CHAPTER 22 Essentials of Immunology

Overview of the Immune Response Cells and Organs of the Immune System

All the cells involved in immunity originate from common stem cells in the bone marrow (Figure 22.1).

The blood and lymph systems (Figure 22.2) circulate cells and proteins that are important for a functional immune system. Whole blood is composed of plasma, a liquid containing proteins and a variety of other solutes and suspended cells.

Outside the body, plasma quickly forms an insoluble clot. Plasma remains liquid only when an anticoagulant is added. After clotting, the remaining fluid, called serum, contains no cells or clotting proteins. Serum does, however, contain a high concentration of other proteins, including soluble antibody proteins, and is widely used in immunological investigations. The use of serum antibodies to detect antigens in vitro is called serology. A variety of leukocytes participate in immune responses.

The Innate Immune Response, The innate immune response is mediated by phagocytes. Phagocytes recognize pathogen- associated molecular patterns (PAMPs) via a family of membrane-bound pattern- recognition molecules (PRMs) (Figure 22.5).

Interaction of the PAMPs with PRMs activates phagocytes to produce metabolic products that kill the pathogen or limit its effects (Figure 22.6). Many pathogens have developed mechanisms to inhibit phagocytes.

Inflammation, Fever, and Septic Shock Inflammation is characterized by pain, swelling (edema), redness (erythema), and heat. The inflammatory response is a normal and generally desirable outcome of an immune response. Uncontrolled systemic inflammation, called septic shock, can lead to serious illness and death.

The first inflammatory cell to arrive at the scene of an infection or tissue injury is the neutrophil. These phagocytic cells are attracted to the site of an active infection or tissue injury by soluble chemoattractants called chemokines.

For example, IL-8 (interleukin-8), a small protein in the chemokine family, is produced by damaged host cells. Neutrophils migrate toward the cells secreting IL-8 and are activated by the interaction with IL-8.

The Adaptive Immune Response In adaptive immunity, nonspecific phagocytes present antigen to specific T cells, triggering the production of effector T cells and antibodies. Immune T cells and antibodies react directly or indirectly to neutralize or destroy the antigen.

The adaptive immune response is characterized by specificity for the antigen, the ability to respond more vigorously when reexposed to the same antigen (memory), and the ability to discriminate self antigens from nonself antigens (tolerance) (Figure 22.8).

Antibody-mediated immunity is particularly effective against pathogens such as viruses and bacteria in the blood or lymph and also against soluble pathogen products such as toxins.

Some T cells, the T C (T-cytotoxic) cells, directly attack and destroy antigen-bearing cells. Other antigen-activated T cells, the T H 1 or T-helper 1 cells, act indirectly by secreting proteins called cytokines that activate other cells such as macrophages to destroy the antigen-bearing cells.

This cell-mediated immunity leads to killing of pathogen-infected cells through recognition of pathogen antigens found on infected host cells.

Antigens, T Cells, and Cellular Immunity Immunogens and Antigens

Immunogens are foreign macromolecules that induce an immune response. Molecular size, complexity, and physical form are intrinsic properties of immunogens. Molecular size is an important component of immunogenicity. For example, low-molecular- weight compounds called haptens cannot induce an immune response but can bind to antibodies. Because haptens are bound by antibodies, they are antigens even though they are not immunogenic. When foreign immunogens are introduced into a host in an appropriate dose and route, they initiate an immune response.

Antigens are molecules recognized by antibodies or T-cell receptors (TCRs) (Figure 22.10).

Antibodies recognize conformational determinants; TCRs recognize linear peptide determinants (Figure 22.9).

The antibody or TCR does not interact with the antigenic macromolecule as a whole but only against a distinct portion of the molecule called an antigenic determinant or epitope.

Presentation of Antigen to T Lymphocytes T cells recognize antigens presented by antigen-presenting cells (APCs) or by pathogen-infected cells. At the molecular level, TCRs bind peptide antigens presented by major histocompatibility complex (MHC) proteins. Class I MHC proteins are found on the surfaces of all nucleated cells. Class II MHC proteins are found only on the surface of B lymphocytes, macrophages, and dendritic cells, all of which are APCs (Figure 22.11).

These molecular interactions stimulate T cells to kill antigen-bearing cells or to produce cell-stimulating proteins known as cytokines. Figure illustrates antigen presentation by MHC I and MHC II proteins.

T-Cytotoxic Cells and Natural Killer Cells T-cytotoxic (T C ) cells recognize antigens on virus-infected host cells and tumor cells through antigen-specific TCRs. Antigen- specific recognition triggers killing via perforin and granzymes (Figure 22.13).

Natural killer (NK) cells use the same effectors to kill virus-infected cells and tumors. However, NK cells do not require stimulation, nor do they exhibit memory. NK cells respond in the absence of MHC proteins.

T-Helper Cells: Activating the Immune Response T H 1 and T H 2 cells play pivotal roles in cell- mediated and antibody-mediated immune responses. Following the initial antigen exposure, each antigen-stimulated B cell multiplies and differentiates to form both antibody-secreting plasma cells and memory cells (Figure 22.14). T H 1 inflammatory and T H 2 helper cells each stimulate effector cells through the action of cytokines.

PART III Antibodies and Immunity, p Antibodies (Immunoglobulins), p. 744

Immunoglobulin (Ig) (antibody) proteins consist of four chains, two heavy and two light (Figure 22.15). Each IgG light chain consists of two protein domains of equal size.

The amino-terminal region is a variable domain, meaning that the amino acid sequence in this structural region differs in each different antibody. The antigen-binding site is formed by the interaction of variable regions of heavy and light chains (Figure 22.16).

Each class of Ig has different structural and functional characteristics (Figure 2.17; Table 22.2).

The structure of IgM is shown in Figure Figure shows the structure of IgA.

Antibody Production Antibody production is initiated by antigen contact with an antigen-specific B cell that processes the antigen and presents it to an antigen-specific T H 2 cell. The activated T H 2 cell then signals the antigen-specific B cell to produce antibody.

Figure shows a typical rearrangement and expression pattern for the human kappa light chain.

Activated B cells live for years as memory cells and can rapidly produce large quantities (high titers) of antibodies upon reexposure to antigen (Figure 22.21).

Plasma cells are relatively short-lived (less than 1 week), but produce and secrete large amounts of IgM antibody in this primary antibody response. The memory B cells generated by the initial exposure to antigen may live for years. If reexposure to the immunizing antigen occurs at a later time, memory cells need no T-cell activation; they quickly transform to plasma cells and begin producing IgG. Upon reexposure, the antibody titer rises rapidly to a level 10–100 times greater than the titer achieved following the first exposure. This rise in antibody titer is referred to as the secondary antibody response.

Complement, Antibodies, and Pathogen Destruction

The complement system catalyzes bacterial cell destruction and opsonization (Figure 22.22).

Complement is triggered by antibody interactions or by interactions with nonspecific activators. Complement is a critical component of both innate and adaptive host defense.

Immunity and Prevention of Infectious Disease Natural Immunity

Innate and adaptive immune responses are necessary for survival. Lack of innate immunity results in death due to recurrent, uncontrollable infections. Lack of adaptive immunity also results in uncontrollable infectious disease.

Artificial Immunity Immunity to infectious disease can be either passive or active, natural or artificial (Table 22.3).

Many exotoxins can be modified chemically so that they retain their antigenicity but are no longer toxic. Such a modified exotoxin is called a toxoid.

Immunization, a form of artificial active immunity, is widely employed to prevent infectious diseases (Table 22.4; Figure 22.24).

Most agents used for immunization are either attenuated or inactivated pathogens or inactivated forms of natural microbial products.

New Immunization Strategies Alternative immunization strategies using bioengineered molecules eliminate exposure to microorganisms and, in some cases, even to protein antigen. Application of these strategies may provide safer and more targeted vaccines.

Immune Response Diseases Allergy, Hypersensitivity, and Autoimmunity

Hypersensitivity results when foreign antigens induce cellular or antibody immune responses, leading to host tissue damage. Table 22.5 lists the four types of hypersensitivity. Autoimmunity occurs when the immune response is directed against self antigens, resulting in host tissue damage.

Immediate (Type I) hypersensitivity reactions, commonly called allergies, occur within minutes after exposure to antigen (Figure 22.25; Table 22.6).

Type IV hypersensitivity, or delayed-type hypersensitivity (DTH), is cell-mediated hypersensitivity characterized by tissue damage due to inflammatory responses produced by T H 1 inflammatory cells. Typical antigens include certain microorganisms, a few self antigens (Table 22.7), and several chemicals that bind covalently to the skin, creating new antigens. Autoantibodies are antibodies that react to self antigens.

Superantigens Superantigens bind and activate large numbers of T cells in a novel fashion (Figure 22.27). Superantigen-activated T cells are capable of producing systemic diseases characterized by massive inflammatory reactions.