R. M. Zinkernagel
■ Resistance to disease is based on innate mechanisms and adaptive or acquired immunity. Acquired immune mechanisms act in a specific manner and function to supplement the important nonspecific or natural resistance mechanisms such as physical barriers, granulocytes, macrophages, and chemical barriers (lysozymes, etc.). The specific immune mechanisms constitute a combination of less specific factors, including the activation of macrophages, complement, and necrosis factors; the early recognition of invading agents, by cells exhibiting a low level of specificity, (natural killer cells, yd [gamma-delta] T cells); and systems geared toward highly specific recognition (antibodies and aß [alpha-beta] T cells).
Many components of the specific immune defenses also contribute to nonspecific or natural defenses such as natural antibodies, complement, interleukins, interferons, macrophages, and natural killer cells. ■
In the strict sense, "immunity" defines an acquired resistance to infectious disease that is specific, i.e., resistance against a particular disease-causing pathogen. For example, a person who has had measles once will not suffer from measels a second time, and is thus called immune. However, such specific or acquired immune mechanisms do not represent the only factors which determine resistance to infection. The canine distemper virus is a close relative of the measles virus, but never causes an infection in humans. This kind of resistance is innate and nonspecific. Our immune system recognizes the pathogen as foreign based on certain surface structures, and eliminates it. Humans are thus born with resistance against many microorganisms (innate immunity) and can acquire resistance to others (adaptive or acquired immunity; Fig. 2.1). Activation of the mechanisms of innate immunity, also known as the primary immune defenses, takes place when a pathogen breaches the outer barriers of the body. Specific immune defense factors are mobilized later to fortify and regulate these primary defenses. Responses of the adaptive immune system not only engender immunity in the strict sense, but can also contribute to pathogenic processes. The terms immuno-pathology, autoimmunity, and allergy designate a group of immune
44 2 Basic Principles of Immunology — The Components of Anti-Infection Defense
Innate, nonspecific defenses
Granulocytes Macrophages NK cells
Acquired, specific immunity
Chemical barriers pH, lipids, enzymes, complement factors, interleukins, acute phase proteins, antimicrobial peptides surfactants
Cytotoxic T cells T helper cells
Fig. 2.1 The innate immune defense system comprises nonspecific physical, cellular, and chemical mechanisms which are distinct from the acquired immune defense system. The latter comprises cellular (T-cell responses) and humoral (antibodies) components. Specific Tcells, together with antibodies, recruit non-specific effector mechanisms to areas of antigen presence.
phenomena causing mainly pathological effects, i.e., tissue damage due to inadequate, misguided, or excessive immune responses. However, a failed immune response may also be caused by a number of other factors. For instance, certain viral infections or medications can suppress or attenuate the immune response. This condition, known as immunosuppression, can also result from rare genetic defects causing congenital immunodeficiency.
The inability to initiate an immune response to the body's own self antigens (also termed autoantigens) is known as immunological tolerance.
Anergy is the term used to describe the phenomenon in which cells involved in immune defense are present but are not functional.
An immune response is a reaction to an immunological stimulus. The stimulating substances are known as antigens and are usually proteins or complex carbohydrates. The steric counterparts of the antigens are the antibodies, i.e., immunoreceptors formed to recognize segments, roughly 8-15 amino acids long, of the folded antigenic protein. These freely accessible structural elements are known as epitopes when present on the antigens, or as antigen-binding sites (ABS) from the point of view of the immunoreceptors. Presented alone, an epitope is not sufficient to stimulate an immunological response. Instead responsiveness is stimulated by epitopes con stituting part of a macromolecule. This is why the epitope component of an antigen is terminologically distinguished from its macromolecular carrier; together they form an immunogen. B lymphocytes react to the antigen stimulus by producing antibodies. The T lymphocytes (T cells) responsible for cellular immunity are also activated. These cells can only recognize protein antigens that have been processed by host cells and presented on their surface. The T-cell receptors recognize antigen fragments with a length of 8-12 sequential amino acids which are either synthesized by the cell itself or produced subsequent to phagocytosis and presented by the cellular transplantation antigen molecules on the cell surface. The T cells can then complete their main task—recognition of infected host cells—so that infection is halted.
Our understanding of the immune defense system began with studies of infectious diseases, including the antibody responses to diphtheria, dermal reactions to tuberculin, and serodiagnosis of syphilis. Characteriztion of pathological antigens proved to be enormously difficult, and instead erythro-cyte antigens, artificially synthesized chemical compounds, and other more readily available proteins were used in experimental models for more than 60 years. Major breakthroughs in bacteriology, virology, parasitology, biochemistry, molecular biology, and experimental embryology in the past 30-40 years have now made a new phase of intensive and productive research possible within the field of immune defenses against infection. The aim of this chapter on immunology, in a compact guide to medical microbiology, is to present the immune system essentially as a system of defense against infections and to identify its strengths and weaknesses to further our understanding of pathogenesis and prevention of disease.
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