IMMUNOLOGY - Royt A. - Mir 2000

Chapter 1. General Overview of the Immune System

THE IMMUNE RESPONSE

Thus, any Immune Response has two main phases:

✵ antigen recognition;

✵ reactions directed at its elimination.

In adaptive immune responses, antigen recognition is carried out by lymphocytes that undergo selective proliferation driven by clonal Selection.

Clonal selection — the proliferation of Cells that have bound a specific antigen

Each lymphocyte (both B AND T populations) is genetically programmed to recognize essentially only a single antigen, but The Immune System as a whole can specifically recognize many thousands of different Antigens. Therefore, the lymphocytes capable of recognizing any given antigen must constitute only a very small fraction of the total population. How then does the body adequately respond to an infection? The explanation is that an antigen, upon binding to the few cells capable of recognizing it, stimulates their rapid proliferation. Within a few days, enough cells are generated to mount an adequate immune response. In other words, the antigen itself selects and promotes The formation of specific clones of cells that bind this antigen (Fig. 1.13)—a process termed clonal selection, which is characteristic of both B and T cells.

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Fig. 1.13. Each antibody-producing Cell (B cell) is programmed to synthesize Antibodies of a single Specificity only. These are displayed on its surface as antigen-binding receptors. The antigen binds exclusively to those B cells bearing the corresponding surface receptor—in our example, B cell 2. This interaction stimulates the proliferation of such cells and their maturation into antibody-producing cells, as well as into long-lived immunological memory cells, all retaining the original antigen-binding specificity.

It seems staggering how the immune system can "anticipate" the repertoire of antibody specificities that will be required over an individual's lifetime. In reality, the situation is quite different. The immune system simply produces antibodies capable of recognizing a vast diversity of antigens even before encountering them. Many of these antibodies will never be called upon to protect the individual from infection. However, the countless pathogenic microorganisms and their ability to alter their antigenic composition through mutation make the presence of all these antibodies essential—just in case they are needed.

Lymphocytes activated by antigen binding enter the Cell Division cycle. They express new receptors that enable them to respond to cytokines secreted by other cells, which serve as signals for proliferation. Lymphocytes may also begin secreting cytokines themselves. Typically, they undergo several rounds of division before differentiating into mature cells, again under METABOLISM/18.html">The Influence of cytokines. For example, proliferating B cells eventually mature into antibody-secreting plasma cells. Even after the infection is cleared, a fraction of the newly formed lymphocytes persists, capable of being reactivated if the antigen is encountered again. These are called memory cells because they retain immunological memory of specific antigens. The existence of memory cells is responsible for long-term Immunity against a given pathogen.

Various effector mechanisms of the immune response exist to eliminate pathogens

The immune system possesses a multitude of mechanisms for destroying pathogenic microbes, and each is tailored to a specific type of infection and a particular stage of the pathogen's life cycle. These defense mechanisms are commonly referred to as effector systems.

Neutralization. In one of the simplest effector systems, it is sufficient for antibodies merely to bind to a specific pathogen to counteract it. For instance, antibodies directed against the outer capsid Proteins of certain rhinoviruses (which cause the common cold) can prevent Viral Particles from binding to host cells and infecting them.

Phagocytosis. Much more frequently, antibodies exert their effect by activating Complement or acting as opsonins that enhance the uptake of microbes by phagocytes. Upon binding to an opsonized microbe, the phagocytic cell engulfs it by extending pseudopodia around it. The pseudopodia fuse, and the microbe becomes enclosed (endocytosed, internalized) within a phagosome (Fig. 1.14). Phagocytes process ingested material in various ways. Macrophages, for instance, reduce molecular oxygen to generate bactericidal reactive oxygen metabolites, which are secreted into the phagosome. Neutrophils contain lactoferrin, which chelates iron, depriving certain Bacteria of this essential nutrient element. Finally, granules and Lysosomes fuse with the phagosome, filling the resulting phagolysosome with Enzymes that degrade its contents (Fig. 1.15). The mechanisms of phagocytosis are described in more detail in Chapters 10 and 17.

Fig. 1.14. Electron microscopic study of phagocytosis. The micrographs show successive stages of membrane invagination and the resulting internalization of material. Having bound an opsonized particle, the phagocyte gradually engulfs it by extending pseudopodia (1–3). The pseudopodia then fuse (4), and the microbial cell becomes enclosed within a phagosome (5). (Photographs kindly provided by Dr. A. Stevens and Prof. J. Lowe.)

Fig. 1.15. Phagocytes migrate to the site of inflammation via chemotaxis. Their non-specific surface receptors then bind to microbes, or, if the microbial surface is opsonized by a fragment of the third complement component (C3b) and/or antibodies, binding occurs via phagocytic receptors for C3b and/or Fc (see Fig. 1.10). Once activated by binding, the phagocyte surrounds the infectious agent with pseudopodia, enclosing it in a phagosome while generating bactericidal oxygen metabolites. As soon as the microbe enters The Cell, lysosomes fuse with the phagosome to form a phagolysosome, within which the infectious agent is destroyed. Microbial debris may subsequently be expelled from the cell.

Cytotoxic reactions and apoptosis. Cytotoxic reactions are effector immune mechanisms directed against whole cells, usually those too large to be phagocytosed. Such target cells are recognized either by specific antibodies interacting with their surface components or by T cells via antigen-specific TCRs. Unlike phagocytosis, in which lysosomal contents are discharged into the phagosome, in a cytotoxic reaction the attacking cell directs the contents of its granules outward toward the target cell. Cytotoxic T cell granules contain compounds called perforins, which are capable of forming Pores in the outer membrane of target cells. (Similarly, antibodies binding to The surface of a target cell can recruit complement to perforate its cytoplasmic membrane.) Certain cytotoxic cells are also able to trigger the target cell's self-destruction program via signals—a process known as apoptosis.