IMMUNOLOGY - Roit I. - Mir 2000

Chapter 1. General Overview of the Immune System

SOLUBLE MEDIATORS OF IMMUNITY

The Development of an Immune Response involves a wide range of messenger molecules, including lymphocyte-secreted Antibodies and cytokines, as well as various Serum Proteins typically present at low concentrations. These proteins are termed acute-phase proteins because their levels rise rapidly during an infection. One example is C-reactive protein (CRP), named for its ability to bind the C-protein of pneumococci. This binding enhances the phagocytosis of pneumococci by phagocytes—a process known as opsonization (see Fig. 1.10). The principal opsonins, or opsonizing molecules, are antibodies and Complement components.

Complement proteins act as mediators of phagocytosis, regulate the inflammatory response, and, by interacting with antibodies, participate in the body's immune defense

The Complement System comprises roughly twenty serum proteins whose overall function is to regulate inflammation. Complement components interact with each other and with other elements of The Immune System. For instance, certain microorganisms spontaneously activate the complement system via The alternative pathway, which represents a mechanism of innate, non-specific Immunity. As a result, complement components bind to the microbial surface, leading to the ingestion of these pathogens by phagocytes. When the complement system participates in adaptive immune responses, it is typically activated via the classical pathway by antibodies bound to The surface of the microorganism.

Complement activation is a cascade of reactions in which each preceding component acts upon the subsequent one, much like Blood Coagulation. Both the classical and Alternative pathways of complement activation result in the generation of proteins or peptide fragments that trigger the following effects:

✵ opsonization of microorganisms followed by their engulfment and intracellular destruction by phagocytes;

✵ recruitment of phagocytes to the site of inflammation (chemotaxis);

✵ enhancement of blood flow at the activation site and increased capillary permeability to plasma components;

✵ damage to the Organism's own Cells, Gram-negative Bacteria, Viruses, or other microbes that triggered complement activation, with pathogen lysis leading to the resolution of the infection;

✵ additional release of inflammatory mediators from mast cells.

These Functions of the complement system are illustrated schematically in Fig. 1.7 and described in detail in Chapter 4.

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Fig. 1.7. 1. The complement system can destroy the membranes of many bacterial species without the involvement of antibodies. 2. Complement activation products recruit phagocytes to the reaction site (chemotaxis). 3. By coating the bacterial surface upon binding (opsonization), complement components facilitate their recognition and engulfment by phagocytes. All these reactions can proceed via complement's intrinsic ability to recognize microbial structures or through antibodies bound to the bacteria.

Cytokines are diverse proteins that mediate signaling between lymphocytes, phagocytes, and other Cells of the body

Cytokines are broadly defined as a large group of compounds involved in Intercellular signaling during an immune response. All cytokines are proteins or Peptides; some are Glycoproteins. Cytokines are divided into several groups; for instance, cytokines secreted by lymphocytes are frequently called lymphokines. The Major Groups of cytokines are outlined below.

Interferons (IFN). These cytokines are particularly crucial in containing certain viral infections. One group of interferons (IFNα and IFNβ) is synthesized by virus-infected cells. Another type of interferon (IFNγ) is secreted by certain activated T cells. Interferons confer antiviral resistance to uninfected tissue cells (Fig. 1.8). They are produced early in infection and establish the first line of defense against most viruses.

Fig. 1.8. Virus-infected cells can synthesize interferon—some produce interferon-α (IFNα), others interferon-β (IFNβ). Certain T-lymphocyte subpopulations generate interferon-γ (IFNγ) upon antigen activation. Acting on other body cells, interferons render them resistant to viral infection. Interferon-γ also exerts numerous other effects.

Interleukins (IL). This is a large family of cytokines (ranging from IL-1 to IL-17) synthesized primarily by T cells, but in some cases also by mononuclear phagocytes or other tissue cells. Interleukins perform diverse functions, though the majority stimulate other cells to divide or differentiate. Each interleukin acts on a distinct, restricted subset of cells expressing receptors specific for that IL.

Colony-Stimulating Factors (CSF). These cytokines regulate the division and differentiation of Bone Marrow stem cells and leukocyte precursor cells. The balance among various CSFs largely determines the proportions of different leukocyte types produced in the bone marrow. Some CSFs stimulate further Cell Differentiation even outside the bone marrow.

Other cytokines. Among these, tumor necrosis factors (TNFα and TNFβ) and transforming growth factor β (TGFβ) play significant roles. They perform diverse functions but are especially vital as mediators of inflammation and cytotoxic reactions.

Antibodies bind specifically to antigen and subsequently mediate secondary effector functions

Antibodies (Ab), also referred to as IMMUNOGLOBULINS (Ig), are a family of serum proteins produced by B lymphocytes. As noted above, they represent the soluble form of antigen-specific B-cell receptors. All polyclonal antibodies of a given isotype share a uniform molecular Structure yet vary within their antigen-binding region. Typically, each antibody can specifically bind to only one antigen.

While one part of the antibody molecule (the Fab fragment) is designed to bind to the antigen, its other part (the Fc fragment) interacts with various elements of the immune system, such as phagocytes or one of the complement components. In effect, antibodies act as adapter molecules that engage different Components of the immune system in recognizing pathogenic microbes and their metabolic products (Fig. 1.9)

Fig. 1.9. If a microbe lacks The ability to activate complement or bind to phagocytes, the host organism produces antibodies against it, which act as bridging molecules linking microbial cells to complement and phagocytes. The Human Body can synthesize several million antibodies with different specificities, capable of recognizing a vast array of diverse infectious agents. For example, the antibody depicted in the diagram binds its antigen-binding fragment (Fab) to microbe 1, but not to microbe 2. The Fc fragment of the antibody can activate complement or bind to Fc receptors on host cells, primarily on phagocytes.

The part of the antibody molecule that interacts with cells of the immune system is called the Fc fragment. Neutrophils, macrophages, and other mononuclear phagocytes carry receptors for the Fc fragment on their surface. Consequently, once antibodies have bound to a pathogenic microorganism, their Fc fragment can interact with phagocytes as well. As a result, the pathogen cells will be engulfed (phagocytosed) and destroyed by the phagocytes. In this case, antibodies act as opsonins. In addition, phagocytes recognize foreign material by using the activated complement component (C3b) as an opsonin, but phagocytosis is most efficient in the presence of both antibodies and complement simultaneously (Fig. 1.10).

Fig. 1.10. 1. Phagocytes have the ability to bind bacteria and other microorganisms directly, i.e., without the involvement of opsonins, but this binding is greatly enhanced when microbes activate complement. 2. In this case, bacteria interact with C3b, enabling phagocytes to bind them via C3b receptors. 3. For the phagocytosis of microbes that either fail to activate complement fully or do not activate it at all, opsonization by antibodies (Abs) capable of binding to Fc receptors on the phagocyte surface is required. 4. Antibodies can themselves activate complement, and if microbes are opsonized not only by antibodies but also by C3b, their binding by phagocytes increases substantially.