I. INTRODUCTION

The immune system is a sophisticated defense mechanism that has evolved in vertebrate organisms. It is designed to protect the body against invasion by microorganisms and to seek out and destroy abnormal (tumor) cells.

The immune system can be divided into two categories. Innate (or natural) immunity provides a first line of defense against infection. It is relatively non-specific, meaning it is more-or-less equally effective against a broad variety of microorganisms. It comprises a number of natural barriers to infection, including:

• Anatomical barriers, such as skin, mucous membranes, ciliated epithelial cells, tears, and saliva.
• Physiological barriers, such as temperature and pH (as in the acid pH of the stomach). Soluble factors such as lysozyme, complement, and interferons are also important. Lysozyme is an enzyme that digests the cell wall of many bacteria, causing them to burst apart (lyse). Interferons are naturally produced substances that help cells to resist infection by viruses. The complement system is discussed briefly below.
• Phagocytosis (also called endocytosis) refers to the ingestion and destruction of microorganisms, foreign matter, and debris from damaged cells by white blood cells (neutrophils and macrophages). You’ll learn much more about this process in the lecture on inflammation.
• Inflammation, which will be the topic of the next lecture.

The complement system consists of 20 proteins that are found in the blood plasma. The complement system can be activated (or "fixed") when these proteins are exposed to the outer surfaces of bacteria or to antibodies bound to their target antigens (more about that later). Activation of the system causes the complement proteins to undergo a series of changes, in which one protein acts on another, which acts on another, etc., much like the blood clotting cascade. Most of these changes involve the splitting of complement proteins into two or more fragments. The end result of these changes is formation of the so-called membrane attack complex (MAC), which can bind to membranes and punch holes in them, leading to destruction (lysis) of the cell that is under attack. When all is working well, these cells will be invading microorganisms. As we shall see, however, sometimes the system is unleashed against the body’s own cells. Certain by-products that are produced when complement is activated are important in inflammation.

The remainder of this lecture will be devoted to acquired immunity. Acquired immunity is more specific than innate immunity. It does not work equally well against all microorganisms; rather, it deals most efficiently with microorganisms that you have encountered before. For this reason, the acquired immune response is said to have memory. However, the acquired immune response is capable of recognizing a great variety of foreign substances, so it is also said to have diversity. Acquired immunity can discriminate between foreign substances and substances that are naturally found in one’s body, that is, it can tell the difference between self and non-self. The reactions of the acquired immune response are critically dependent on lymphocytes, a type of leukocyte (white blood cell).

II. ANTIGENS

The reactions of acquired immunity are triggered by antigens. A formal definition of an antigen is a foreign substance that binds specifically to antibody molecules or to receptors on T cells to elicit an immune response.

Not all substances are antigens. To be an antigen, a substance must by viewed by the immune system as foreign. A substance that is naturally a part of your body does not normally trigger an immune response. Antigens must have a molecular weight greater than 10,000 daltons. This is fortunate; otherwise, all the nutrients that you eat might trigger an immune reaction. Foreign proteins are best at eliciting an immune response, but some carbohydrates can also act as antigens. Finally, antigens must be able to be taken up by macrophages and digested; the reason for this requirement will soon become clear.

Sometimes, a substance that is too small to serve as an antigen by itself can stimulate an immune reaction if it is coupled to a larger, "carrier" protein. Such substances are called haptens. A good example is penicillin, which can bind to the surface of red blood cells and trigger an immune reaction. The immune system, using mechanisms that will be described, then attacks both the penicillin and the red blood cell to which it is attached. Resulting destruction of the red blood cells can cause anemia.

An antibody molecule generally reacts with only a small part of an antigen. This portion is referred to as an epitope or an antigenic determinant. An epitope of a protein consists of only about 10 to 20 of the many amino acid building blocks that make up the protein chain. Usually, a single protein contains a number of different epitopes.

III. HUMORAL IMMUNITY

Acquired immunity itself can be subdivided into two categories. Humoral immunity refers to the production of soluble antibody molecules that circulate in the blood plasma. Humoral immunity involves interactions of so-called B lymphocytes with antigen, which eventually results in their transformation into antibody-producing plasma cells. The process of cell-mediated immunity is carried out by T lymphocytes. Cell-mediated immunity is important for providing protection against abnormal cells, such as virally infected cells or tumor cells.

The antibody molecules that are produced by the reactions of the humoral immune response are also known as immunoglobulins (Ig). Based on their molecular structure, immunoglobulins can be divided into five categories: IgA, IgD, IgE, IgG, and IgM. You should be familiar with the structure of IgG, which is a "Y"-shaped molecule composed of two heavy chains and two light chains. The two tips of the Y are called the antigen-binding or variable regions. These regions are where epitopes bind to the antibody molecule. Each type of antibody molecule has antigen-binding regions with a unique structure that can interact with only a limited array of epitopes. To react with one another, the epitope must fit into the antigen-binding region, just as a key fits into a lock. This requirement for a "proper fit" is what gives the acquired immune response specificity.

The antigen-binding regions on a single IgG molecule are identical. Therefore, each IgG molecule can bind two epitopes, but only if the epitopes are identical (or nearly so). This ability to bind two epitopes is called bivalency. Because IgG molecules are bivalent, they can cause target antigens to agglutinate (clump). If this is not obvious to you, refer to the diagram on Slide 12. This ability to cause agglutination formed the basis for many immunological tests that were used in the past.

The "tail" of the Y is called the Fc region. In contrast to the antigen-binding regions, the Fc regions of all IgG molecules are fairly similar. The Fc region has some important functions. When the antibody molecule binds to its target antigen, the Fc region can react with complement and trigger its activation. The Fc region can also bind to phagocytic leukocytes (such as neutrophils and macrophages), which respond by ingesting the antibody molecule along with the antigen to which it is attached. Since all Fc regions have similar structures, most IgG molecules can activate complement and trigger ingestion of antigens by white cells, no matter what their target antigen.

The other classes of immunoglobulin molecules each have their own unique structures. For example, IgM consists of five IgG-like structures joined together. This means that each IgM molecule can bind ten epitopes!

The different classes of immunoglobulins each have specific functions, as well. IgG is the most common type of antibody found in the blood, constituting about 80% of the total immunoglobulin in plasma. It is the longest-lived immunoglobulin. Some IgGs can cross the placenta to provide immune protection to the fetus and to the newborn until the child’s own immune system develops fully. Some IgGs, when bound to antigen, can trigger activation of the complement system.

IgM constitutes 5-10% of plasma immunoglobulin. It is the first type of antibody to be produced in a primary immune response (see below). Recall that IgM is very large (five times the size of IgG). This large size prevents it from crossing the placenta, so IgM antibodies do not confer protection to the fetus. Of all the immunoglobulins, IgM is the best at fixing complement. Also, its large number of antigen-binding regions (10/molecule) means that it can agglutinate antigens (such as bacteria) very efficiently. IgM is present on the membrane of B lymphocytes, where it binds antigen. Important point: Note that the structure of IgM on the cell membrane is very similar to that of IgG: it is a Y-shaped molecule with only two antigen-binding sites. The large, pentameric form of IgM with ten binding sites is found only in the plasma.

IgA makes up 10 to 15% of plasma immunoglobulin. It is, however, the major immunoglobulin in bodily secretions, such as saliva, tears, mucus, and breast milk. It can survive a trip through a nursing infant’s stomach, so it is an important source of protection for the newborn. IgE is present in the blood only at very low levels. IgE stimulates mast cells to trigger allergic reactions, which will be discussed in more detail later. Its normal function is to provide protection against infection with parasites. This function of IgE is of limited use in the United States, but certainly is of critical importance in developing countries, where parasitic infections often present a major health problem. The function of IgD is not clear. It is present in only low amount in the plasma. Like IgM, it is found on the membranes of B lymphocytes, where it can bind antigen.

As mentioned, the humoral immune response is responsible for producing antibody molecules. The major cell type involved is the B lymphocyte, which matures in the bone marrow. Each B lymphocyte has immunoglobulin (Ig) molecules bound to its outer membrane (remember, these are IgM and IgD molecules). These Ig molecules bind to antigen and lead to activation of the B cell. Important point: The antibodies on the surface of any one B lymphocyte all have identical antigen-binding regions. Therefore, each B cell can be activated by only one type of antigen (or by a limited number of very similar antigens). How then can your body recognize the thousands or perhaps millions of different antigens that you will encounter during your lifetime? The answer is that your immune system contains a huge number of different B cells, all coated with antibodies that will recognize different antigens. These cells are pre-existing in your body, just waiting for trouble to come along. It is estimated that an individual’s B cells can recognize as many as 10⁸ different epitopes. If you are infected with a bacterium, only a few of these many different B lymphocytes will be able to recognize epitopes on the bacterium. However, lymphocytes constantly circulate throughout the body, and, sooner or later, a B lymphocyte that can recognize that bacterium will bump into it and become activated.

When a B lymphocyte becomes activated by binding the proper antigen, it divides and differentiates to form plasma cells. Instead of having its antibody molecules bound to its membrane, the plasma cell secretes them in large quantities. The plasma cell may be regarded as an antibody-producing factory. All of the antibody molecules that it secretes will recognize the same epitope that the B cell originally recognized ­ in other words, one B cell produces only a single type of antibody. At first, the secreted antibody molecules will be of the IgM subclass. However, with time, the plasma cell will switch to making IgG molecules. The IgM and the IgG that this B cell makes will both recognize the same epitope.

The plasma cell is not the only type of cell that is formed as the activated B cell reproduces. It will also make memory B cells. Like the parent B cell, the memory B cell has IgM and IgD molecules on its surface. These Igs have antigen-binding regions that are identical to those of the original parent B cell. The memory B cells persist in the body, waiting until the same antigen attacks again. This time around, the body will be better prepared to mount an immune response, since it will have this larger pool of memory B cells around to deal with the problem. The next time the antigen is encountered, it will be recognized more quickly and the response will be more vigorous, because there are many more B cells of the right specificity present to deal with it.

It is important to recognize that an encounter with its antigen is, by itself, not enough to activate a B cell fully. Complete activation also requires the assistance of T helper (Th) lymphocytes, which produce factors that are necessary for the production of plasma cells and memory B cells. Therefore, full activation of a B cell requires that the cell binds to its target antigen and that it receives help from Th cells. Like B cells, Th cells must be activated by specific antigen before they become functional. The mechanism of activation of Th cells is described later on.

Antibodies that are produced in response to microbial invaders can prevent infection by several means. As we have already seen, they may cause microbes to agglutinate (clump), thus preventing their spread and their normal functioning. Second, when antibodies bind to a microbe, they may activate the complement system, which will produce a MAC to lyse the microbe. Third, the Fc parts of antibody molecules bound to microbes allow the microbes to be ingested by phagocytic cells (neutrophils and macrophages). Lastly, antibodies coating a microorganism may be able to prevent the bug from binding to host cells. Viruses need to bind to and enter host cells to replicate, and even some bacteria need to enter or be anchored to host cells to establish infections.

IV. CELL-MEDIATED IMMUNITY

The humoral immune response provides protection against many antigens, but viruses present a special challenge to the body’s defense systems. Viruses replicate within host cells, where they are shielded from the action of antibodies. Although a virus is vulnerable to antibodies when it is released from a cell to spread to other cells, humoral immunity is not always sufficient to wipe out the invaders during their brief period of life outside of the host cell. Therefore, so-called cell-mediated immunity has evolved to deal with the problem of viral infections. Although the discussion here will focus on virally infected cells, cell-mediated immunity can also help to destroy tumor cells, which often display abnormal ("non-self") proteins on their surfaces.

The reactions of cell-mediated immunity are carried out by T lymphocytes, which mature in the thymus. Due to the particular mechanisms of cell-mediated immunity, only proteins can serve as antigens for this response.

The major player in cell-mediated immunity is the T cytotoxic (Tc) lymphocyte. Tc cells can recognize and destroy altered "self" cells (e.g., virally infected cells or tumor cells). Some texts refer to Tc cells as "T suppressor" cells, but most experts in the field now use the T cytotoxic terminology. Under the microscope, T cytotoxic cells and T helper cells cannot be distinguished. However, specialized techniques can be used to detect specific "marker" proteins on the surfaces of these cells. Tc cells have a protein called CD8 on their surfaces; Th cells have a protein known as CD4.

Like B lymphocytes, T lymphocytes also recognize antigens. However, the T cells do not have antibodies on their surfaces to accomplish this purpose. Rather, they have so-called T cell receptors. These receptors recognize fragments of protein antigens (= peptides), but only when the peptides are bound to specific cell surface proteins called Major Histocompatibility Complex (MHC) proteins. Similar to antibodies on a B cell, the receptors on each T cell recognize only one specific peptide. Any T cells that recognize peptides from the body’s own proteins are eliminated during development in the thymus. If this elimination fails to occur normally, autoimmune disease (where the immune system attacks normal tissues of the body) may result.

A crucial concept is that T cytotoxic cells recognize only antigens that are produced within the body’s cells. The body has a "quality control mechanism" to monitor what’s going on inside cells. A sampling of peptide fragments from all the proteins that a cell is producing is transported to the cell surface and held in MHC proteins. If the peptide fragments are from proteins that are normally supposed to be made by the cell, they will not be recognized by Tc cells. However, if the cell is infected with a virus, the virus will use the cell’s machinery to make proteins needed for its own replication. As a consequence, the quality control system will transport bits of the virus’s proteins to the cell surface, where they will be bound to MHC molecules. These viral peptides on the surface of the infected cell serve as a warning signal to alert the immune system that something abnormal is occurring within this cell. Eventually, a Tc lymphocyte that can recognize and bind to the viral peptide will cruise by, and its T cell receptor will latch onto the viral peptide. The Tc cell will then become activated, just as B lymphocytes become activated when they bind the proper antigen. The activated Tc cell will divide to form fully functional Tc cells, which are capable of binding to and destroying any cell that displays that particular viral peptide on its surface. This destruction is mediated by a variety of toxic substances that are contained in granules within the fully mature Tc lymphocytes. The Tc cell must be in contact with its target cell to kill it. The Tc cell itself is not harmed during this process; consequently, one Tc cell can destroy multiple infected target cells. Upon activation, the T cell will also divide to form memory Tc cells. Just like memory B cells, these memory Tc cells will hang around, waiting for the antigen that they recognize to reappear. Again, the response the second time the antigen is encountered will be more vigorous than the first time, since there will be many more Tc cells of the right specificity to deal with the problem.

Another similarity between B lymphocytes and Tc lymphocytes is that both need factors provided by Th cells to become fully functional. Thus, T helper cells serve an essential role in both humoral and cell-mediated immunity.

V. T HELPER LYMPHOCYTES

The central role of Th cell in immunity has already been emphasized. As you will see in the lecture on Infectious Diseases, the CD4-bearing Th lymphocyte is a primary target for infection and destruction by the human immunodeficiency virus (HIV). From what you have just learned, it should be evident that the loss of Th cells will lead to a loss of both humoral and cell-mediated immunity, since both B lymphocytes and Tc lymphocytes need the assistance of Th cells to become fully functional. The critical importance of the Th cell explains why AIDS is such a devastating disease.

Just like B and Tc lymphocytes, the Th lymphocyte must be activated by the proper antigen to become fully functional and provide help to the other players of the immune response. As mentioned, Th cells use T cell receptors to recognize antigens, and individual Th cells recognize only one type of antigen. Tc cells can recognize foreign peptides on almost any cell of the body. In contrast, Th cells recognize foreign peptides only when they are displayed on the surfaces of specialized antigen-presenting cells (APC). The most common types of APCs are macrophages and B lymphocytes. APCs ingest foreign proteins by the process of phagocytosis and break them down into peptide fragments. These fragments are then transported to the surface of the APC, where they are bound to MHC molecules and "presented" to T helper cells. The Th cell is then activated and divides to form 1) fully functional Th cells that will promote the maturation of B and Tc lymphocytes and (you guessed it) 2) memory Th cells, which will hang around to provide a more vigorous response the next time the antigen is encountered.

Think about the similarities and differences in the ways that Tc and Th cells are activated. Both use special T cell receptors to recognize foreign peptides that are bound to MHC on the surfaces of cells. However, in the case of Tc cells, the peptides come from foreign (i.e., viral) proteins that are produced within an infected cell. In the case of Th cells, the peptides come from foreign proteins that are initially outside the APC, but that are taken up and broken down within the APC. Another important point is that Tc cells can recognize foreign peptides that are displayed on almost any type of cell. Th cells recognize foreign protein only on APCs. What accounts for this difference? The answer lies in the kind of MHC molecule that each cell type recognizes. Tc cells bind to peptides that are held in MHC Class I molecules, which are found on most cells in the body. Th cells interact exclusively with peptides that are held in MHC Class II molecules, which are found only on APC.

VI. SUMMARY OF THE IMMUNE RESPONSE

One of the slides for this lecture provides a diagram that summarizes the key cell types involved in humoral and cell-mediated immunity, the mechanisms by which they are activated, and the ways in which they interact. Make sure that you understand this diagram! It is important to realize that, in any real-life situation, many immune reactions will be occurring simultaneously. For example, during a viral infection, cells harboring the virus will start to trigger activation of Tc cells. At the same time, some viral particles that are released from infected cells will be ingested by APCs, allowing Th cells to be turned on. Lastly, some of the free virus particles may be recognized by B cells, leading to production of antibodies that can attack the virus.

Another important point that bears repeating is that immune responses have memory ­ that is, they are more efficient the second time an antigen is encountered than the first time, due to presence of a larger pool of memory lymphocytes. If we consider just the humoral response, the body’s first encounter with an antigen triggers what is referred to as a primary immune response. During a primary response, antibody is not produced immediately; rather, there is a lag phase due to the time needed for the proper B cells to find the antigen and divide to produce substantial numbers of plasma cells. The amounts of antibodies produced are relatively low, and they tend to be mostly of the IgM subtype. However, if the antigen is encountered again, the memory B cells and memory Th cells that are formed during the primary immune response ensure that the secondary immune response starts more quickly, lasts longer, and produces higher levels of antibodies (which are mostly IgG). In fact, the secondary immune response is often so efficient that you will be completely protected from the invader the second time around. For example, most people who have had chicken pox will never get the disease again.

The efficiency of the secondary immune response also forms the basis for vaccines. A vaccine consists of a non-toxic or non-infectious form of an antigen. Often, it may consist of just a single protein or a mixture of proteins from a given microorganism. The vaccine will not produce illness, but it will stimulate the formation of memory B cells and memory T cells. When the "real thing" is encountered, the body will eliminate it with a vigorous secondary immune response before it can establish an infection. Some microbes are better antigens than others. For a very efficient antigen, one vaccine may confer protection for a lifetime. For less efficient antigens, "booster" shots may be needed periodically to restimulate the immune system.

VII. MALFUNCTIONS OF THE IMMUNE SYSTEM (with an emphasis on hypersensitivities)

The immune system can cause problems if it acts excessively or if it is deficient. An excess or unregulated response underlies hypersensitivities, which will be the major focus of our discussion. Autoimmune disease results from a misdirected response, in which the immune system mistakenly attacks the body’s healthy tissues. You will encounter some examples of autoimmune diseases as the course proceeds.

The immune response may also be deficient, meaning that the body can no longer protect itself adequately against invading microorganisms. Some immune deficiencies are inherited; some are acquired. AIDS is an excellent example of the latter; you will be hearing much more about AIDS in the lecture on infectious diseases.

Lastly, cells and tissues of the immune system may give rise to malignancies, which can disrupt their proper functioning. You will be hearing about some of these malignancies in the lecture on blood and the lymphatic system.

Hypersensitivities are of two types:

• Immediate hypersensitivities are so called because the onset of symptoms occurs within minutes to hours after exposure to antigen. There are three types of immediate hypersensitivities, classified as Types 1, II, and III, and all are caused by malfunctioning antibodies or antibody-antigen complexes.
• Delayed-type hypersensitivity (Type IV) is so called because the symptoms take one to three days to develop. This reaction is caused by macrophages and certain T lymphocytes.

A. Type I Hypersensitivity

Type I hypersensitivities are caused by improperly regulated expression of IgE, which normally serves an important role in protecting against parasitic infections. Some people suffer from an inherited defect in the regulation of IgE. These people are said to be atopic, which simply means that they display allergic symptoms. Atopy is quite common, as you probably know. Allergic or atopic reactions are caused only by certain antigens, which are referred to as allergens. Common allergens include pollens, molds, certain foods, insect venoms, drugs, and animal dander. Symptoms range from annoying (as in hay fever and eczema) to life-threatening (as in systemic anaphylaxis.)

People who are atopic have excess levels of IgE directed against specific allergen(s). In contrast, non-allergic individuals produce little IgE unless they contract a parasitic infection. The Fc portions of these excess IgE molecules bind to receptors that are present on mast cells. Mast cells reside in the tissues, often near blood vessels; they are particularly abundant in skin and mucous membranes. When an atopic person encounters the allergen to which he or she is sensitive, the allergen will bind to the IgE molecules on the mast cells. Often, the allergen binds to more than one IgE molecule (remember, antigens often have multiple epitopes). When this happens, the IgE receptors are said to be cross-linked. This cross-linking or clustering of IgE receptors triggers the mast cells to release a variety of inflammatory substances that are stored within granules of the cells. One of the most important of these is histamine, which causes blood vessels to dilate and to become leaky (more about these processes to come in the lecture on inflammation.) If this happens in your nose, the mucous tissues will become swollen and red due to increased blood flow and leakage of blood plasma into the tissues. Your nose will also "run," as the leaked fluid exits. Histamine also causes itching, as those of you with allergies are well aware.

A much more serious scenario can occur if the allergen gets into the bloodstream. This can happen with insect venoms that are injected by bug stings or with some food allergies. In this case, mast cells throughout the body are triggered to release large amounts of histamine and other inflammatory mediators. Widespread vasodilation and fluid leakage lead to a rapid drop in blood pressure and massive edema (fluid in the tissues). The mediators also cause constriction of the bronchioles. This condition has a high rate of fatality unless it is promptly treated with epinephrine, which reverses the effects of histamine.

So-called "allergy shots" may be used to treat atopic individuals. These shots contain very small amounts of the appropriate allergen ­ not enough to trigger much of an allergic reaction, but enough to stimulate production of IgG antibodies directed against the allergen. The patient is repeatedly injected with increasing amounts of allergen so that high levels of IgG build up in the blood. The theory is that this IgG will bind to allergen molecules and neutralize them before they can make their way to the IgE receptors on mast cells.

B. Type II Hypersensitivity

Type II hypersensitivities are caused when antibodies bind to the body’s own cells and cause them to be destroyed. The antibodies can be directed against foreign antigens that are bound to cells (refer to the concept of haptens above), or, in autoimmune conditions, they may be directed against normal constituents of the body. When antibodies bind to target cells, they may lead to the destruction of those cells either through binding of complement and subsequent lysis of the cells or by triggering phagocytosis of these cells by neutrophils or macrophages.

Examples of Type II hypersensitivities include transfusion reactions, which may occur when a patient is given improperly matched blood, and hemolytic disease of the newborn (Rh incompatibility), which will be discussed at length in the lecture on blood. As mentioned, certain drugs may bind to red blood cells and trigger a Type II reaction, leading to destruction of the red cells and consequent anemia. There are many examples of Type II autoimmune reactions, including autoimmune hemolytic anemia, idiopathic thrombocytopenia purpura (where the target of destruction is the blood platelet), Hashimoto’s thyroiditis (in which antibodies attack the thyroid), and myasthenia gravis. In myasthenia gravis, antibodies react with the acetylcholine receptors on muscle cells. These receptors are needed for stimulation of muscle by nerves. Not only do the antibodies block stimulation of muscle cells by nerves, but their presence also leads to eventual destruction of the muscle cells by complement and phagocytic cells. Consequently, people with myasthenia gravis suffer from progressive fatigue and muscle weakness, often first affecting the eyelids and face. Weakness can also eventually involve the limbs and even the respiratory muscles, which may prove fatal.

C. Type III Hypersensitivity

Type III hypersensitivities are caused by immune complexes (clumps of antibodies bound to antigens) that deposit in the tissues. The deposited complexes activate complement. As a result, the complement factor C5a is released, which serves to attract neutrophils to the area (this scenario will be explained in much more detail in the lecture on inflammation). Neutrophils secrete a variety of toxic products, which normally serve to kill microorganisms. In Type III reactions, however, these toxic products instead damage normal cells and tissues in the area where the immune complexes are deposited. Some examples of conditions that involve Type III reactions include: systemic lupus erythematosus, rheumatoid arthritis, poststreptococcal glomerulonephritis, farmer’s lung, and pigeon fancier’s disease.

Note the important distinction between Type II and Type III hypersensitivities. Both are caused by antibodies. However, in Type II reactions, the antibodies bind directly to cell surface structures. In Type III reactions, the antibodies bind to soluble antigens. These antigen-antibody complexes then get trapped in tissues, and these tissues are "innocent bystanders" that are destroyed nonspecifically when neutrophils arrive to deal with the immune complexes.

D. Type IV Hypersensitivity

Type IV hypersensitivity reactions differ from Types I, II, and III in several ways. First of all, the symptoms of Type IV reactions take 24 to 72 hours to develop; the onset of the other hypersensitivities is much more rapid. For this reason, a Type IV reaction is often referred to as delayed-type hypersensitivity (DTH). Second, Type IV reactions are not abnormal. Rather, they serve a very important purpose, which is to defend the body against bacteria and fungi that live within cells (e.g., Mycobacterium tuberculosis and Pneumocystis carinii). Unlike viruses, these intracellular pathogens do not use a cell’s machinery to manufacture their proteins. These bugs have everything that they need to replicate on their own; they are just using the cell as a cozy place in which to hide from the immune system. Therefore, the cell’s quality control mechanism does not sample pieces of proteins from these invaders and display them on the cell surface. As a consequence, T cytotoxic cells are not signaled that these cells are infected, as they would be if the invader were a virus. The only way that the body knows that these intracellular pathogens are present is when they are released from an infected cell to spread to new host cells. At this point, T lymphocytes that recognize antigens from these bugs are activated. These specialized T cells begin to secrete factors that call macrophages into the area. The macrophages, in turn, secrete toxic factors that kill the surrounding cells. Since the macrophages have no way of knowing precisely which cells are infected, they just destroy everything in the area indiscriminately. Think of the macrophages as bombardiers, destroying everything in a village in the hopes of routing out the unseen enemy. T cytotoxic cells, on the other hand, are sharpshooters that can pick off an enemy soldier when they spy a glimpse of him in a window. Delayed-type hypersensitivity reactions can be drastic and destructive, but it is the only way that the body can deal with microorganisms that shield themselves from attack by hiding in the body’s own cells.

Note that the T lymphocytes involved in DTH reactions function like other T cells. They must be activated by encountering antigen. The first encounter produces memory DTH T cells, so that the DTH reaction is more vigorous the second time the antigen is seen.

Although Type IV hypersensitivities are often beneficial, there are a few antigens that trigger an inappropriate DTH response. These include poison ivy, poison oak, and nickel salts (which are often found in inexpensive jewelry).

The PPD test for tuberculosis relies on a Type IV reaction. In this test, purified protein derivative (PPD) from M. tuberculosis is injected under the skin. If the patient has previously been exposed to M. tuberculosis, then a vigorous DTH response will ensue 48 to 72 hours later. The skin at the site of injection will become swollen, reddened (erythematous), and hard (indurated) due to accumulation of macrophages and resulting inflammation. Note that this test only measures whether one has ever been exposed to the tuberculosis bacillus; it cannot distinguish an infection in the past from a currently active one. Also, the PPD that is injected is not a sufficient antigen to trigger immune activation by itself ­ in other words, having repeated PPD tests will not result in eventual development of "false positive" responses.

A summary of the hypersensitivities is given in the slide set. Make sure you know the mechanisms that cause all four types!

IMPORTANT CORRECTION TO YOUR TEXT (Damjanov)

The descriptions of activation of B lymphocytes on p. 47 and in Figs. 3-5 and 3-6 are incorrect. B cells are not stimulated to produce antibody by antigen-presenting cells (APC). Rather, B cells are stimulated when two events occur: 1) antigen of the proper type binds to immunoglobulin on the surface of the B cell, and 2) activated T helper cells secrete soluble factors, such as interleukins, that help the B cells to mature. (The T helper cells do not "pass" antigen to B cells, as stated on p. 47.) When these two events both occur, the activated B lymphocyte will divide to form antibody-secreting plasma cells and memory B cells.

Your book is correct in stating that Type I (usually called Class I) major histocompatibility complex (MHC) proteins interact with CD8⁺ T suppressor cells (more properly called T cytotoxic cells). Likewise, it correctly states that MHC Class II proteins interact only with CD4⁺ T helper cells. What it does not make clear is that nearly all cells in the body have MHC Class I molecules on their surfaces and can therefore interact with T cytotoxic cells. In contrast, only APC express MHC Class II molecules, so they are the only cells that can interact with and activate T helper cells. You are not responsible for knowing the difference between MHC Class I and Class II molecules, but I mention it here in case you find the text confusing.

The descriptions of activation of B and T lymphocytes that were given in lecture are correct. Any contradictory information in your text should be ignored.