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
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Monomer
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Monomer
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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

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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.

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