Acquired Adaptive Immunity

In addition to its generalized innate immunity, the human body has the ability to develop extremely powerful specific immunity against individual invading agents such as lethal bacteria, viruses, toxins, and even foreign tissues from other animals. This is called acquired or adaptive immunity. Acquired immunity is caused by a special immune system that forms antibodies and/or activated lymphocytes that attack and destroy the specific invading organism or toxin. It is with this acquired immunity mechanism and some of its associated reactions— especially the allergies—that this chapter is concerned.

Acquired immunity can often bestow extreme protection. For instance, certain toxins, such as the paralytic botulinum toxin or the tetanizing toxin of tetanus, can be protected against in doses as high as 100,000 times the amount that would be lethal without immunity. This is the reason the treatment process known as immunization is so important in protecting human beings against disease and against toxins, as explained in the course of this chapter.

Basic Types of Acquired Immunity

Two basic but closely allied types of acquired immunity occur in the body. In one of these the body develops circulating antibodies, which are globulin molecules in the blood plasma that are capable of attacking the invading agent. This type of immunity is called humoral immunity or B-cell immunity (because B lymphocytes produce the antibodies). The second type of acquired immunity is achieved through the formation of large numbers of activated T lymphocytes that are specifically crafted in the lymph nodes to destroy the foreign agent. This type of immunity is called cell-mediated immunity or T-cell immunity (because the activated lymphocytes are T lymphocytes). We shall see shortly that both the antibodies and the activated lymphocytes are formed in the lym-phoid tissues of the body. Let us discuss the initiation of the immune process by antigens.

Both Types of Acquired Immunity Are Initiated by Antigens

Because acquired immunity does not develop until after invasion by a foreign organism or toxin, it is clear that the body must have some mechanism for recognizing this invasion. Each toxin or each type of organism almost always contains one or more specific chemical compounds in its makeup that are different from all other compounds. In general, these are proteins or large polysaccharides, and it is they that initiate the acquired immunity. These substances are called antigens (antibody generations).

For a substance to be antigenic, it usually must have a high molecular weight, 8000 or greater. Furthermore, the process of antigenicity usually depends on regularly recurring molecular groups, called epitopes, on the surface of the large molecule. This also explains why proteins and large polysaccharides are almost always antigenic, because both of these have this ster-eochemical characteristic.

Lymphocytes Are Responsible for Acquired Immunity

Acquired immunity is the product of the body's lymphocytes. In people who have a genetic lack of lymphocytes or whose lymphocytes have been destroyed by radiation or chemicals, no acquired immunity can develop. And within days after birth, such a person dies of fulminating bacterial infection unless treated by heroic measures. Therefore, it is clear that the lymphocytes are essential to survival of the human being.

The lymphocytes are located most extensively in the lymph nodes, but they are also found in special lymphoid tissues such as the spleen, submucosal areas of the gastrointestinal tract, thymus, and bone marrow. The lymphoid tissue is distributed advantageously in the body to intercept invading organisms or toxins before they can spread too widely.

In most instances, the invading agent first enters the tissue fluids and then is carried by way of lymph vessels to the lymph node or other lymphoid tissue. For instance, the lymphoid tissue of the gastrointestinal walls is exposed immediately to antigens invading from the gut. The lymphoid tissue of the throat and pharynx (the tonsils and adenoids) is well located to intercept antigens that enter by way of the upper respiratory tract. The lymphoid tissue in the lymph nodes is exposed to antigens that invade the peripheral tissues of the body. And, finally, the lymphoid tissue of the spleen, thymus, and bone marrow plays the specific role of intercepting antigenic agents that have succeeded in reaching the circulating blood.

Two Types of Lymphocytes Promote "Cell-Mediated" Immunity or "Humoral" Immunity—the T and the B Lymphocytes.

Although most lymphocytes in normal lymphoid tissue look alike when studied under the microscope, these cells are distinctly divided into two major populations. One of the populations, the T lymphocytes, is responsible for forming the activated lymphocytes that provide "cell-mediated" immunity, and the other population, the B lymphocytes, is responsible for forming antibodies that provide "humoral" immunity.

Both types of lymphocytes are derived originally in the embryo from pluripotent hematopoietic stem cells that form lymphocytes as one of their most important offspring as they differentiate. Almost all of the lymphocytes that are formed eventually end up in the lymphoid tissue, but before doing so, they are further differentiated or "preprocessed" in the following ways.

The lymphocytes that are destined to eventually form activated T lymphocytes first migrate to and are preprocessed in the thymus gland, and thus they are called "T" lymphocytes to designate the role of the thymus. They are responsible for cell-mediated immunity.

The other population of lymphocytes—the B lymphocytes that are destined to form antibodies—are preprocessed in the liver during midfetal life and in the bone marrow in late fetal life and after birth. This population of cells was first discovered in birds, which have a special preprocessing organ called the bursa of Fabri-cius. For this reason, these lymphocytes are called "B" lymphocytes to designate the role of the bursa, and they are responsible for humoral immunity. Figure 34-1 shows the two lymphocyte systems for the formation, respectively, of (1) the activated T lymphocytes and (2) the antibodies.

Preprocessing of the T and B Lymphocytes

Although all lymphocytes in the body originate from lymphocyte-committed stem cells of the embryo, these

Figure 34-1

Formation of antibodies and sensitized lymphocytes by a lymph node in response to antigens. This figure also shows the origin of thymic (T) and bursal (B) lymphocytes that respectively are responsible for the cell-mediated and humoral immune processes.

Cell-Mediated Immunity

Thymus

Fetal liver, bone marrow

Humoral Immunity stem cells themselves are incapable of forming directly either activated T lymphocytes or antibodies. Before they can do so, they must be further differentiated in appropriate processing areas as follows.

Thymus Gland Preprocesses the T Lymphocytes. The T lymphocytes, after origination in the bone marrow, first migrate to the thymus gland. Here they divide rapidly and at the same time develop extreme diversity for reacting against different specific antigens. That is, one thymic lymphocyte develops specific reactivity against one antigen. Then the next lymphocyte develops specificity against another antigen. This continues until there are thousands of different types of thymic lymphocytes with specific reactivities against many thousands of different antigens. These different types of preprocessed T lymphocytes now leave the thymus and spread by way of the blood throughout the body to lodge in lymphoid tissue everywhere.

The thymus also makes certain that any T lymphocytes leaving the thymus will not react against proteins or other antigens that are present in the body's own tissues; otherwise, the T lymphocytes would be lethal to the person's own body in only a few days. The thymus selects which T lymphocytes will be released by first mixing them with virtually all the specific "self-antigens" from the body's own tissues. If a T lymphocyte reacts, it is destroyed and phagocytized instead of being released. This happens to as many as 90 per cent of the cells. Thus, the only cells that are finally released are those that are nonreactive against the body's own antigens—they react only against antigens from an outside source, such as from a bacterium, a toxin, or even transplanted tissue from another person.

Most of the preprocessing of T lymphocytes in the thymus occurs shortly before birth of a baby and for a few months after birth. Beyond this period, removal of the thymus gland diminishes (but does not eliminate) the T-lymphocytic immune system. However, removal of the thymus several months before birth can prevent development of all cell-mediated immunity. Because this cellular type of immunity is mainly responsible for rejection of transplanted organs, such as hearts and kidneys, one can transplant organs with much less likelihood of rejection if the thymus is removed from an animal a reasonable time before its birth.

Liver and Bone Marrow Preprocess the B Lymphocytes. Much less is known about the details for preprocessing B lymphocytes than for preprocessing T lymphocytes. In the human being, B lymphocytes are known to be pre-processed in the liver during midfetal life and in the bone marrow during late fetal life and after birth.

B lymphocytes are different from T lymphocytes in two ways: First, instead of the whole cell developing reactivity against the antigen, as occurs for the T lymphocytes, the B lymphocytes actively secrete antibodies that are the reactive agents. These agents are large protein molecules that are capable of combining with and destroying the antigenic substance, which is explained elsewhere in this chapter and in Chapter 33. Second, the B lymphocytes have even greater diversity than the T lymphocytes, thus forming many millions of types of B-lymphocyte antibodies with different specific reactivities. After preprocessing, the B lymphocytes, like the T lymphocytes, migrate to lym-phoid tissue throughout the body, where they lodge near but slightly removed from the T-lymphocyte areas.

T Lymphocytes and B-Lymphocyte Antibodies React Highly Specifically Against Specific Antigens—Role of Lymphocyte Clones

When specific antigens come in contact with T and B lymphocytes in the lymphoid tissue, certain of the T lymphocytes become activated to form activated T cells, and certain of the B lymphocytes become activated to form antibodies. The activated T cells and antibodies in turn react highly specifically against the particular types of antigens that initiated their development. The mechanism of this specificity is the following.

Millions of Specific Types of Lymphocytes Are Stored in the Lymphoid Tissue. Millions of different types of preformed B lymphocytes and preformed T lymphocytes that are capable of forming highly specific types of antibodies or T cells have been stored in the lymph tissue, as explained earlier. Each of these preformed lymphocytes is capable of forming only one type of antibody or one type of T cell with a single type of specificity. And only the specific type of antigen with which it can react can activate it. Once the specific lymphocyte is activated by its antigen, it reproduces wildly, forming tremendous numbers of duplicate lymphocytes. If it is a B lymphocyte, its progeny will eventually secrete the specific type of antibody that then circulates throughout the body. If it is a T lymphocyte, its progeny are specific sensitized T cells that are released into the lymph and then carried to the blood and circulated through all the tissue fluids and back into the lymph, sometimes circulating around and around in this circuit for months or years.

All the different lymphocytes that are capable of forming one specificity of antibody or T cell are called a clone of lymphocytes. That is, the lymphocytes in each clone are alike and are derived originally from one or a few early lymphocytes of its specific type.

Origin of the Many Clones of Lymphocytes

Only several hundred to a few thousand genes code for the millions of different types of antibodies and T lymphocytes. At first, it was a mystery how it was possible for so few genes to code for the millions of different specificities of antibody molecules or T cells that can be produced by the lymphoid tissue, especially when one considers that a single gene is usually necessary for the formation of each different type of protein. This mystery has now been solved.

The whole gene for forming each type of T cell or B cell is never present in the original stem cells from which the functional immune cells are formed. Instead, there are only "gene segments"—actually, hundreds of such segments—but not whole genes. During preprocessing of the respective T- and B-cell lymphocytes, these gene segments become mixed with one another in random combinations, in this way finally forming whole genes.

Because there are several hundred types of gene segments, as well as millions of different combinations in which the segments can be arranged in single cells, one can understand the millions of different cell gene types that can occur. For each functional T or B lymphocyte that is finally formed, the gene structure codes for only a single antigen specificity. These mature cells then become the highly specific T and B cells that spread to and populate the lymphoid tissue.

Mechanism for Activating a Clone of Lymphocytes

Each clone of lymphocytes is responsive to only a single type of antigen (or to several similar antigens that have almost exactly the same stereochemical characteristics). The reason for this is the following: In the case of the B lymphocytes, each of these has on the surface of its cell membrane about 100,000 antibody molecules that will react highly specifically with only one specific type of antigen. Therefore, when the appropriate antigen comes along, it immediately attaches to the antibody in the cell membrane; this leads to the activation process, which we describe in more detail subsequently. In the case of the T lymphocytes, molecules similar to antibodies, called surface receptor proteins (or T-cell markers), are on the surface of the T-cell membrane, and these, too, are highly specific for one specified activating antigen.

Role of Macrophages in the Activation Process. Aside from the lymphocytes in lymphoid tissue, literally millions of macrophages are also present in the same tissue. These line the sinusoids of the lymph nodes, spleen, and other lymphoid tissue, and they lie in apposition to many of the lymph node lymphocytes. Most invading organisms are first phagocytized and partially digested by the macrophages, and the antigenic products are liberated into the macrophage cytosol. The macrophages then pass these antigens by cell-to-cell contact directly to the lymphocytes, thus leading to activation of the specified lymphocytic clones. The macrophages, in addition, secrete a special activating substance that promotes still further growth and reproduction of the specific lymphocytes. This substance is called interleukin-1.

Role of the T Cells in Activation of the B Lymphocytes. Most antigens activate both T lymphocytes and B lymphocytes at the same time. Some of the T cells that are formed, called helper cells, secrete specific substances (collectively called lymphokines) that activate the specific B lymphocytes. Indeed, without the aid of these helper T cells, the quantity of antibodies formed by the B lymphocytes is usually slight. We will discuss this cooperative relationship between helper T cells and B cells again after we have an opportunity to describe the mechanisms of the T-cell system of immunity.

Specific Attributes of the B-Lymphocyte System—Humoral Immunity and the Antibodies

Formation of Antibodies by Plasma Cells. Before exposure to a specific antigen, the clones of B lymphocytes remain dormant in the lymphoid tissue. On entry of a foreign antigen, macrophages in the lymphoid tissue phagocytize the antigen and then present it to adjacent B lymphocytes. In addition, the antigen is presented to T cells at the same time, and activated helper T cells are formed. These helper cells also contribute to extreme activation of the B lymphocytes, as we discuss more fully later.

Those B lymphocytes specific for the antigen immediately enlarge and take on the appearance of lymphoblasts. Some of the lymphoblasts further differentiate to form plasmablasts, which are precursors of plasma cells. In the plasmablasts, the cytoplasm expands and the rough endoplasmic reticulum vastly proliferates. The plasmablasts then begin to divide at a rate of about once every 10 hours for about nine divisions, giving in 4 days a total population of about 500 cells for each original plasmablast. The mature plasma cell then produces gamma globulin antibodies at an extremely rapid rate—about 2000 molecules per second for each plasma cell. In turn, the antibodies are secreted into the lymph and carried to the circulating blood. This process continues for several days or weeks until finally exhaustion and death of the plasma cells occur.

Formation of "Memory" Cells—Difference Between Primary Response and Secondary Response. A few of the lym-phoblasts formed by activation of a clone of B lymphocytes do not go on to form plasma cells but instead form moderate numbers of new B lymphocytes similar to those of the original clone. In other words, the B-cell population of the specifically activated clone becomes greatly enhanced, and the new B lymphocytes are added to the original lymphocytes of the same clone. They also circulate throughout the body to populate all the lymphoid tissue; immunologically, however, they remain dormant until activated once again by a new quantity of the same antigen. These lymphocytes are called memory cells. Subsequent exposure to the same antigen will cause a much more rapid and much more potent antibody response this second time around, because there are many more memory cells than there were original B lymphocytes of the specific clone.

Figure 34-2 shows the differences between the primary response for forming antibodies that occurs on first exposure to a specific antigen and the secondary response that occurs after second exposure to the same antigen. Note the 1-week delay in the appearance of the primary response, its weak potency, and its short life. The secondary response, by contrast, begins rapidly after exposure to the antigen (often within hours), is far more potent, and forms antibodies for many months rather than for only a few weeks. The

Weeks

Figure 34-2

Weeks

Figure 34-2

Time course of the antibody response in the circulating blood to a primary injection of antigen and to a secondary injection several months later.

increased potency and duration of the secondary response explain why immunization is usually accomplished by injecting antigen in multiple doses with periods of several weeks or several months between injections.

Nature of the Antibodies

The antibodies are gamma globulins called immunoglobulins (abbreviated as Ig), and they have molecular weights between 160,000 and 970,000. They usually constitute about 20 per cent of all the plasma proteins.

All the immunoglobulins are composed of combinations of light and heavy polypeptide chains. Most are a combination of two light and two heavy chains, as shown in Figure 34-3. However, some of the immunoglobulins have combinations of as many as 10 heavy and 10 light chains, which gives rise to high-molecular-weight immunoglobulins. Yet, in all immunoglobulins, each heavy chain is paralleled by a light chain at one of its ends, thus forming a heavy-light pair, and there are always at least 2 and as many as 10 such pairs in each immunoglobulin molecule.

Figure 34-3 shows by the circled area a designated end of each light and heavy chain, called the variable portion; the remainder of each chain is called the constant portion. The variable portion is different for each specificity of antibody, and it is this portion that attaches specifically to a particular type of antigen. The constant portion of the antibody determines other properties of the antibody, establishing such factors as diffusivity of the antibody in the tissues, adherence of the antibody to specific structures within the tissues, attachment to the complement complex, the ease with which the antibodies pass through membranes, and other biological properties of the antibody.

Structure of the typical IgG antibody, showing it to be composed of two heavy polypeptide chains and two light polypeptide chains. The antigen binds at two different sites on the variable portions of the chains.

Figure 34-4

Binding of antigen molecules to one another by bivalent antibodies.

Structure of the typical IgG antibody, showing it to be composed of two heavy polypeptide chains and two light polypeptide chains. The antigen binds at two different sites on the variable portions of the chains.

Figure 34-4

Binding of antigen molecules to one another by bivalent antibodies.

Specificity of Antibodies. Each antibody is specific for a particular antigen; this is caused by its unique structural organization of amino acids in the variable portions of both the light and heavy chains. The amino acid organization has a different steric shape for each antigen specificity, so that when an antigen comes in contact with it, multiple prosthetic groups of the antigen fit as a mirror image with those of the antibody, thus allowing rapid and tight bonding between the antibody and the antigen. When the antibody is highly specific, there are so many bonding sites that the antibody-antigen coupling is exceedingly strong, held together by (1) hydrophobic bonding, (2) hydrogen bonding, (3) ionic attractions, and (4) van der Waals forces. It also obeys the thermodynamic mass action law.

Concentration of bound antibody-antigen Concentration of antibody x Concentration of antigen

Ka is called the affinity constant and is a measure of how tightly the antibody binds with the antigen.

Note, especially, in Figure 34-3 that there are two variable sites on the illustrated antibody for attachment of antigens, making this type of antibody bivalent. A small proportion of the antibodies, which consist of combinations of up to 10 light and 10 heavy chains, have as many as 10 binding sites.

Classes of Antibodies. There are five general classes of antibodies, respectively named IgM, IgG, IgA, IgD, and IgE. Ig stands for immunoglobulin, and the other five respective letters designate the respective classes.

For the purpose of our present limited discussion, two of these classes of antibodies are of particular importance: IgG, which is a bivalent antibody and constitutes about 75 per cent of the antibodies of the normal person, and IgE, which constitutes only a small percentage of the antibodies but is especially involved in allergy. The IgM class is also interesting because a large share of the antibodies formed during the primary response are of this type. These antibodies have 10 binding sites that make them exceedingly effective in protecting the body against invaders, even though there are not many IgM antibodies.

Mechanisms of Action of Antibodies

Antibodies act mainly in two ways to protect the body against invading agents: (1) by direct attack on the invader and (2) by activation of the "complement system" that then has multiple means of its own for destroying the invader.

Direct Action of Antibodies on Invading Agents. Figure 34-4 shows antibodies (designated by the red Y-shaped bars) reacting with antigens (designated by the shaded objects). Because of the bivalent nature of the antibodies and the multiple antigen sites on most invading agents, the antibodies can inactivate the invading agent in one of several ways, as follows:

1. Agglutination, in which multiple large particles with antigens on their surfaces, such as bacteria or red cells, are bound together into a clump

2. Precipitation, in which the molecular complex of soluble antigen (such as tetanus toxin) and antibody becomes so large that it is rendered insoluble and precipitates

3. Neutralization, in which the antibodies cover the toxic sites of the antigenic agent

4. Lysis, in which some potent antibodies are occasionally capable of directly attacking membranes of cellular agents and thereby cause rupture of the agent

These direct actions of antibodies attacking the anti-genic invaders often are not strong enough to play a major role in protecting the body against the invader. Most of the protection comes through the amplifying effects of the complement system described next.

Antigen-antibody complex y

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