Resistance of the Body to Infection

T and B Lymphocytes Promote “Cell-Mediated” Immunity or “Humoral” Immunity.

Although most lymphocytes in normal lymphoid tissue look alike when studied under a 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 common lymphoid progenitor cells 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 lymphoid progenitor cells 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 mid fetal 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 Fabricius. For this reason, these lymphocytes are called “B” lymphocytes to designate the role of the bursa, and they are responsible for humoral immunity. Figure 35-1 shows the two lymphocyte systems for the formation, respectively, of (1) the activated T lymphocytes and (2) the antibodies.

The 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, and then the next lymphocyte develops specificity against another antigen. This process 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, which happens to up to 90 percent 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.

In humans, B lymphocytes are preprocessed in the liver during mid fetal 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 proteins that are capable of combining with and destroying the antigenic substance, which is explained elsewhere in this chapter and in Chapter 34. 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 lymphoid tissue throughout the body, where they lodge near but slightly removed from the T-lymphocyte areas.

Millions of Specific Types of Lymphocytes Are Stored in the Lymphoid Tissue.

Millions of different types of preformed B lymphocytes and preformed T lymphocytes 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 can activate it. Once the specific lymphocyte is activated by its antigen, it reproduces wildly, forming tremendous numbers of duplicate lymphocytes (Figure 35-2). 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 specific 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.

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 macrophages 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, interleukin-1, that promotes still further growth and reproduction of the specific lymphocytes.

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 T-helper cells, secrete specific substances (collectively called lymphokines) that activate the specific B lymphocytes. Indeed, without the aid of these T-helper cells, the quantity of antibodies formed by the B lymphocytes is usually slight. We discuss this cooperative relationship between helper T cells and B cells after describing the mechanisms of the T-cell system of immunity.

Formation of Antibodies by Plasma Cells.

Before exposure to a specific antigen, the clones of B lymphocytes remain dormant in the lymphoid tissue. Upon entry of a foreign antigen, macrophages in 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 T-helper cells are formed. These helper cells also contribute to extreme activation of the B lymphocytes, as discussed later.

The 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 Enhances the Anti­body Response to Subsequent Antigen Exposure.

A few of the lymphoblasts 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 35-3 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 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.

Specificity of Antibodies.

Each antibody is specific for a particular antigen; this characteristic 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 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.

Ka=Concentration of bound antibody-antigenConcentration of antibody× Concentration of antigen

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

Note especially in Figure 35-4 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.

Five General 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 percent 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.

Direct Action of Antibodies on Invading Agents.

Figure 35-5 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:

These direct actions of antibodies 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.

Classical Pathway.

The classical pathway is initiated by an antigen-antibody reaction. That is, when an antibody binds with an antigen, a specific reactive site on the “constant” portion of the antibody becomes uncovered, or “activated,” and this in turn binds directly with the C1 molecule of the complement system, setting into motion a “cascade” of sequential reactions, shown in Figure 35-6, beginning with activation of the proenzyme C1. The C1 enzymes that are formed then activate successively increasing quantities of enzymes in the later stages of the system so that from a small beginning, an extremely large “amplified” reaction occurs. Multiple end products are formed, as shown to the right in the figure, and several of these cause important effects that help to prevent damage to the body's tissues caused by the invading organism or toxin. Among the more important effects are the following:

Release of Activated T Cells from Lymphoid Tissue and Formation of Memory Cells.

Upon exposure to the proper antigen, as presented by adjacent macrophages, the T lymphocytes of a specific lymphocyte clone proliferate and release large numbers of activated, specifically reacting T cells in ways that parallel antibody release by activated B cells. The principal difference is that instead of releasing antibodies, whole activated T cells are formed and released into the lymph. These T cells then pass into the circulation and are distributed throughout the body, passing through the capillary walls into the tissue spaces, back into the lymph and blood once again, and circulating again and again throughout the body, sometimes lasting for months or even years.

Also, T-lymphocyte memory cells are formed in the same way that B memory cells are formed in the antibody system. That is, when a clone of T lymphocytes is activated by an antigen, many of the newly formed lymphocytes are preserved in the lymphoid tissue to become additional T lymphocytes of that specific clone; in fact, these memory cells even spread throughout the lymphoid tissue of the entire body. Therefore, on subsequent exposure to the same antigen anywhere in the body, release of activated T cells occurs far more rapidly and much more powerfully than during first exposure.

Antigen-Presenting Cells, MHC Proteins, and Antigen Receptors on the T Lymphocytes.

T-cell responses are extremely antigen specific, like the antibody responses of B cells, and are at least as important as antibodies in defending against infection. In fact, acquired immune responses usually require assistance from T cells to begin the process, and T cells play a major role in helping to eliminate invading pathogens.

Although B lymphocytes recognize intact antigens, T lymphocytes respond to antigens only when they are bound to specific molecules called MHC proteins on the surface of antigen-presenting cells in the lym­phoid tissues (Figure 35-7). The three major types of antigen-presenting cells are macrophages, B lymphocytes, and dendritic cells. The dendritic cells, the most potent of the antigen-presenting cells, are located throughout the body, and their only known function is to present antigens to T cells. Interaction of cell adhesion proteins is critical in permitting the T cells to bind to antigen-presenting cells long enough to become activated.

The MHC proteins are encoded by a large group of genes called the major histocompatibility complex (MHC). The MHC proteins bind peptide fragments of antigen proteins that are degraded inside antigen-presenting cells and then transport them to the cell surface. There are two types of MHC proteins: (1) MHC I proteins, which present antigens to cytotoxic T cells, and (2) MHC II proteins, which present antigens to T-helper cells. The specific functions of cytotoxic and T-helper cells are discussed later.

The antigens on the surface of antigen-presenting cells bind with receptor molecules on the surfaces of T cells in the same way that they bind with plasma protein antibodies. These receptor molecules are composed of a variable unit similar to the variable portion of the humoral antibody, but its stem section is firmly bound to the cell membrane of the T lymphocyte. There are as many as 100,000 receptor sites on a single T cell.

Specific Regulatory Functions of the Lymphokines.

In the absence of the lymphokines from the T-helper cells, the remainder of the immune system is almost paralyzed. In fact, it is the T-helper cells that are inactivated or destroyed by the human immunodeficiency virus (HIV), which leaves the body almost totally unprotected against infectious disease, therefore leading to the now well-known debilitating and lethal effects of acquired immunodeficiency syndrome (AIDS). Some of the specific regulatory functions are described in the following sections.

Stimulation of Growth and Proliferation of Cytotoxic T Cells and Suppressor T Cells.

In the absence of T-helper cells, the clones for producing cytotoxic T cells and suppressor T cells are activated only slightly by most antigens. The lymphokine interleukin-2 has an especially strong stimulatory effect in causing growth and proliferation of both cytotoxic and suppressor T cells. In addition, several of the other lymphokines have less potent effects.

Stimulation of B-Cell Growth and Differentiation to Form Plasma Cells and Antibodies.

The direct actions of antigens to cause B-cell growth, proliferation, formation of plasma cells, and secretion of antibodies are also slight without the “help” of the T-helper cells. Almost all the interleukins participate in the B-cell response, but especially interleukins 4, 5, and 6. In fact, these three interleukins have such potent effects on the B cells that they have been called B-cell stimulating factors or B-cell growth factors.

Activation of the Macrophage System.

The lym­phokines also affect the macrophages. First, they slow or stop the migration of the macrophages after they have been chemotactically attracted into the inflamed tissue area, thus causing great accumulation of macrophages. Second, they activate the macrophages to cause far more efficient phagocytosis, allowing them to attack and destroy increasing numbers of invading bacteria or other tissue-destroying agents.

Feedback Stimulatory Effect on the T-Helper Cells.

Some of the lymphokines, especially interleukin-2, have a direct positive feedback effect in stimulating activation of the T-helper cells. This acts as an amplifier by further enhancing the helper cell response, as well as the entire immune response to an invading antigen.

Most Tolerance Results from Clone Selection During Preprocessing.

Most tolerance is believed to develop during preprocessing of T lymphocytes in the thymus and of B lymphocytes in the bone marrow. The reason for this belief is that injecting a strong antigen into a fetus while the lymphocytes are being preprocessed in these two areas prevents development of clones of lymphocytes in the lymphoid tissue that are specific for the injected antigen. Experiments have shown that specific immature lymphocytes in the thymus, when exposed to a strong antigen, become lymphoblastic, proliferate considerably, and then combine with the stimulating antigen—an effect that is believed to cause the cells to be destroyed by the thymic epithelial cells before they can migrate to and colonize the total body lymphoid tissue.

It is believed that during the preprocessing of lymphocytes in the thymus and bone marrow, all or most of the clones of lymphocytes that are specific to damage the body's own tissues are self-destroyed because of their continual exposure to the body's antigens.

Failure of the Tolerance Mechanism Causes Auto­immune Diseases.

Sometimes people lose immune tolerance of their own tissues. This phenomenon occurs to a greater extent the older a person becomes. It usually occurs after destruction of some of the body's own tissues, which releases considerable quantities of “self-antigens” that circulate in the body and presumably cause acquired immunity in the form of either activated T cells or antibodies.

Several specific diseases that result from autoim­munity include (1) rheumatic fever, in which the body becomes immunized against tissues in the joints and heart, especially the heart valves, after exposure to a specific type of streptococcal toxin that has an epitope in its molecular structure similar to the structure of some of the body's own self-antigens; (2) one type of glomerulonephritis, in which the person becomes immunized against the basement membranes of glomeruli; (3) myasthenia gravis, in which immunity develops against the acetylcholine receptor proteins of the neuromuscular junction, causing paralysis; and (4) systemic lupus erythematosus (SLE), in which the person becomes immunized against many different body tissues at the same time, a disease that causes extensive damage and even death when SLE is severe.

Anaphylaxis.

When a specific allergen is injected directly into the circulation, the allergen can react with basophils of the blood and mast cells in the tissues located immediately outside the small blood vessels if the basophils and mast cells have been sensitized by attachment of IgE reagins. Therefore, a widespread allergic reaction occurs throughout the vascular system and closely associated tissues. This reaction is called anaphylaxis. Histamine is released into the circulation and causes body-wide vasodilation, as well as increased permeability of the capillaries with resultant marked loss of plasma from the circulation. Occasionally, a person who experiences this reaction dies of circulatory shock within a few minutes unless treated with epinephrine to oppose the effects of the histamine.

Also released from the activated basophils and mast cells is a mixture of leukotrienes called slow-reacting substance of anaphylaxis. These leukotrienes can cause spasm of the smooth muscle of the bronchioles, eliciting an asthma-like attack, sometimes causing death by suffocation.

Urticaria.

Urticaria results from antigen entering specific skin areas and causing localized anaphylactoid reactions. Histamine released locally causes (1) vasodilation that induces an immediate red flare and (2) increased local permeability of the capillaries that leads to local circumscribed areas of swelling of the skin within another few minutes. The swellings are commonly called hives. Administration of antihistamine drugs to a person before exposure will prevent the hives.

Hay Fever.

In hay fever, the allergen-reagin reaction occurs in the nose. Histamine released in response to the reaction causes local intranasal vascular dilation, with resultant increased capillary pressure and increased capillary permeability. Both these effects cause rapid fluid leakage into the nasal cavities and into associated deeper tissues of the nose, and the nasal linings become swollen and secretory. Here again, use of antihistamine drugs can prevent this swelling reaction. However, other products of the allergen-reagin reaction can still cause irritation of the nose, eliciting the typical sneezing syndrome.

Asthma.

Asthma often occurs in the “allergic” type of person. In such a person, the allergen-reagin reaction occurs in the bronchioles of the lungs. Here, an important product released from the mast cells is believed to be the slow-reacting substance of anaphylaxis (a mixture of three leukotrienes), which causes spasm of the bronchiolar smooth muscle. Consequently, the person has difficulty breathing until the reactive products of the allergic reaction have been removed. Administration of antihistamine medication has less effect on the course of asthma because histamine does not appear to be the major factor eliciting the asthmatic reaction.