The Immune System

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The Immune System

WHY YOU NEED TO KNOW

HISTORY

Outbreaks of infectious pathogenic diseases, pestilences, epidemics, pandemics, and plagues have and continue to threaten annihilation of the human race. One of the earliest, chronicled by Thucydides in 431 bce, was a plague in Athens that lasted for more than a year. Later, in the 1300s ce, the Black Death from Yersinia pestis and opportunistic microbes killed an estimated one third of the known population of Asia and Europe. In the twentieth century, the Spanish Influenza virus of 1917–1918 killed an estimated 100 million worldwide in just over 9 months!

Can the “fittest” survive without an immune system? No. Immediately after exposure and later survival ultimately becomes a game of numbers. How many invaders (antigens) against how many antibodies? How virulent are the microbes versus how specific are the antibodies or the T cell response? How able is our own immune system to effectively challenge and control the antigens?

IMPACT

Today we are threatened by Ebola virus, bird flu viruses, HIV, the reemergence of smallpox virus, and, most recently in 2004, the severe acute respiratory syndrome (SARS) virus. The SARS virus is a coronavirus and coronaviruses are generally weak, causing diarrhea or other mild symptoms. But the SARS virus is extremely virulent and can be lethal, particularly among those over 40 years of age. Although a measure of protection against the flu viruses in general is afforded by annual flu shots with vaccines grown in egg culture that is purified and chemically killed, the best protection against the SARS virus is a healthy immune system. Although vaccines are effective, many of these viruses mutate and spread rapidly. For vaccines to be useful, they must be produced in quantity, and delivered in time to meet the viral challenge du jour.

Immunity first comes from the mother, through the umbilical cord before birth, but this is only temporary and helps us survive exposure to pathogens until our own immune system has matured and is functional. The effectiveness of the immediate response of our immune system to pathogens initially depends on our general state of health. This response is enhanced by the presence of antibodies from previous exposure to the same or similar pathogens. Further strengthening is obtained by timely vaccinations. Compliance with all these factors shifts the balance toward a more successful response to and survival after exposure to pathogens.

THE FUTURE

Egg culture vaccines are effective but are produced slowly. New methods being explored that more rapidly produce better vaccines include growing virus in human cell cultures and the development of genetically engineered vaccines. Yet any of these deadly flu viruses, as well as HIV, Ebola, and smallpox viruses, left unchecked, could either decimate or wipe out civilization.

Although our current armory of drugs is generally effective, the occurrence of microbial mutations is eliciting a rising resistance of pathogens to successful, well-established antibiotic therapies. The tried-and-true drugs of the past are becoming ineffective. New and improved therapies, based on better understanding of what assists the immune system, are needed to confront “new and improved” pathogens.

In other words, serendipitous trial and error can only take us so far. It is essential to understand how our immune system works and responds to the presence of any antigens or foreign substances so that we can strengthen our response to them and rationally tip the numbers in favor of survival.

Fundamentals of the Immune System

Immunology

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.

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.

• 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).

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.

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 image
Monomer
image
Monomer
image
Monomer
image
Monomer, dimer
image
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

image

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.

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).

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.

Lymphoid (Lymphatic) Tissue

Lymphoid tissue consists of a framework of loose connective tissue with accumulations of lymphocytes in the interspaces. Lymphoid tissues are the secondary lymphoid organs and can be divided into two basic types: diffuse and nodular lymphatic tissue. Diffuse lymphatic tissue consists of any unorganized collections of lymphocytes, whereas nodular lymphatic tissue is much more organized (see the next section, Lymphatic Nodules). Lymphoid tissue is widely distributed in the body and is typically found at sites that provide possible routes of entry for pathogens. This type of tissue therefore plays a major role in the defense against microorganisms and is found in the connective tissues of mucous membranes in the gastrointestinal, respiratory, urinary, and reproductive tracts (Figure 20.7).

Lymphatic Nodules

Lymphatic nodules are oval-shaped concentrations of lymphoid tissue (nodular lymphatic tissue) not surrounded by a connective tissue capsule. The lymphocytes are densely packed within loose connective tissue in the mucous membranes of the gastrointestinal tract, the respiratory tract, the urinary tract, and the reproductive tract. Collectively this type of tissue is referred to as mucosa-associated lymphoid tissue (MALT). The extensive collections of lymphoid nodules in the digestive tract are specifically called gut-associated lymphoid tissue (GALT). Examples of GALT are the Peyer’s patches, which are concentrated in the ileum. Lymphatic nodules should not be confused with lymph nodes, which are specific anatomical organs surrounded by a distinct connective tissue capsule (see the section Lymph Nodes, later in this chapter).

Tonsils

Tonsils are large lymphatic nodules that are essential components of early defense mechanisms. Located strategically in the wall of the pharynx, they can remove foreign substances entering the body by ingestion or inhalation. The five tonsils are as follows:

Tonsils are comparatively larger in children than in adults, and can obstruct the air passageways if enlarged, such as can occur in tonsillitis. The palatine tonsils are the ones commonly removed in a tonsillectomy. However, lingual tonsils may require removal such as in chronic tonsillitis, sleep apnea, difficulty swallowing, or cancer.

image

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).

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

image

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

image

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):

• 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.

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:

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.

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).

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):

• 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).

Steps of inflammation include the following:

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.

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).

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:

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.

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.

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:

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:

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

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

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*Also see the section Autoimmune Diseases in this chapter.

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.

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

image

MRI, Magnetic resonance imaging; MRS, magnetic resonance spectroscopy; TSH, thyroid-stimulating hormone.

Myasthenia Gravis

The autoimmune disease myasthenia gravis is characterized by the presence of autoantibodies against acetylcholine receptors at the neuromuscular junctions. Under normal physiological conditions acetylcholine is released from the presynaptic terminal in response to nerve impulses. Acetylcholine then binds to its receptors on the postsynaptic membrane, resulting in muscle contraction. The binding of autoantibodies with the acetylcholine receptors at the neuromuscular junction interferes with the contraction of the muscle fibers involved. Individuals affected by the disease experience progressive muscle weakness and all other functions involving skeletal muscles become increasingly weak and difficult. Although the disease affects all skeletal muscles, weakness of the muscles of the eyes (high nerve-to-muscle innervation ratio) and throat often represent the first signs of the disease. As the disease progresses a complete loss of muscle function occurs, eventually leading to paralysis and death.

Multiple Sclerosis

Multiple sclerosis (MS) is a chronic paralyzing autoimmune disease of the central nervous system in which demyelination of axons in both the brain and the spinal cord occurs. Because of the lesions in the myelin sheets caused by T cells and autoantibodies, the capacity of neurons to send impulses is severely compromised. MS can affect any area of the central nervous system (both motor and sensory pathways), resulting in diffuse and varied symptoms. Motor symptoms include but are not limited to muscle weakness, tremors, difficulty walking, lack of coordination, impaired speech, constipation, and problems with control of urination. Sensory symptoms include numbness, itching, tingling, burning sensations, pain, and visual problems. General fatigue is common, combined with depression, mood swings, and sometimes cognitive impairment. Symptoms may last from days to months, and remissions of the symptoms in the early stages of the disease occur in many patients. The cause of MS is still unknown but it has been suggested that the trigger of the disease might be a viral infection, environmental factors, genetic predisposition, or a combination thereof.

Immune Deficiency Diseases

An immune deficiency disease arises when a specific cell or cells within the immune system do not function properly or if part or all of the system is absent. Primary immune deficiency occurs when the abnormalities of the immune system develop because of an inborn abnormality (genetic defect) of the immune system. Secondary immune deficiencies arise when damage is caused by an environmental factor such as infections, radiation, chemotherapy, or burns.

Primary Immune Deficiencies

More than 70 different types of primary immune deficiencies have been reported. Each type of deficiency results in somewhat different symptoms depending on the part of the immune system affected. Although all immune deficiencies result in high susceptibility to infections, some conditions can be mild whereas others might be lethal. These diseases are complex but can now be traced to the failure of one or more parts of the immune system. They can accordingly be classified as:

Some cases of primary immune deficiency can be combined deficiencies and nearly any infection is a threat to life.

Severe Combined Immunodeficiency (SCID)

Severe combined immunodeficiency (SCID) is a rare disorder in which B cells and T cells are inactive or missing; therefore the body is without an immune response. T-cell deficiencies in infants are usually recognized within days of birth and a variety of infections such as sepsis, pneumonia, and systemic viral infections can occur. Probably the most publicized case of SCID involved a child from Texas who spent his life in an isolation chamber for protection from microbes and was often referred to as “the boy in the bubble.”

There are several major causes of SCID, each caused by a different genetic defect. The most common type is caused by a defect in an X-linked gene, resulting in the inability of T and B cells to evoke an immune response. Other types are adenosine deaminase (ADA) deficiencies and purine nucleoside phosphorylase deficiencies, both resulting from lack of an enzyme that helps immune cells remove toxic substances (by-products of cellular metabolism) from their cytoplasm.

Secondary Immune Deficiencies

Acquired immunodeficiency syndrome (AIDS) is a secondary immune deficiency disease caused by human immunodeficiency viruses (HIVs). HIV infection occurs when helper T cells (CD4+), monocytes, and macrophages are infected with the virus. Tests for HIV only disclose antibodies the immune system produces and therefore a negative test for the antibody does not necessarily mean that the virus is not present in the system. The eventual decline in the immune response is believed to be due to the depletion of the helper T cells, which play a major role in the activation of B cells. Once AIDS develops the symptoms vary because the infections that result are caused by different opportunistic organisms such as viruses, fungi, protozoans, and bacteria. Drug “cocktails” are the treatment of choice to inhibit the replication of HIV.

Aging and the Immune System

During the aging process humans become more susceptible to disease, including microbial infections. This is sometimes called immune senescence, a description of the progressive decline in immune function with age. The decrease in the functioning of the immune system appears to be a combination of the normal decrease in the metabolic rates of cells combined with stress factors associated with aging.

The decline of immune function during aging may be related to the decline in the production of lymphocytes. In addition, the production of thymosins starts to decline around age 20 years. The thymus gland (responsible for T-cell maturation) atrophies with age and basically is nonfunctional in many people after the age of 60 years. Older adults produce fewer helper T cells, but most of the memory T cells are still present to assist in the immune response.

Summary

• Immunology is the study of the events in the immune system, whereas immunity describes the immune response to invading microorganisms.

• The circulatory system (lymphatic and cardiovascular) helps to facilitate the immune response, by distributing immune system cells and antibodies throughout the body. Antigens and antibodies interact to form antigen–antibody complexes during an immune reaction.

• Tissues and organs of the immune system include the lymphatic vessels, lymphoid tissue, lymphatic nodules, tonsils, adenoids, lymph nodes, spleen, thymus, and red bone marrow. The cells of the immune system are leukocytes, including basophils, eosinophils, neutrophils, monocytes, macrophages, lymphocytes (B and T cells), and dendritic cells. Each of these components fulfills a particular function in the immune response.

• Antigens stimulate phagocytosis, provided by a variety of phagocytes, and the production of antibodies by B cells. The immune response can be nonspecific (innate) and/or specific (adaptive).

• The first line of defense is a nonspecific defense mechanism and consists of physical and chemical barriers. Physical barriers include the skin, mucous membranes, sweat, tears, and urine flow. Chemical barriers include the pH of the skin, fatty acids and lactic acids from sebum, mucus containing lysozymes, and the pH of the stomach.

• The second line of defense is also part of the innate immune system, involving phagocytes (phagocytosis), inflammation, fever, interferons, cytokines, and the complement system.

• The third line of defense is composed of acquired/adaptive defense mechanisms, consisting of cell-mediated (T and B cells) and humoral (antibody-mediated) immune responses.

• Active and passive immunity require the presence of antibodies. In active immunity, B cells produce antibodies, whereas in passive immunity the body receives antibody from an external source. Both active and passive immunity can be naturally or artificially acquired.

• An overactive immune system can cause autoimmune diseases and hypersensitivity reactions. Autoimmune diseases occur when the immune system is unable to distinguish between self and nonself. They are classified as organ specific and nonorgan specific.

• Hypersensitivity reactions are classified as types I, II, III, and IV.

• During the aging process, people become more susceptible to microbial infections and autoimmune diseases because of deficiencies in their lymphatic and immune systems.

Review Questions

1. The antibody found in body secretions is:

2. An antibody is a:

3. Which of the following cell types secretes antibodies?

4. Which of the following provide defense against viral infections?

5. Which of the following cells is a granulocyte?

6. Immunity that is a result of an actual infection is called:

7. A substance capable of raising the body temperature is:

8. When an organ or tissue is transplanted between genetically different individuals from the same species it is called a(n):

9. Which of the following is a systemic autoimmune disease?

10. Which of the following is not part of the second line of defense?

11. Enzymes that attack the peptidoglycan layer of bacteria and are present in perspiration, nasal secretion, saliva, and tears are __________.

12. Delayed hypersensitivity is a result of __________.

13. B cells are responsible for __________-mediated immunity.

14. Substances that stimulate the production of antibodies are called __________.

15. The body’s decreased ability to fight infections is called __________.

16. Describe and explain the three lines of host immune defense.

17. Name and describe the steps of inflammation.

18. Describe the structure and function of the various antibodies.

19. Discuss type I hypersensitivity reactions.

20. Name and describe two autoimmune diseases.