Type and Source	Biologic Activity	Clinical Outcomes
Histamine
Mast cell and basophil granules	Increases vascular permeability. Constricts smooth muscle; stimulates irritant receptors	Edema of airways and larynx, bronchial constriction, urticaria, angioedema, pruritus, nausea, vomiting, diarrhea, shock
Leukotrienes
Metabolites of arachidonic acid by lipoxygenase pathway*	Constrict bronchial smooth muscle, increase vascular permeability	Bronchial constriction, enhanced effect of histamine on smooth muscle
Prostaglandins
Metabolites of arachidonic acid by cyclooxygenase pathway*	Stimulate vasodilation, constrict smooth muscle	Wheal-and-flare reaction on skin, hypotension, bronchospasm
Platelet-Activating Factor
Mast cell	Aggregates platelets, stimulates vasodilation	Increase in pulmonary artery pressure, systemic hypotension
Kinins
Kininogen	Stimulate slow, sustained smooth muscle contraction. Increase vascular permeability, stimulate secretion of mucus, stimulate pain receptors	Angioedema with painful swelling, bronchial constriction
Serotonin
Platelets	Increases vascular permeability, stimulates smooth muscle contraction	Mucosal edema, bronchial constriction
Anaphylatoxins
C3a, C4a, C5a from complement activation	Stimulate histamine release	Same as for histamine

^*See Fig. 12-2.

eTABLE 14-2

TECHNOLOGIES IN IMMUNOLOGY

Monoclonal Antibodies

What Are They?

Monoclonal antibodies are homogeneous populations of identical antibody molecules produced by specialized tissue cell culture lines.

How Are They Made?

• The procedure uses cell fusion techniques and standard in vitro tissue culture systems (see eFig. 14-2).

• The two essential biologic components are immunized mice or rats and myeloma tumor cell lines, which are of lymphoid origin.

• Single antibody-forming cells (lymphocytes) from rodents previously immunized with antigen are fused with myeloma cells to create hybrid cells with properties of both parent cell types.

• The hybrids have an unlimited capacity to grow, similar to that of the myeloma parent cell. The hybrids produce the single type of antibody molecule that they inherited from the normal, antibody-forming parent cell.

• Hybrid cells derived in this way can produce unlimited quantities of specific antibodies.

• With appropriate selection techniques, producing monoclonal antibodies to virtually any antigen is possible.

• Because the monoclonal antibodies are a completely homogeneous population, their use incurs fewer problems than conventional polyclonal antisera.

Uses of Monoclonal Antibodies

• They have wide application in many areas of medicine and biologic science.

• Thousands of monoclonal antibodies have been made against many different types of antigens.

• Monoclonal antibodies have begun to replace conventional antibodies in blood banking and are used in the identification of organisms in the bacteriology laboratory.

• Monoclonal antibodies have also been used extensively in radioimmunoassays to measure serum levels of various substances (e.g., parathyroid hormone).

• They have been useful in quantitating types of white blood cells (WBCs) and subtypes of lymphocytes. They are also used in the diagnosis of leukemia.

• More recently, monoclonal antibodies have been used in the treatment of malignancies (see Chapter 16).

• They have been used to treat transplant rejection episodes, purge bone marrow of tumor cells in bone marrow transplants, and remove mature T cells that cause graft-versus-host (GVH) disease in bone marrow transplant patients.

• A major limitation of monoclonal antibodies used for humans is that they are mouse antibodies and therefore can elicit an antibody response by the host against the foreign agent. Recently, human hybridomas have been produced using human myelomas. These hybrids synthesize human monoclonals and are therefore advantageous for in vivo use in diagnosis and therapy.

Recombinant DNA Technology

• Recombinant DNA technology, a form of genetic engineering, involves taking segments of DNA from one type of organism and combining them with genes from a second organism (see eFig. 14-1).

• When the cell divides, the DNA is transcribed and a specific protein coded by the DNA is made. In this way, relatively simple organisms such as Escherichia coli and yeast or mammalian tissue culture cells can be used to make large quantities of human proteins.

• This process is used to make human insulin and cytokines (e.g., α-interferon, interleukin-2), as well as many other substances.

Polymerase Chain Reaction

What Is It?

• Polymerase chain reaction (PCR) is a way to make many copies of a DNA or RNA sequence in only a few hours.

• PCR involves the artificial replication of a DNA or RNA sequence. The DNA or RNA strands can be separated to form new templates that are used for replication.

• PCR requires only small amounts of sample (e.g., blood, buccal swabs, secretions), in contrast to other laboratory assays.

Uses of PCR

• Used when rapid genetic diagnosis is necessary.

• Used extensively in forensic medicine to identify DNA of criminal suspects by using samples from blood, hair, and semen.

• May also be used as a confirmatory test in human immunodeficiency virus (HIV) testing. This is especially important when an infant of a mother who is HIV-antibody positive also tests HIV positive. In this situation, it is not known whether the antibodies from the infant’s blood are from the baby or the mother. PCR techniques can be used on the baby’s lymphocytes to determine whether the baby is infected with HIV.

TABLE 14-1

TYPES OF ACQUIRED SPECIFIC IMMUNITY

Type	Natural	Artificial
Active	Natural contact with antigen through clinical infection (e.g., recovery from chickenpox, measles, mumps)	Immunization with antigen (e.g., immunization with live or killed vaccines)
Passive	Transplacental and colostrum transfer from mother to child (e.g., maternal immunoglobulins in neonate)	Injection of serum from immune human (e.g., injection of human gamma globulin)

Active Acquired Immunity.

Active acquired immunity results from the invasion of the body by foreign substances such as microorganisms and subsequent development of antibodies and sensitized lymphocytes. With each reinvasion of the microorganisms, the body responds more rapidly and vigorously to fight off the invader. Active acquired immunity may result naturally from a disease or artificially through immunization with a less virulent antigen. Because antibodies are synthesized, immunity takes time to develop but is long lasting.

Healthy People

Health Impact of Immunization

• Can help control the spread of infections within communities.

• Can prevent disability and death from infectious disease for individuals.

• Reduces and can possibly eliminate polio, measles, and other diseases with widespread use.

• Decreased incidence of infectious diseases (e.g., influenza, pneumonia) when more people are vaccinated against these diseases.

Passive Acquired Immunity.

Passive acquired immunity implies that the host receives antibodies to an antigen rather than synthesizing them. This may take place naturally through the transfer of immunoglobulins across the placental membrane from mother to fetus. Artificial passive acquired immunity occurs through injection with gamma globulin (serum antibodies). The benefit of this immunity is its immediate effect. Unfortunately, passive immunity is short lived because the person does not synthesize the antibodies and consequently does not retain memory cells for the antigen.

Lymphoid Organs

The lymphoid system is composed of central (or primary) and peripheral lymphoid organs. The central lymphoid organs are the thymus gland and bone marrow. The peripheral lymphoid organs are the lymph nodes; tonsils; spleen; and gut-, genital-, bronchial-, and skin-associated lymphoid tissues (Fig. 14-1).

Lymphocytes are produced in the bone marrow and eventually migrate to the peripheral organs. The thymus is involved in the differentiation and maturation of T lymphocytes and is therefore essential for a cell-mediated immune response. During childhood the thymus is large. It shrinks with age, and in the older person the thymus is a collection of reticular fibers, lymphocytes, and connective tissue.

When antigens are introduced into the body, they may be carried by the bloodstream or lymph channels to regional lymph nodes. The antigens interact with B and T lymphocytes and macrophages in the lymph nodes. The two important functions of lymph nodes are (1) filtration of foreign material brought to the site and (2) circulation of lymphocytes.

The tonsils are an example of lymphoid tissue. The spleen, a peripheral lymph organ, is important as the primary site for filtering foreign antigens from the blood. It consists of two kinds of tissue: white pulp containing B and T lymphocytes and red pulp containing erythrocytes. Macrophages line the pulp and sinuses of the spleen.

Lymphoid tissue is found in the submucosa of the gastrointestinal (GI) (gut-associated), genitourinary (genital-associated), and respiratory (bronchial-associated) tracts. This tissue protects the body surface from external microorganisms.

The skin-associated lymph tissue primarily consists of lymphocytes and Langerhans’ cells (a type of dendritic cell) found in the epidermis of skin. When Langerhans’ cells are depleted, the skin can neither initiate an immune response nor support a skin-localized delayed hypersensitivity reaction.

Cells Involved in Immune Response

Mononuclear Phagocytes.

The mononuclear phagocyte system includes monocytes in the blood and macrophages found throughout the body. Mononuclear phagocytes have a critical role in the immune system. They are responsible for capturing, processing, and presenting the antigen to the lymphocytes. This stimulates a humoral or cell-mediated immune response. Capturing is accomplished through phagocytosis. The macrophage-bound antigen, which is highly immunogenic, is presented to circulating T or B lymphocytes and thus triggers an immune response (Fig. 14-2).

FIG. 14-2 The immune response to a virus. A, A virus invades the body through a break in the skin or another portal of entry. The virus must make its way inside a cell to replicate itself. B, A macrophage recognizes the antigens on the surface of the virus. The macrophage digests the virus and displays pieces of the virus (antigens) on its surface. C, A T helper cell recognizes the antigen displayed and binds to the macrophage. This binding stimulates the production of cytokines (interleukin-1 *[IL-1]* and tumor necrosis factor *[TNF]* ) by the macrophage and interleukin-2 *(IL-2)* and γ-interferon *(γ-IFN)* by the T cell. These cytokines are intracellular messengers that provide communication among the cells. D, IL-2 instructs other T helper cells and T cytotoxic cells to proliferate (multiply). T helper cells release cytokines, causing B cells to multiply and produce antibodies. E, T cytotoxic cells and natural killer cells destroy infected body cells. F, The antibodies bind to the virus and mark it for macrophage destruction. G, Memory B and T cells remain behind to respond quickly if the same virus attacks again.

Lymphocytes.

Lymphocytes are produced in the bone marrow (Fig. 14-3). They then differentiate into B and T lymphocytes.¹

B Lymphocytes.

In the early research on B lymphocytes (bursa-equivalent lymphocytes) in birds, it was discovered that they mature under the influence of the bursa of Fabricius, hence the name B cells. However, this lymphoid organ does not exist in humans. The bursa-equivalent tissue in humans is the bone marrow. B cells differentiate into plasma cells when activated. Plasma cells produce antibodies (immunoglobulins) (Table 14-2).

TABLE 14-2

CHARACTERISTICS OF IMMUNOGLOBULINS

Class	Serum Concentration	Location	Characteristics
IgG	76%	Plasma, interstitial fluid	Is only immunoglobulin that crosses placenta Is responsible for secondary immune response
IgA	15%	Body secretions, including tears, saliva, breast milk, colostrum	Lines mucous membranes and protects body surfaces
IgM	8%	Plasma	Is responsible for primary immune response Forms antibodies to ABO blood antigens
IgD	1%	Plasma	Is present on lymphocyte surface Assists in the differentiation of B lymphocytes
IgE	0.002%	Plasma, interstitial fluids	Causes symptoms of allergic reactions Fixes to mast cells and basophils Assists in defense against parasitic infections

T Lymphocytes.

Cells that migrate from the bone marrow to the thymus differentiate into T lymphocytes (thymus-dependent cells). The thymus secretes hormones, including thymosin, that stimulate the maturation and differentiation of T lymphocytes. T cells make up 70% to 80% of the circulating lymphocytes and are primarily responsible for immunity to intracellular viruses, tumor cells, and fungi. T cells live from a few months to the life span of an individual and account for long-term immunity.

T lymphocytes can be categorized into T cytotoxic and T helper cells. Antigenic characteristics of WBCs have now been classified using monoclonal antibodies. These antigens are classified as clusters of differentiation, or CD antigens. Many types of WBCs, especially lymphocytes, are referred to by their CD designations. All mature T cells have the CD3 antigen.

T Cytotoxic Cells.

T cytotoxic (CD8) cells are involved in attacking antigens on the cell membrane of foreign pathogens and releasing cytolytic substances that destroy the pathogen. These cells have antigen specificity and are sensitized by exposure to the antigen. Much like B lymphocytes, some sensitized T cells do not attack the antigen but remain as memory T cells. As in the humoral immune response, a second exposure to the antigen results in a more intense and rapid cell-mediated immune response.

T Helper Cells.

T helper (CD4) cells are involved in the regulation of cell-mediated immunity and the humoral antibody response. T helper cells differentiate into subsets of cells that produce distinct types of cytokines (discussed in a later section). These subsets are called T_H1 cells and T_H2 cells. T_H1 cells stimulate phagocyte-mediated ingestion and killing of microbes, the key component of cell-mediated immunity. T_H2 cells stimulate eosinophil-mediated immunity, which is effective against parasites and is involved in allergic responses.

Natural Killer Cells.

Natural killer (NK) cells are also involved in cell-mediated immunity. These cells are not T or B cells but are large lymphocytes with numerous granules in the cytoplasm. NK cells do not require prior sensitization for their generation. These cells are involved in recognition and killing of virus-infected cells, tumor cells, and transplanted grafts. The mechanism of recognition is not fully understood. NK cells have a significant role in immune surveillance for malignant cell changes.

Dendritic Cells.

Dendritic cells make up a system of cells that are important to the immune system, especially the cell-mediated immune response. They have an atypical shape with extensive dendritic processes that form and retract. They are found in many places in the body, including the skin (where they are called Langerhans cells) and the lining of the nose, the lungs, the stomach, and the intestine. Especially in the immature state, they are found in the blood.²

They primarily function to capture antigens at sites of contact with the external environment (e.g., skin, mucous membranes) and then transport an antigen until it encounters a T cell with specificity for the antigen. In this role, dendritic cells can have an important function in activating the immune response.

Cytokines

The immune response involves complex interactions of T cells, B cells, monocytes, and neutrophils. These interactions depend on cytokines (soluble factors secreted by WBCs and a variety of other cells in the body) that act as messengers between the cell types. Cytokines instruct cells to alter their proliferation, differentiation, secretion, or activity.

Currently more than 100 different cytokines are known, and they can be classified into distinct categories. Some of these cytokines are listed in Table 14-3. In general, the interleukins act as immunomodulatory factors, colony-stimulating factors act as growth-regulating factors for hematopoietic cells, and interferons are antiviral and immunomodulatory.

TABLE 14-3

TYPES AND FUNCTIONS OF CYTOKINES *

Type	Primary Functions
Interleukins (ILs)
IL-1	Proinflammatory mediator. Promotes maturation and clonal expansion of B cells, enhances activity of NK cells, activates T cells, activates macrophages.
IL-2	Induces proliferation and differentiation of T cells; activation of T cells, NK cells, and macrophages. Stimulates release of other cytokines (α-IFN, TNF, IL-1, IL-6).
IL-3 (multicolony colony-stimulating factor)	Hematopoietic growth factor for hematopoietic precursor cells.
IL-4	Antiinflammatory mediator. B-cell growth factor, stimulates proliferation and differentiation of B cells. Induces differentiation into T_H2 cells. Stimulates growth of mast cells.
IL-5	B cell growth and differentiation. Promotes growth and differentiation of eosinophils.
IL-6	Proinflammatory mediator: T- and B-cell growth factor, promotes differentiation of B cells into plasma cells, stimulates antibody secretion, induces fever, synergistic effects with IL-1 and TNF.
IL-7	Promotes growth of T and B cells.
IL-8	Chemotaxis of neutrophils and T cells, stimulates superoxide and granule release.
IL-9	Enhances T cell survival, mast cell activation.
IL-10	Antiinflammatory mediator, inhibits cytokine production by T cells and NK cells, promotes B cell proliferation and antibody responses, potent suppressor of macrophage function.
Interferons (IFNs)
α-IFN β-IFN γ-IFN	Inhibit viral replication, activate NK cells and macrophages, antiproliferative effects on tumor cells. Proinflammatory mediator: activates macrophages, neutrophils, and NK cells; promotes B cell differentiation. Inhibits viral replication.
Tumor Necrosis Factor (TNF)	Proinflammatory mediator; activates macrophages and granulocytes; promotes the immune and inflammatory responses; kills tumor cells; responsible for weight loss associated with chronic inflammation and cancer.
Colony-Stimulating Factors (CSFs)
Granulocyte colony-stimulating factor (G-CSF)	Stimulates proliferation and differentiation of neutrophils, enhances functional activity of mature PMNs.
Granulocyte-macrophage colony-stimulating factor (GM-CSF)	Stimulates proliferation and differentiation of PMNs and monocytes.
Macrophage colony-stimulating factor (M-CSF)	Promotes proliferation, differentiation, and activation of monocytes and macrophages.
Erythropoietin	Stimulates erythroid progenitor cells in bone marrow to produce red blood cells.

NK, Natural killer; PMNs, polymorphonuclear neutrophils.

^*A more comprehensive presentation of cytokines is available at www.rndsystems.com/molecule_group.aspx?g=704&;r=4.

The net effect of an inflammatory response is determined by a balance between proinflammatory and antiinflammatory mediators. Sometimes cytokines are classified as proinflammatory or antiinflammatory (see Table 14-3). However, it is not that clear-cut, since many other factors (e.g., target cells, environment) influence the inflammatory response to a given injury or insult.

Cytokines have a beneficial role in hematopoiesis and immune function. They can also have detrimental effects such as those seen in chronic inflammation, autoimmune diseases, and sepsis. Cytokines such as erythropoietin (see Chapter 47), colony-stimulating factors (see Table 16-14), interferons (see Table 16-13), and interleukin-2 (see Table 16-13) are used clinically to (1) stimulate hematopoiesis, (2) stimulate the bone marrow to make WBCs, and (3) treat various malignancies. In addition, inhibitors of cytokines such as soluble tumor necrosis factor receptor antagonist and interleukin-1 are used as antiinflammatory agents. (Clinical uses of cytokines are listed in Table 14-4.)

TABLE 14-4

CLINICAL USES OF CYTOKINES

Cytokine	Clinical Uses
α-Interferon (Roferon-A, Intron A)*	Hairy cell leukemia, chronic myelogenous leukemia, malignant melanoma, renal cell carcinoma, ovarian cancer, multiple myeloma, Kaposi sarcoma, hepatitis B and C
β-Interferon (Betaseron, Avonex, Rebif)	Multiple sclerosis
Colony-Stimulating Factors
*G-CSF*
• filgrastim (Neupogen) • pegfilgrastim (Neulasta)	Chemotherapy-induced neutropenia
*GM-CSF*
• sargramostim (Leukine)	Neutropenia, myeloid recovery after bone marrow transplantation
Soluble TNF Receptor
etanercept (Enbrel)	Rheumatoid arthritis
Interleukin-2
aldesleukin (Proleukin)	Metastatic renal cell carcinoma, metastatic melanoma
Interleukin 11 (platelet growth factor)
oprelvekin (Neumega)	Prevention of thrombocytopenia after chemotherapy
Erythropoietin
epoetin alfa (Epogen, Procrit) darbepoetin alfa (Aranesp)	Anemia of chronic cancer, anemia related to chemotherapy, anemia of chronic kidney disease
IL-1 Receptor Antagonist
anakinra (Kineret)	Rheumatoid arthritis

G-CSF, Granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; TNF, tumor necrosis factor.

^*eFig. 14-1 on the website for this chapter shows how interferon is commercially made.

Interferon helps the body’s natural defenses attack tumors and viruses. Three types of interferon have now been identified (see Table 14-3). In addition to their direct antiviral properties, interferons have immunoregulatory functions. These include enhancement of NK cell production and activation, and inhibition of tumor cell growth.

Interferon is not directly antiviral but produces an antiviral effect in cells by reacting with them and inducing the formation of a second protein termed antiviral protein (Fig. 14-4). This protein mediates the antiviral action of interferon by altering the cell’s protein synthesis and preventing new viruses from becoming assembled.

FIG. 14-4 Mechanism of action of interferon *(IFN)*. When a virus attacks a cell, the cell begins to synthesize viral DNA and interferon. Interferon serves as an intercellular messenger and induces the production of antiviral proteins. Then the virus is not able to replicate in the cell.

Comparison of Humoral and Cell-Mediated Immunity

Humans need both humoral and cell-mediated immunity to remain healthy. Each type of immunity has unique properties, different methods of action, and reactions against particular antigens. Table 14-5 compares humoral and cell-mediated immunity.

TABLE 14-5

COMPARISON OF HUMORAL AND CELL-MEDIATED IMMUNITY

Characteristics	Humoral Immunity	Cell-Mediated Immunity
Cells involved	B lymphocytes	T lymphocytes, macrophages
Products	Antibodies	Sensitized T cells, cytokines
Memory cells	Present	Present
Protection	Bacteria Viruses (extracellular) Respiratory and GI pathogens	Fungus Viruses (intracellular) Chronic infectious agents Tumor cells
Examples	Anaphylactic shock Atopic diseases Transfusion reaction Bacterial infections	Tuberculosis Fungal infections Contact dermatitis Graft rejection Destruction of cancer cells

Humoral Immunity.

Humoral immunity consists of antibody-mediated immunity. The term humoral comes from the Greek word humor, which means body fluid. Since antibodies are produced by plasma cells (differentiated B cells) and found in plasma, the term humoral immunity is used. Production of antibodies is an essential component in a humoral immune response. Each of the five classes of immunoglobulins (Igs)—that is, IgG, IgA, IgM, IgD, and IgE—has specific characteristics (see Table 14-2).

When a pathogen (especially bacteria) enters the body, it may encounter a B lymphocyte that is specific for antigens located on that bacterial cell wall. In addition, a monocyte or macrophage may phagocytize the bacteria and present its antigens to a B lymphocyte. The B lymphocyte recognizes the antigen because it has receptors on its cell surface specific for that antigen. When the antigen comes in contact with the cell surface receptor, the B cell becomes activated, and most B cells differentiate into plasma cells (see Fig. 14-3). The mature plasma cell secretes immunoglobulins. Some stimulated B lymphocytes remain as memory cells.

The primary immune response becomes evident 4 to 8 days after the initial exposure to the antigen (Fig. 14-5). IgM is the first type of antibody formed. Because of the large size of the IgM molecule, this immunoglobulin is confined to the intravascular space. As the immune response progresses, IgG is produced, and it can move from intravascular to extravascular spaces.

FIG. 14-5 Primary and secondary immune responses. The introduction of antigen induces a response dominated by two classes of immunoglobulins, IgM and IgG. IgM predominates in the primary response, with some IgG appearing later. After the host’s immune system is primed, another challenge with the same antigen induces the secondary response, in which some IgM and large amounts of IgG are produced.

When the individual is exposed to the antigen the second time, a secondary antibody response occurs. This response occurs faster (1 to 3 days), is stronger, and lasts for a longer time than a primary response. Memory cells account for the memory of the first exposure to the antigen and the more rapid production of antibodies. IgG is the primary antibody found in a secondary immune response.

IgG crosses the placental membrane and provides the newborn with passive acquired immunity for at least 3 months. Infants may also get some passive immunity from IgA in breast milk and colostrum.

Cell-Mediated Immunity.

Immune responses that are initiated through specific antigen recognition by T cells are termed cell-mediated immunity. Several cell types and factors are involved in cell-mediated immunity. The cell types involved include T lymphocytes, macrophages, and NK cells. Cell-mediated immunity is of primary importance in (1) immunity against pathogens that survive inside of cells, including viruses and some bacteria (e.g., mycobacteria); (2) fungal infections; (3) rejection of transplanted tissues; (4) contact hypersensitivity reactions; and (5) tumor immunity.

Gerontologic Considerations

Effects of Aging on the Immune System

With advancing age, there is a decline in the function of the immune response (Table 14-6). The primary clinical evidence of immunosenescence is the high incidence of malignancies in older adults. Older people are also more susceptible to infections (e.g., influenza, pneumonia) from pathogens that they were relatively immunocompetent against earlier in life. Bacterial pneumonia is the leading cause of death from infections in older adults. The antibody response to immunizations (e.g., flu vaccine) in older adults is considerably lower than in younger adults.

The bone marrow remains relatively unaffected by increasing age. Immunoglobulin levels decrease with age and therefore lead to a suppressed humoral immune response in older adults. Thymic involution (shrinking) occurs with aging, along with decreased numbers of T cells. These changes in the thymus gland are a primary cause of immunosenescence. Both T and B cells show deficiencies in activation, transit time through the cell cycle, and subsequent differentiation. However, the most significant alterations involve T cells. As thymic output of T cells diminishes, the differentiation of T cells increases. Consequently, there is an accumulation of memory cells rather than new precursor cells responsive to previously unencountered antigens.

The delayed hypersensitivity reaction, as determined by skin testing with injected antigens, is frequently decreased or absent in older adults. This altered response reflects anergy (an immunodeficient condition characterized by lack of or diminished reaction to an antigen or a group of antigens).

Altered Immune Response

Immunocompetence exists when the body’s immune system can identify and inactivate or destroy foreign substances. When the immune system is incompetent or underresponsive, severe infections, immunodeficiency diseases, and malignancies may occur. When the immune system overreacts, hypersensitivity disorders such as allergies and autoimmune diseases may develop.

Hypersensitivity Reactions

Sometimes the immune response is overreactive against foreign antigens or reacts against its own tissue, resulting in tissue damage. These responses are termed hypersensitivity reactions. Autoimmune diseases, a type of hypersensitivity response, occur when the body fails to recognize self-proteins and reacts against self-antigens.

Hypersensitivity reactions can be classified according to the source of the antigen, the time sequence (immediate or delayed), or the basic immunologic mechanisms causing the injury. Four types of hypersensitivity reactions exist (Table 14-7). Types I, II, and III are immediate and are examples of humoral immunity. Type IV is a delayed hypersensitivity reaction and is related to cell-mediated immunity.

TABLE 14-7

TYPES OF HYPERSENSITIVITY REACTIONS

Type I: IgE-Mediated	Type II: Cytotoxic	Type III: Immune-Complex	Type IV: Delayed Hypersensitivity
Antigen
Exogenous pollen, food, drugs, dust	Cell surface of RBCs Cell basement membrane	Extracellular fungal, viral, bacterial	Intracellular or extracellular
Antibody Involved
IgE	IgG, IgM	IgG, IgM	None
Complement Involved
No	Yes	Yes	No
Mediators of Injury
Histamine Mast cells Leukotrienes Prostaglandins	Complement lysis Macrophages in tissues	Neutrophils Complement lysis Monocytes, macrophages Lysosomal enzymes	Cytokines T cytotoxic cells
Examples
Allergic rhinitis Asthma	Transfusion reaction Goodpasture syndrome Immune thrombocytopenic purpura Graves’ disease	Systemic lupus erythematosus Rheumatoid arthritis	Contact dermatitis to poison ivy
Skin Test
Wheal and flare	None	Erythema and edema in 3-8 hr	Erythema and edema in 24-48 hr (e.g., TB test)