced by cells infected with a virus. These proteins are considered antiviral because they interfere with the replication of a virus and impede the spread of the pathogen. The different types of interferons (alpha, α; beta, β; gamma, γ) are activated by different stimuli: bacteria, viruses, foreign cells, and tumors. Interferon-α proteins are produced by B cells, monocytes, and macrophages. Interferon-β proteins are produced by fibroblasts and other virus-infected cells, whereas interferon-γ proteins are released by T cells and natural killer (NK) cells. These interferons do not save the infected cell but bind to receptors on uninfected cells, where they stimulate the production of antiviral proteins. Interferons are species specific but not virus specific. In other words, interferons from a rabbit are ineffective in humans. Although interferons can prevent the spread of viruses they also can elicit nonspecific flulike symptoms that are associated with viral infections.

Cytokines

Cytokines are small proteins considered to be chemical mediators of the immune response and are secreted by cells of the immune system. They are chemical messengers that allow cells within the immune system to communicate with each other and organize the attack on an invader. The same cytokine may be produced by several different cells and the same cytokine might have a different effect in different circumstances. This phenomenon is called pleiotropy. In addition, different cytokines may mediate the same activity depending on the situation; this is called redundancy. Many cytokines are referred to as interleukins (ILs) and are numbered according to when they were discovered, similar to the numbering of blood-clotting factors. The term interleukin describes the chemicals that function as mediators between the white blood cells (inter + leukocytes). Three groups of cytokines have been described according to their functional properties: cytokines that play a role in the regulation of hematopoiesis, cytokines that affect the inflammatory response, and cytokines that regulate the adaptive immune response (Table 20.3).

TABLE 20.3

Selected Cytokines and Their Activities

Cytokine	Source	Function
IL-1	Macrophage, monocytes	T- and B-cell activation; fever; inflammation
IL-2	T cells	T-cell proliferation; activation of B cells
IL-3	T cells	Stimulates growth of stem cells and mast cells
IL-4	T cells	Stimulates growth of B cells and some T cells
IL-5	T cells	B cells; eosinophil differentiation
IL-6	Macrophages, B cells and T cells, other cells	Inflammation, hematopoiesis, differentiation of B cells
IL-7	Fibroblasts, endothelial cells	Early B- and T-cell differentiation
IL-8	Monocytes	Attracts granulocytes
IL-11	Bone marrow	Hematopoiesis
IL-14	Dendritic cells, T cells	B-cell memory

Complement System

The complement system can be activated by the immune system for the recruitment of phagocytes to areas of microbial invasion. This system consists of more than 35 different soluble proteins found in extracellular fluid and influences both innate and acquired immunity. The complement proteins are synthesized primarily by hepatocytes but are also produced by monocytes, macrophages, and epithelial cells of the gastrointestinal and genitourinary tracts. The major complement proteins are named C1 through C9 according to their time of discovery and not the order of their activation in the immune response. Activation of the complement system is called the complement cascade, and it is activated through three biochemical pathways:

1. The classical complement pathway, triggered when an antigen–antibody complex (IgG or IgM) binds to the C1 component

2. The alternative complement pathway, activated by C3 component hydrolysis on the surface of a pathogen

3. The lectin pathway, activated when mannose-binding lectin bound to carbohydrate of a pathogen interacts with an enzyme similar to C1

The three pathways merge at the final stages into a common pathway, with similar end results, namely inflammation, phagocytosis, and/or direct lysis of the antigen.

Third Line of Defense

The third line of defense is provided by the specific or adaptive defense mechanisms. These mechanisms are triggered by a specific antigen. The two fundamental mechanisms in adaptive defense are cell-mediated immunity and humoral immunity. When challenged by an antigen, both B cells and T cells further differentiate, proliferate, and elicit the antigen-specific immune response.

Cell-mediated Immunity

The cell-mediated immune system is controlled by T cells, which are highly specialized lymphocytes circulating in the blood and lymph to fight bacteria, viruses, fungi, protozoans, and any other substances or cells that are foreign to the body. Neither cytotoxic T cells nor helper T cells can recognize an antigen floating in the blood or lymph and must be activated by an antigen-presenting cell, such as a macrophage (Figure 20.20).

The categories of T cells (T lymphocytes) are as follows:

• Cytotoxic/killer T cells (CD8) recognize antigens presented within class I MHC molecules and will attack and destroy antigen-bearing cells such as virus-infected cells and cancer cells by releasing perforin and granzymes. Perforin molecules form a hole in the infected cells, allowing entry of the granzymes, which initiate apoptosis.

• Helper T cells (CD4) recognize antigens presented within class II MHC molecules and will aid the immune response by releasing cytokines that stimulate growth and division of cytotoxic T cells and B cells. In addition, they attract macrophages and further enhance the capabilities of macrophages to phagocytose microbes.

• Suppressor T cells (a subpopulation of CD8 T cells) release chemicals to regulate the immune response by suppressing both the further development of helper T cells and the antibody production by plasma B cells.

• Memory T cells represent the population of T cells that persists after suppression of the immune response. These cells recognize and respond to pathogens that previously invaded the body. They secrete cytokines to stimulate macrophages and B cells in response to repeated invasions.

Antibody-mediated Immunity (Humoral Immunity)

B cells produce specific antibodies and regulate the antibody-mediated immune response to viral and bacterial antigens. Small, naive B cells are mature immunocompetent cells that are stimulated to proliferate and differentiate by antigens that bind to their surface receptors. Each B cell carries a specific surface antibody that recognizes a specific antigen. After an antigen has been recognized, B cells become activated (sensitized) and start dividing into plasma cells and memory cells. This process is called clonal selection (Figure 20.21) and is enhanced by helper T cells (CD4). The majority of the clones become short-lived plasma cells that produce the specific antibodies and the others become long-lasting memory cells. Once enough antibodies have been produced by the B cells to eliminate the antigens, the development of plasma cells ceases under the direction of suppressor T cells. Memory B cells remain and they are responsible for long-term immunity. They will recognize the same antigen when it enters the system again and will divide quickly to produce new plasma and memory cells.

FIGURE 20.21 The process of B-cell activation.
Antigen binds to a specific B cell, clonal selection—the activated B cells form one colony of plasma cells and one colony of memory cells; antibody synthesis—B cells produce specific antibodies to the invading antigen.

When the immune system is exposed to a specific antigen for the first time, it undergoes a primary response. The earliest part of the response is characterized by a latent period (lag period) during which no antibodies specific to the antigen are present. Recognition of foreign substances occurs when the epitope of an antigen fits into the antigen-binding site of the antibody. The antigen is concentrated in lymphoid tissue during this time period and processed by the appropriate B lymphocyte, which then undergoes clonal expansion. Early in the primary response the B cells produce primarily IgM-type antibodies, which are later switched to IgG or another class such as IgE or IgA. The specificity of the antibody for this antigen does not change.

A secondary immune response occurs when the system is exposed to the same immunogen weeks, months, or years later. The rate of antibody synthesis is significantly higher during the secondary response compared with the primary response. The antibody concentration in serum is referred to as the antibody titer. The rapid amplification of antibodies is due to the presence of memory B cells in the secondary immune response. This occurrence is the basis for booster shots in vaccination to increase the antibody titer against dangerous pathogens (see next section). Humeral immunity can also be divided into two categories: active immunity and passive immunity.

Active Immunity

In active immunity, antigens enter the body, which then responds by making its own antibodies via B lymphocytes. This type of immunity is induced by disease or vaccination and can be long-lived or permanent.

• Naturally acquired active immunity results when an individual becomes ill from a particular pathogen and recovers by producing specific antibodies (immunoglobulins) via the immune system. This type of immunity provides long-term protection against this particular pathogen. The extent of time for protection is dependent on the nature of the pathogen.

• Artificially acquired active immunity is a result of a controlled, intentional exposure to weakened, fragmented, killed pathogens or bacterial toxins. By administering a safe amount and form of an antigen, the body’s immune system will produce its own antibodies and memory cells. This type of antigen is called a vaccine. A successful vaccine should have the ability to elicit the appropriate immune response, provide long-term protection, and be safe, stable, and inexpensive. Several different types of vaccines are currently used in the practice of immunization.

• Attenuated microbes are living but nonvirulent strains of a microorganism. This type of live vaccine provides long-lived immunity by administration of a single dose. Although not likely, a reversion to virulence of the attenuated microbes is possible and especially dangerous for immunocompromised people.

• Vaccines from killed or fragmented microbes do not elicit as strong an immune response, the immunity is short-lived, and multiple doses are needed. It is expensive to prepare and the efficacy of the vaccine does not rely on the viability of the organisms.

• DNA immunization through recombinant DNA technology uses genes for viral antigens and not the antigen itself as the immunogen source. The host cells in the individual to be immunized take up the DNA and produce viral antigens by the usual cellular mechanisms. The newly produced antigen is then presented on the cell surface with host MHC class I and class II molecules. Subsequent contact with immunocompetent cells evokes an immune response.

• Toxoids are bacterial or viral toxins that have been altered to become nontoxic. Injections of toxoids provide protection against the toxin, but not against the pathogen itself.

The quantity of antibodies produced and ultimately found in serum after vaccination or an actual infection is the antibody titer. The initial vaccination triggers a rise in the antibody titer that gradually weakens, and booster shots (second injections) are often administered to keep the antibody titer high enough to prevent infection. The secondary response is more effective than the primary response. The memory B cells quickly divide to form more memory B cells and a large number of plasma cells produce a great number of antibodies at a moment’s notice. When an immunized individual is later exposed to the particular pathogen, the immune response is even more intense, thus preventing the infection. For more information about vaccination, see the Life Application box.

LIFE APPLICATION

Vaccination

Immunization (vaccination) against microbes has been an essential component in disease prevention since Edward Jenner’s discovery that live cowpox virus provided protection against the human smallpox virus. Since that time, scientists have developed a variety of vaccines against a large number of pathogens. Today, vaccines are given under two different circumstances: as preexposure prophylaxis and as postexposure prophylaxis. Vaccines in general use today include those against measles, mumps, pertussis, rubella, polio, hepatitis A and B, yellow fever, influenza, diphtheria, tetanus, and many more.

The Vaccine Research Center (VRC), part of the National Institutes of Health (NIH), together with other federal agencies and drug companies, is actively testing new vaccines for future use. Clinical trials for vaccines against SARS virus, West Nile virus, Ebola virus, and HIV are in progress. Approval of many of these vaccines is currently under review by the U.S. Food and Drug Administration (FDA). The FDA has approved a vaccine against the human papillomavirus (HPV), which is known for its capacity to cause cervical cancer.

Passive Immunity

In passive immunity, antibodies are exogenous (from an outside source) rather than endogenous after stimulation of the immune system. Because the body is not producing the antibodies, this immunity is temporary and lasts only as long as the antibodies are present in the bloodstream and lymph.

Naturally acquired passive immunity is obtained from maternal immunoglobulins (IgGs) that have crossed the placenta and entered the fetal circulation. It provides infants with antibodies from the mother for immunity against a specific pathogen. This type of immunity generally lasts for 6 to 12 months after birth, during which time the newborn’s immune system is developing. IgA and IgG in colostrum and breast milk provide additional passive immunity for the newborn. In addition, colostrum and breast milk contain the following substances to help the infant fight infection:

• Oligosaccharides and mucins, which interfere with the adherence of microbes to host cells

• The iron-binding substance lactoferrin, which makes iron unavailable to most bacteria

• Fibronectin, which increases the activity of the infant’s macrophages

• Cytokines, which enhance the activity of certain immune cells

• Lysozymes, which break down the peptidoglycan layer in bacterial cell walls

Artificially acquired passive immunity is achieved by the administration of exogenous protective antibodies from another person or animal. These antibodies may be serum immunoglobulins, or monoclonal antibodies produced in the laboratory. The injection of serum carries a risk of allergic responses to foreign antigens, resulting in serum sickness.

Diseases Caused by the Immune System

Immune system diseases and disorders occur when the immune response is faulty, excessive, or lacking. An altered immune response can occur when one or many of the components of the immune system are structurally or functionally impaired.

Allergy/Hypersensitivity Reactions

An allergy is a strong immune response to an allergen, a substance that usually is not harmful to the body but causes hypersensitivity reactions. Substances such as pollen, mold, dust (most likely dust mites), cat dander, foods, insect stings or bites, certain foods, and medicines can cause these reactions (Table 20.4). Allergies are caused by an overactive immune system producing antibodies against substances that are nonpathogenic and do not cause problems for the human body.

TABLE 20.4

Examples of Allergic Responses, Symptoms, and the Causative Allergens

Allergic Response	Symptoms	Allergen
Allergic rhinitis (hay fever), asthma	Sneezing, nasal congestion, difficulty breathing	Mold, pollen, animal dander, dust mites
Food allergy	Nausea, vomiting, abdominal cramps, diarrhea	Eggs (mostly egg white), fish (especially shellfish), chicken, milk and milk products, nuts, wheat, soybeans
Hives	Reddening and swelling of specific skin areas	Selected foods and food additives, insect bites, drugs (e.g., penicillin), cosmetics
Anaphylactic shock	Dilation of blood vessels, dizziness, nausea, diarrhea, unconsciousness, possibly death	Insect stings, medications, certain foods

Immediate Hypersensitivity (Type I)

The type of allergy called immediate hypersensitivity type I is caused by an excessive response of B lymphocytes to an allergen. Symptoms occur within seconds or minutes of exposure in type I hypersensitivity reactions. These symptoms include the following:

• A runny or stuffy nose

• Gastrointestinal symptoms

The various types of reactions in this category are either local or systemic, involving airway obstruction and even circulatory collapse. A genetic predisposition to allergies is believed to play an important role in the development of this hypersensitivity reaction. However, other factors such as age, the type of allergen, portal of entry, geographic location, and general health of the patient have an impact on the development of hypersensitivity type I reactions.

The production of IgE antibodies instead of IgG antibodies is responsible for the allergic reactions. IgEs do not circulate in the blood but attach to mast cells and basophils within the tissues and bind to the surface receptors of these cells. Mast cells and basophils then release various substances including histamines. The symptoms of hay fever are caused primarily by histamines and are often treated effectively with antihistamines. On the other hand, food allergies are mediated primarily by prostaglandins and are often treated with aspirin, which inhibits prostaglandin synthesis. The difficulty with breathing that occurs in asthma is due to inflammation and smooth muscle contraction of the respiratory system, which can be treated with epinephrine. Probably the most commonly observed allergic symptoms are fever, asthma, hives, and gastrointestinal symptoms.

HEALTHCARE APPLICATION
Examples of Hypersensitivity Reactions

Allergy	Symptoms	Cause	Treatment
Type I Hypersensitivity Reactions: Immediate or Anaphylactic
Dermatitis (eczema)	Itchy, inflamed skin caused by a variety of antigens with different ports of entry	Contact with an antigen found in gloves, new clothes, plants, foods; stress or neurological conditions	Frequent washing and shampooing with medicated soap; topical corticosteroids, and antibiotics
Allergic rhinitis (hay fever)	Nasal congestion, sneezing, coughing, extensive mucous secretion, itchy and teary eyes occurring seasonally or year round	Pollens (tree, grass, and weed), molds, house dust mites, pets, cockroaches, rodents	Environmental control measures; allergen avoidance; antihistamines, decongestants, or both; immunotherapy (desensitization)
Asthma	Impaired breathing, bronchoconstriction, wheezing, shortness of breath, coughing, abnormal breathing sounds, chest tightness	Dust mites, pet dander, pollen, molds, etc.	Antiinflammatory agents, bronchodilators
Food allergies	Tingling sensation in the mouth, swelling of the tongue and throat, difficulty breathing, hives, vomiting, abdominal cramps, diarrhea, drop in blood pressure, loss of consciousness and death	Products in food, food additives, and/or preservatives	Avoidance of the allergy-causing food, treatment of symptoms; no medications are currently available to cure food allergies
Drug allergies	Hives, skin rash, itching of skin or eyes, wheezing, swelling of the lips, tongue, or face; anaphylaxis	A side effect to chemotherapy; antibiotics (most often penicillin)	Avoidance of offending medication; treatment of symptoms, desensitization
Anaphylactic reactions	Dizziness, nausea, difficulty breathing, profound fall in blood pressure, unconsciousness, and sometimes death. Response usually after first exposure	Insect bites, certain foods, medications	Adrenalin, antihistamine, corticosteroids, oxygen when needed. Usual treatment for shock
Type II Hypersensitivity Reactions: Antibody Dependent or Cytotoxic
Hemolytic disease of the newborn	Jaundice, pallor, enlarged liver and/or spleen, generalized swelling, respiratory distress, death	Sensitized mother against fetal blood (see earlier in this chapter)	Before birth: intrauterine transfusion or early induction of labor; plasma exchange in the motherAfter birth: transfusion with compatible packed red blood; exchange transfusion with a compatible blood type; sodium bicarbonate for correction of acidosis, assisted ventilation
Goodpasture’s syndrome	Lung disease: dry cough, minor breathlessness, symptoms may last for many years before severe symptoms such as impairment of oxygenation and coughing up blood develop Kidney disease: affects the glomeruli causing a form of nephritis; acute renal failure can occur Lung and kidney disease may occur alone or together depending on the patient

Unknown Corticosteroids, immunosuppressant; antibiotic treatment of lung infection Autoimmune hemolytic anemia (Coombs test positive) Early destruction of red blood cells; abnormally pale skin, jaundice, dark-colored urine, dizziness, weakness, enlarged spleen and liver, fever, heart murmur, increased heart rate; may be fatal Chemical agents; drugs (e.g., ibuprofen); infections; spider bites (rare); autoimmune disorders Intubation, assisted ventilation, and hemodialysis in the acute phase followed by high-dose corticosteroids, immunosuppression with cyclophosphamide; aggressive wound care in case of spider bite Immune-mediated neutropenia Fever, rash, lymphadenopathy, hepatitis, nephritis, aplastic anemia Drugs that act as haptens to stimulate antibody formation (e.g., penicillin) Offending drugs should be stopped; treatment of symptoms Type III Hypersensitivity Reactions: Immune Complex Serum sickness Rashes, joint pain, fever, lymph node swelling, shock, decreased blood pressure Exposure to antibodies derived from animals; some drugs Symptoms generally disappear on their own; antihistamines and corticosteroids may be prescribed Rheumatoid arthritis Fatigue, morning stiffness for more than 1 h, muscle aches, loss of appetite, weakness, eventually joint pain, swollen joints, limited range of motion, deformation of hands and feet, skin redness or inflammation, swollen glands, numbness or tingling Considered to be an autoimmune disease of unknown origin* Lifelong treatment, including medications, physical therapy, exercise, surgery if required Type IV Hypersensitivity Reactions: Cell Mediated or Delayed Contact dermatitis Skin rashes; dry, itchy, scaly skin Poison ivy, poison oak, poison sumac; exposure to dyes and rubbers, soaps, preservatives, creams, or lotions and other substances at the workplace or home Topical corticosteroid, oral antihistamines. In severe cases oral or injectable corticosteroids, antibiotics, and other antiinflammatory medications may be necessary Temporal arteritis Fever, headache, tenderness and sensitivity on the scalp, blurred vision, sudden blindness Unknown Corticosteroids, sometimes aspirin and immunosuppressive medications

^*Also see the section Autoimmune Diseases in this chapter.

Cytotoxic Hypersensitivity Reactions (Type II)

In type II hypersensitivity (cytotoxic hypersensitivity) the antigens are located on the surface of specific cells or tissues and provide the binding site for circulating antibodies. All type II reactions involve IgG or IgM antibodies, resulting in destruction of the antigen-bearing cells by activating cytolytic enzymes of the complement system (C1 of the classical pathway) or by phagocytosis. Examples of such a reaction would be blood transfusion with an incompatible ABO blood group as well as Rh incompatibility reactions. Damage caused by type II reactions is localized to a particular tissue or cell type, in contrast with type III reactions, which affect organs where antigen–antibody complexes are deposited.

Immune Complex Hypersensitivity Reactions (Type III)

Type III hypersensitivity reactions form immune complexes found in certain autoimmune diseases. These reactions include soluble antigens that combine with an antibody to produce free-floating complexes. These complexes can be deposited in the basement membranes of epithelial tissue or other tissues, causing an immune complex reaction. An example of an immune complex disease is serum sickness, in which a systemic reaction occurs after receiving animal serum or hormones. This condition can cause enlarged lymph nodes, fever, rashes, joint pain, and renal dysfunction. Because of the reduced use of animal serum for immunization, serum sickness is now less common. Type III reactions involve IgG or IgM antibodies, complement proteins, and neutrophils.

Delayed Hypersensitivity (Type IV)

Delayed hypersensitivity (type IV) usually takes more than 24 hours and the reaction occurs when an antigen interacts with antigen-specific lymphocytes that release inflammatory substances. These are cell-mediated immune reactions and therefore part of cell-mediated immunity. The response is caused by T lymphocytes sensitized to an antigen, resulting in the release of lymphokines or other chemical mediators that initiate inflammation followed by destruction of the antigen. An example of this type of allergic reaction is contact dermatitis and the epidermal response often caused by haptens.

Autoimmune Diseases

Autoimmunity occurs when the immune system is unable to distinguish between self-antigens and nonself-antigens and attacks cells, tissues, or organs of the body. Autoimmune diseases can be subdivided into organ-specific diseases, such as Graves’ disease, and nonorgan-specific diseases, such as myasthenia gravis. Autoimmune diseases often occur after an individual has experienced an infection or traumatic injury that activates cytotoxic T cells and antibody production against the body’s own cells and/or organs. Exact causes of autoimmune diseases are still unknown, but susceptibility based on genetics and gender is a possibility. This chapter addresses a few of the most common autoimmune diseases (Table 20.5).

TABLE 20.5

Common Autoimmune Diseases

Disease	System	Symptoms	Tests
Myasthenia gravis	Skeletal muscles	Progressive muscle weakness, paralysis, death	Autoantibodies against acetylcholine receptors
Multiple sclerosis	Central nervous system	Problems with coordination and balance, difficulty in speaking and walking; paralysis, tremors, numbness and tingling sensation in extremities	Neurological examinations, MRI, MRS, testing of the cerebrospinal fluid
Graves’ disease	Thyroid gland	Insomnia, irritability, weight loss, sweating, muscle weakness, bulging eyes, shaky hands	Blood test for TSH
Hashimoto’s thyroiditis	Thyroid gland	Tiredness, depression, cold sensitivity, weight gain, dry hair, muscle weakness, constipation; sometimes asymptomatic	Blood test for TSH
Systemic lupus erythematosus	Affects many organ systems	Swelling and damage to joints, skin, kidneys, heart, lungs, blood vessels, and brain; rash across nose and cheeks (“butterfly rash”)	Blood and urine tests
Rheumatoid arthritis	Systemic, mostly affecting joints, but also the nervous system, lungs, and skin	Inflammation of joints, muscle pain, weakness, fatigue, loss of appetite, weight loss	Blood tests