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Resistance of the Body to Infection: II. Immunity and Allergy
The human body has the ability to resist almost all types of organisms or toxins that tend to damage the tissues and organs. This capability is called immunity . Much of the immunity is acquired immunity that does not develop until after the body is first attacked by a bacterium, virus, or toxin; often, weeks or months are required for the immunity to develop. An additional element of immunity that results from general processes, rather than from processes directed at specific disease organisms, is called innate immunity , which includes the following aspects:
- 1.
Phagocytosis of bacteria and other invaders by white blood cells and cells of the tissue macrophage system, as described in Chapter 34
- 2.
Destruction of swallowed organisms by the acid secretions of the stomach and the digestive enzymes
- 3.
Resistance of the skin to invasion by organisms
- 4.
Presence in the blood of certain chemicals and cells that attach to foreign organisms or toxins and destroy them.
Some of these are: (1) lysozyme , a mucolytic polysaccharide that attacks bacteria and causes them to dissolute; (2) basic polypeptides , which react with and inactivate certain types of gram-positive bacteria; (3) the complement complex , described later, a system of about 20 proteins that can be activated in various ways to destroy bacteria; and (4) natural killer lymphocytes that can recognize and destroy foreign cells, tumor cells, and even some infected cells.
This innate immunity makes the human body resistant to diseases such as some paralytic viral infections of animals, hog cholera, cattle plague, and distemper—a viral disease that kills a large percentage of dogs that become afflicted with it. Likewise, many animals are resistant or even immune to many human diseases, such as poliomyelitis, mumps, human cholera, measles, and syphilis, which are very damaging or even lethal to humans.
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 ability 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.
Acquired immunity can often bestow an extreme degree of protection. For example, 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. It is for this reason that the treatment process known as immunization is so important in protecting people against disease and against toxins, as explained later in this chapter.
Basic Types of Acquired Immunity—Humoral and Cell-Mediated
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 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 formation of large numbers of activated T lymphocytes , which are specifically crafted in the lymph nodes to destroy the foreign agent. This type of immunity is called cell-mediated immunit y or T-cell immunity because the activated lymphocytes are T lymphocytes. Both the antibodies and activated lymphocytes are formed in the lymphoid tissues of the body.
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 organism almost always contains one or more specific chemical compounds in its makeup that is (are) different from all other compounds. In general, these are proteins or large polysaccharides that initiate the acquired immunity; these substances are called antigens ( anti body gen erators).
For a substance to be antigenic, it usually must have a high molecular weight of 8000 or more. Furthermore, the process of antigenicity usually depends on regularly recurring molecular groups, called epitopes , on the surface of the large molecule. This factor also explains why proteins and large polysaccharides are almost always antigenic because both these substances have this stereochemical 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. Within days after birth, such a person dies of fulminating bacterial infection unless he or she is treated by heroic measures. Therefore, it is clear that lymphocytes are essential to the survival of humans.
Lymphocytes are located most extensively in the lymph nodes, but 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 cases, the invading agent first enters the tissue fluids and then is carried by lymph vessels to the lymph node or other lymphoid tissue. For example, the lymphoid tissue of the gastrointestinal walls is exposed immediately to antigens invading from the gut. The lymphoid tissue of the throat and pharynx (including 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 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.
T and B Lymphocytes Promote Cell-Mediated and 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 multipotent hematopoietic stem cells that form common lymphoid progenitor cells as one of their most important offspring as they differentiate. Almost all 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 eventually destined to form activated T lymphocytes first migrate to and are preprocessed in the thymus gland; 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 formation, respectively, of (1) activated T lymphocytes and (2) antibodies.
Preprocessing of T and B Lymphocytes
Although all lymphocytes in the body originate from lymphocyte-committed stem cells of the embryo, these stem cells are incapable of forming activated T lymphocytes or antibodies directly. Before they can do so, they must be further differentiated in appropriate processing areas, as follows.
Thymus Gland Preprocesses 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 via 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 in to up to 90% 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, toxin, or even transplanted tissue from another person.
Most of the preprocessing of T lymphocytes in the thymus occurs shortly before the 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, including rejection of transplanted organs.
Liver and Bone Marrow Preprocess B Lymphocytes
In humans, B lymphocytes are preprocessed 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:
- 1.
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, explained elsewhere in this chapter and in Chapter 34 .
- 2.
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.
T Lymphocytes and B-Lymphocyte Antibodies React Against Specific Antigens—Role of Lymphocyte Clones
When specific antigens come into contact with T and B lymphocytes in the lymphoid tissue, some of the T lymphocytes become activated to form activated T cells, and some 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 described next.
Millions of Specific Types of Lymphocytes Are Stored in 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 are 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, carried to the blood, and then 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, 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 antibodies or T cells produced by the lymphoid tissue. 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, 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 Lymphocyte CloneS
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 its cell surface membrane about 100,000 antibody molecules that will react highly specifically with only one 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, described in more detail subsequently. In the case of the T lymphocytes, molecules similar to antibodies, called surface receptor proteins (or T-cell receptors ), are on the surface of the T-cell membrane, and these are also highly specific for one specified activating antigen. An antigen therefore stimulates only those cells that have complementary receptors for the antigen and are already committed to respond to it.
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 T Cells in Activation of 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 small. We discuss this cooperative relationship between helper T cells and B cells after describing the mechanisms of the T-cell system of immunity.
Specific Attributes of The B-Lymphocyte System—Humoral Immunity and Antibodies
Antibody Formation 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 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 proliferates vastly. The plasmablasts then begin to divide at a rate of about once every 10 hours for about nine divisions, giving a total population of about 500 cells for each original plasmablast in 4 days. 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.
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