FIG. 18.1 Schematic overview of humoral and cellular immunologic pathways and resulting effector substances or mechanisms of activity.
The immunoglobulins are large proteins (molecular weights from 150,000 to 900,000 daltons) with specific structural arrangements of polypeptide chains with specific amino acid sequences. The immunoglobulins are divided into five primary classes on the basis of structural arrangements: IgA, IgD, IgE, IgG, and IgM. Each of the immunoglobulins is described as follows.
IgA is a small molecule that constitutes approximately 15% of the total immunoglobulins and is present in most body secretions. Secretory IgA is effective against viruses and some bacteria that invade the mucous membranes. Secretory immunity is also mediated by IgA. The secretory antibodies are found on the mucosal surfaces of the oral cavity (saliva), the lungs (sputum), and the intestinal and urogenital tracts and in mammary secretions. This secretory IgA differs from other antibodies in that it has a protein molecule, called a secretory piece, attached to it. IgA activates the complement system through a particular sequence of events called the properdin pathway. The complement system is a complex cascade of activations of more than 20 proteins that result in the improved ability of phagocytes’ cell killing.
IgD constitutes about 1% of the total immunoglobulins. The exact function of IgD is unknown. Similar to IgA, IgD is situated in the upper respiratory mucosa and works to activate B lymphocytes. IgD has been described as “an ancestral surveillance system at the interface between immunity and inflammation.”2 IgD has also been suggested for relationships in antibody activity directed toward insulin, penicillin, milk proteins, diphtheria toxoid, thyroid antigens, and the products of abnormal tissue growth.
IgE is present in minute quantities (approximately 0.002% of total serum immunoglobulins) and is associated with type I immediate hypersensitivity reaction.
IgG is the smallest antibody by size but constitutes approximately 75% of the total plasma antibodies. The complement system is activated when an antigen binds to IgG. IgG is the only antibody that can cross the placental barrier and thus confer passive immunity to the fetus. IgG is the primary antibody involved in the secondary response. It is active against many bloodborne infectious agents such as bacteria, viruses, parasites, and some fungi.
IgM is the largest antibody by size; it constitutes approximately 10% of plasma antibody. IgM is found almost exclusively in body serums because of its large size and inability to cross membranes; it is the first antibody that responds to an antigen. IgM is involved in the primary antibody response, effectively marking antigens for phagocytic destruction. In addition, IgM is effective in the activation of the complement system.
Cellular Immunity
Cellular immunity is the second type of specific immunity; it uses T lymphocytes and macrophages. Some specific functions of the cellular immunity system are protection against most viruses, slow-acting bacteria, and fungal infections; mediation of cutaneous delayed hypersensitivity reactions; rejection of foreign grafts; and immunologic surveillance.
The T lymphocytes, like the B lymphocytes, originate from primitive stem cells and go through stages of maturation (see Fig. 18.1). When the immature lymphocyte leaves the bone marrow, it migrates to the thymus gland where it is acted on by the hormone thymosin. The T lymphocyte then becomes mature and immunocompetent. The origin of the name T lymphocyte is derived from this thymus-dependent maturation. These mature T lymphocytes can circulate in the blood and lymph, or they may come to rest in the inner cortex of the lymph nodes where they may form subgroups of T lymphocytes.
These T lymphocytes function overall in the immune system by serving in regulatory, effector, and cytotoxic capacities. The regulatory T lymphocytes are the helper or suppressor T lymphocytes. These lymphocytes amplify or suppress responses of other T lymphocytes or responses of B lymphocytes. The helper T lymphocytes produce a soluble factor that is necessary, in some instances, for antibody formation by B lymphocytes. This helper action is most important for IgE and IgG production. The underproduction of helper cells is associated with AIDS. The suppressor T lymphocytes appear to regulate or suppress the activity of B lymphocytes in the production of antibodies. Evidence indicates that the suppressor T lymphocytes can become pathologically active against helper T lymphocytes and other aspects of cellular immunity. For this reason, these suppressor T lymphocytes may have a role in immune tolerance and in the development of autoimmune disease such as myasthenia gravis. Effector T lymphocytes are probably responsible for the delayed hypersensitivity reactions, the rejection of foreign tissue grafts and tumors, and the elimination of virus-infected cells. Effector T lymphocytes have antigen receptors on their surfaces that are significant in the initiation of cellular immunity.
When an antigen enters the body, it undergoes processing by the phagocytes. The antigen then travels to the regional lymph node, which drains the area of antigen invasion. In this lymph node, the T lymphocyte recognizes the antigen, binds to the antigen, and proliferates. The T lymphocyte becomes sensitized when it comes into contact with the antigen. In addition, memory T lymphocytes result from this interaction. On a second exposure to the antigen, a more intense, efficient, and rapid cellular immunity results. This contact also results in the release of lymphokines by the T lymphocyte. Some of the lymphokines are (1) chemotactic factor, which recruits phagocytes into the area; (2) migration inhibitory factor, which prevents the migration of phagocytes away from the area; (3) transfer factor, which induces noncommitted T lymphocytes to form T lymphocytes of the same antigen-specific clone as the original cells; (4) lymphotoxin, which is a nonspecific cellular toxin; and (5) interferon, which inhibits the replication of viruses.
The direct cellular cytotoxicity mediated by cellular immunity involves cytotoxic lymphocytes or killer cells and macrophages. The role of these cytotoxic T lymphocytes is not well established; however, they are believed to be involved in nonspecific killing of viruses, rejection of allografts, and immune surveillance of malignant diseases.
Hypersensitivity Reactions
The immune system serves mainly as protection from harmful substances; however, in some instances, the activation of the immune system can cause deleterious effects, which are termed an allergic response or hypersensitivity reaction. This response represents a magnified or inappropriate reaction by the host to an antigenic substance; it can result in immunologic disease. Hypersensitivity reactions are divided into four major categories: type I, type II, type III, and type IV hypersensitivity reactions (Table 18.1).
Type I Hypersensitivity Reaction (Anaphylactic, Immediate)
Type I hypersensitivity reaction occurs in persons who were previously sensitized to a specific antigen. The antibodies formed against that antigen are of the IgE classification. The term reagins is used to describe these IgE antibodies. Reaginic antibodies bind to mast cells in tissues that surround the blood vessels and to blood basophils. When the previously sensitized host is reexposed to the same antigen, the antigen reacts with the reaginic antibody attached to the cell, and an immediate swelling, then rupture, of the basophil or mast cell results in a release of chemical mediators into the local environment. These chemical mediators include (1) histamine, which causes local vasodilatation and increased permeability of the capillaries; (2) slow-reacting substance of anaphylaxis, which causes prolonged contraction of some smooth muscle such as that of the bronchi; (3) chemotactic factor, which draws neutrophils and macrophages into the area of the antigen-antibody reaction; and (4) lysosomal enzymes, which elicit a local inflammatory reaction. These chemical mediators act on the “shock organs” such as the mucosa, skin, bronchi, and heart. The resulting clinical manifestations of the type I reaction include urticaria, allergic rhinitis, allergic asthma, and, in severe cases, systemic anaphylaxis.3
Type II Hypersensitivity Reaction (Cytotoxic)
In the type II hypersensitivity reaction, the antigen and the antibody complex react, thereby injuring the cell membrane or a surface tissue with direct destruction by antibody of cellular elements. The antibodies involved in the type II reaction are either IgG or IgM, and the reaction is enhanced by complement. Hemolytic anemia is an example of a type II reaction that affects the red blood cells (RBCs). For example, when penicillin is absorbed on the RBC membrane, the interaction of antipenicillin antibody, penicillin, and complement causes a reaction that results in the lysis of RBCs.3
Type III Hypersensitivity Reaction (Arthus)
The type III hypersensitivity reaction involves the formation of immune complexes of antigen and antibody (IgG or IgM). These immune complexes precipitate in and around small vessels and damage the target tissue by activating complement over several hours. Also involved in this process is an inflammatory reaction initiated by the gathering of inflammatory cells and the release of vasoactive amines from platelets. As this process continues, polymorphonuclear leukocytes phagocytize the immune complexes and cause inflammation and necrosis of the blood vessels and surrounding tissue because of the release of lysosomal enzymes. Serum sickness and systemic lupus erythematosus are clinical examples of type III hypersensitivity reactions.3
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