Y

C5b67

C5b6789

Lysis of cells

Figure 34-5

Cascade of reactions during activation of the classic pathway of complement. (Modified from Alexander JW, Good RA: Fundamentals of Clinical Immunology. Philadelphia: WB Saunders, 1977.)

Complement System for Antibody Action

"Complement" is a collective term that describes a system of about 20 proteins, many of which are enzyme precursors. The principal actors in this system are 11 proteins designated C1 through C9, B, and D, shown in Figure 34-5. All these are present normally among the plasma proteins in the blood as well as among the proteins that leak out of the capillaries into the tissue spaces. The enzyme precursors are normally inactive, but they can be activated mainly by the so-called classic pathway.

Classic Pathway. The classic 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 34-5, beginning with activation of the proenzyme C1 itself. 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:

1. Opsonization and phagocytosis. One of the products of the complement cascade, C3b, strongly activates phagocytosis by both neutrophils and macrophages, causing these cells to engulf the bacteria to which the antigen-antibody complexes are attached. This process is called opsonization. It often enhances the number of bacteria that can be destroyed by many hundredfold.

2. Lysis. One of the most important of all the products of the complement cascade is the lytic complex, which is a combination of multiple complement factors and designated C5b6789. This has a direct effect of rupturing the cell membranes of bacteria or other invading organisms.

3. Agglutination. The complement products also change the surfaces of the invading organisms, causing them to adhere to one another, thus promoting agglutination.

4. Neutralization of viruses. The complement enzymes and other complement products can attack the structures of some viruses and thereby render them nonvirulent.

5. Chemotaxis. Fragment C5a initiates chemotaxis of neutrophils and macrophages, thus causing large numbers of these phagocytes to migrate into the tissue area adjacent to the antigenic agent.

6. Activation of mast cells and basophils. Fragments C3a, C4a, and C5a activate mast cells and basophils, causing them to release histamine, heparin, and several other substances into the local fluids. These substances in turn cause increased local blood flow, increased leakage of fluid and plasma protein into the tissue, and other local tissue reactions that help inactivate or immobilize the antigenic agent. The same factors play a major role in inflammation (which was discussed in Chapter 33) and in allergy, as we discuss later.

7. Inflammatory effects. In addition to inflammatory effects caused by activation of the mast cells and basophils, several other complement products contribute to local inflammation. These products cause (1) the already increased blood flow to increase still further, (2) the capillary leakage of proteins to be increased, and (3) the interstitial fluid proteins to coagulate in the tissue spaces, thus preventing movement of the invading organism through the tissues.

Special Attributes of the T-Lymphocyte System-Activated T Cells and Cell-Mediated Immunity

Release of Activated T Cells from Lymphoid Tissue and Formation of Memory Cells. On 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 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 had occurred 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 actually 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 34-6). 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

Activation of T cells requires interaction of T-cell receptors with an antigen (foreign protein) that is transported to the surface of the antigen-presenting cell by a major histocompatibility complex (MHC) protein. Cell-to-cell adhesion proteins enable the T cell to bind to the antigen-presenting cell long enough to become activated.

Activation of T cells requires interaction of T-cell receptors with an antigen (foreign protein) that is transported to the surface of the antigen-presenting cell by a major histocompatibility complex (MHC) protein. Cell-to-cell adhesion proteins enable the T cell to bind to the antigen-presenting cell long enough to become activated.

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 helper T 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.

Several Types of T Cells and Their Different Functions

It has become clear that there are multiple types of T cells. They are classified into three major groups: (1) helper T cells, (2) cytotoxic T cells, and (3) suppressor T cells. The functions of each of these are distinct.

Helper T Cells—Their Role in Overall Regulation of Immunity

The helper T cells are by far the most numerous of the T cells, usually constituting more than three quarters

Preprosessor areas

Preprosessor areas

-Antigen

Antigen-specific receptor

Helper T cells

Lymphokines!!

-Antigen

Antigen-specific receptor

Cytotoxic T cells

Helper T cells

Cytotoxic T cells

Lymphokines!!

Suppressor T cells

Proliferation

Differentiation

Antigen

B cell

Plasma cells

Suppressor T cells

IgM IgG IgA IgE

B cell

Plasma cells

IgM IgG IgA IgE

Figure 34-7

Regulation of the immune system, emphasizing a pivotal role of the helper T cells. MHC, major histocompatibility complex.

of all of them. As their name implies, they help in the functions of the immune system, and they do so in many ways. In fact, they serve as the major regulator of virtually all immune functions, as shown in Figure 34-7. They do this by forming a series of protein mediators, called lymphokines, that act on other cells of the immune system as well as on bone marrow cells. Among the important lymphokines secreted by the helper T cells are the following:

Interleukin-2 Interleukin-3 Interleukin-4 Interleukin-5 Interleukin-6

Granulocyte-monocyte colony-stimulating factor Interferon-g

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

Stimulation of Growth and Proliferation of Cytotoxic T Cells and Suppressor T Cells. In the absence of helper T 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 antigen to cause B-cell growth, proliferation, formation of plasma cells, and secretion of antibodies are also slight without the "help" of the helper T 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 lym-phokines 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 Helper Cells Themselves. Some of the lymphokines, especially inter-leukin-2, have a direct positive feedback effect in stimulating activation of the helper T cells themselves. This acts as an amplifier by further enhancing the helper cell response as well as the entire immune response to an invading antigen.

Cytotoxic T Cells

The cytotoxic T cell is a direct-attack cell that is capable of killing micro-organisms and, at times, even some of the body's own cells. For this reason, these cells are called killer cells. The receptor proteins on the surfaces of the cytotoxic cells cause them to bind tightly to those organisms or cells that contain the appropriate binding-specific antigen. Then, they kill the attacked cell in the manner shown in Figure 34-8. After binding, the cytotoxic T cell secretes hole-forming proteins, called perforins, that literally punch round holes in the membrane of the attacked cell. Then fluid flows rapidly into the cell from the interstitial space. In addition, the cytotoxic T cell releases cytotoxic substances directly into the attacked cell. Almost immediately, the attacked cell becomes greatly swollen, and it usually dissolves shortly thereafter.

Especially important, these cytotoxic killer cells can pull away from the victim cells after they have punched holes and delivered cytotoxic substances and

Direct destruction of an invading cell by sensitized lymphocytes (cytotoxic T cells).

then move on to kill more cells. Indeed, some of these cells persist for months in the tissues.

Some of the cytotoxic T cells are especially lethal to tissue cells that have been invaded by viruses because many virus particles become entrapped in the membranes of the tissue cells and attract T cells in response to the viral antigenicity. The cytotoxic cells also play an important role in destroying cancer cells, heart transplant cells, or other types of cells that are foreign to the person's own body.

Suppressor T Cells

Much less is known about the suppressor T cells than about the others, but they are capable of suppressing the functions of both cytotoxic and helper T cells. It is believed that these suppressor functions serve the purpose of preventing the cytotoxic cells from causing excessive immune reactions that might be damaging to the body's own tissues. For this reason, the suppressor cells are classified, along with the helper T cells, as regulatory T cells. It is probable that the suppressor T-cell system plays an important role in limiting the ability of the immune system to attack a person's own body tissues, called immune tolerance, as we discuss in the next section.

Tolerance of the Acquired Immunity System to One's Own Tissues—Role of Preprocessing in the Thymus and Bone Marrow

If a person should become immune to his or her own tissues, the process of acquired immunity would destroy the individual's own body. The immune mechanism normally "recognizes" a person's own tissues as being distinctive from bacteria or viruses, and the person's immunity system forms few antibodies or activated T cells against his or her own antigens.

Most Tolerance Results from Clone Selection During Preprocessing. It is believed that most tolerance develops 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 themselves 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 those 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 their immune tolerance of their own tissues. This 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 autoim-munity 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) lupus erythematosus, in which the person becomes immunized against many different body tissues at the same time, a disease that causes extensive damage and often rapid death.

Immunization by Injection of Antigens

Immunization has been used for many years to produce acquired immunity against specific diseases. A person can be immunized by injecting dead organisms that are no longer capable of causing disease but that still have some of their chemical antigens. This type of immunization is used to protect against typhoid fever, whooping cough, diphtheria, and many other types of bacterial diseases.

Immunity can be achieved against toxins that have been treated with chemicals so that their toxic nature has been destroyed even though their antigens for causing immunity are still intact. This procedure is used in immunizing against tetanus, botulism, and other similar toxic diseases.

And, finally, a person can be immunized by being infected with live organisms that have been "attenuated." That is, these organisms either have been grown in special culture media or have been passed through a series of animals until they have mutated enough that they will not cause disease but do still carry specific antigens required for immunization. This procedure is used to protect against poliomyelitis, yellow fever, measles, smallpox, and many other viral diseases.

Passive Immunity

Thus far, all the acquired immunity we have discussed has been active immunity. That is, the person's own body develops either antibodies or activated T cells in response to invasion of the body by a foreign antigen. However, temporary immunity can be achieved in a person without injecting any antigen. This is done by infusing antibodies, activated T cells, or both obtained from the blood of someone else or from some other animal that has been actively immunized against the antigen.

Antibodies last in the body of the recipient for 2 to 3 weeks, and during that time, the person is protected against the invading disease. Activated T cells last for a few weeks if transfused from another person but only for a few hours to a few days if transfused from an animal. Such transfusion of antibodies or T lymphocytes to confer immunity is called passive immunity.

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Essentials of Human Physiology

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