The term “immunity” in a biologic context has historically referred to resistance to pathogens; however, reactions to some noninfectious substances including harmless environmental molecules, tumors, and even unaltered host components are also considered forms of immunity (allergy, tumor immunity, and autoimmunity, respectively). The collection of cells, tissues, and molecules that mediate these reactions is called the immune system , and the coordinated response of these cells and molecules to pathogens and other substances comprises an immune response .
The most important physiologic function of the immune system is to prevent or eradicate infections ( Fig. 1.1 ), and this is the principal context in which immune responses are discussed throughout this book. In addition, it prevents the growth of some tumors, and some cancers can be treated by stimulating immune responses against tumor cells. The immune system also plays a major role in the repair of damaged tissues. Because the immune system can respond to microbial and nonmicrobial substances and also can cause disease under some circumstances, a more inclusive definition of the immune response is a reaction to microbes, as well as to other molecules that are recognized as foreign, regardless of the physiologic or pathologic consequence of such a reaction. Immunology is the study of immune responses in this broader sense and of the cellular and molecular events that occur after an organism encounters microbes and other foreign molecules.
The importance of the immune system for health is dramatically illustrated by the frequent observation that individuals with defective immune responses are susceptible to serious, often life-threatening infections. Conversely, stimulating immune responses against microbes through vaccination is the most effective method for protecting individuals against infections; this approach has led to the worldwide eradication of smallpox, the only disease that has been eliminated from civilization by human intervention ( Fig. 1.2 ). The appearance of acquired immunodeficiency syndrome (AIDS) in the 1980s tragically emphasized the importance of the immune system for defending individuals against infection.
In contrast to these beneficial roles, abnormal immune responses cause many inflammatory diseases with serious morbidity and mortality. The immune response is the major barrier to the success of organ transplantation, which is often used to treat organ failure. The products of immune cells can also be of great practical use. For example, antibodies, which are proteins made by certain cells of the immune system, are used in clinical laboratory testing and in research as highly specific reagents for detecting a wide variety of molecules in the circulation and in cells and tissues. Antibodies designed to block or eliminate potentially harmful molecules and cells are used widely for the treatment of immunologic diseases, cancers, and other types of disorders. For all these reasons, the field of immunology has captured the attention of clinicians, scientists, and the lay public.
This chapter introduces the nomenclature of immunology, important general properties of all immune responses, and the cells and tissues that are the principal components of the immune system. In particular, the following questions are addressed:
What types of immune responses protect individuals from infections?
What are the important characteristics of immunity, and what mechanisms are responsible for these characteristics?
How are the cells and tissues of the immune system organized to find and respond to microbes in ways that lead to their elimination?
The basic principles introduced here set the stage for more detailed discussions of immune responses in later chapters. A Glossary of the important terms used in this book is provided near the end of the book.
Innate and Adaptive Immunity
Host defenses are grouped under innate immunity, which provides immediate protection against microbial invasion, and adaptive immunity, which develops more slowly and provides more specialized defense against infections ( Fig. 1.3 ). Innate immunity, also called natural immunity or native immunity, is always present in healthy individuals (hence the term innate ), prepared to block the entry of microbes and to rapidly eliminate microbes that do succeed in entering host tissues. Adaptive immunity, also called specific immunity or acquired immunity, requires proliferation and differentiation of lymphocytes in response to microbes before it can provide effective defense (i.e., it adapts to the presence of microbial invaders). Innate immunity is phylogenetically older, and the more specialized and powerful adaptive immune response evolved later.
In innate immunity, the first line of defense is provided by epithelial barriers of the skin and mucosal tissues and by cells and natural antibiotics present in epithelia, all of which function to block the entry of microbes. If microbes do breach epithelia and enter the tissues or circulation, several other components of the innate immune system defend against them, including phagocytes and innate lymphoid cells, and several plasma proteins, such as the complement system. In addition to providing early defense against infections, innate immune responses are required to initiate adaptive immune responses against the infectious agents. The components and mechanisms of innate immunity are discussed in detail in Chapter 2 .
The adaptive immune system consists of lymphocytes with highly diverse and variable receptors for foreign substances, and the products of these cells, such as antibodies . Adaptive immune responses are essential for defense against infectious microbes that are pathogenic for humans (i.e., capable of causing disease) and may have evolved to resist innate immunity. The cells and molecules of innate immunity recognize structures shared by classes of microbes, whereas the lymphocytes of adaptive immunity express receptors that specifically recognize a much wider variety of molecules produced by microbes, as well as noninfectious molecules. Any molecule that is specifically recognized by lymphocytes or antibodies is called an antigen . Adaptive immune responses often use the cells and molecules of the innate immune system to eliminate microbes. For example, antibodies (a component of adaptive immunity) bind to microbes, and these coated microbes avidly bind to and activate phagocytes (a component of innate immunity), which ingest and destroy the microbes. Examples of the cooperation between innate and adaptive immunity are discussed in later chapters.
By convention, the term immune response generally refers to adaptive immunity, and that is the focus of most of this chapter.
The cells of the immune system are located in different tissues and serve different roles in host defense. Most of these cells are derived from bone marrow precursors that circulate in the blood and are called leukocytes (white blood cells). Others are present in tissues at all times. Some of these cells function mainly in innate immunity, others in adaptive immunity, and some function in both types of responses. These cells are grouped into two broad categories— lymphoid cells (most of which are the mediators of adaptive immune responses) and nonlymphoid cells, also called myeloid cells , which play diverse roles, including in innate immune responses.
Tissue-resident dendritic cells, macrophages, and mast cells serve as sentinels to detect the presence of microbes in tissues and initiate immune responses. Dendritic cells (DCs), so called because of their many protruding membrane extensions, also have the specialized function of capturing microbial antigens and displaying them to T lymphocytes to initiate adaptive immune responses and are therefore called antigen-presenting cells (APCs, discussed later).
Phagocytes ingest and destroy microbes. They are myeloid cells and include neutrophils, which are recruited from the blood, and macrophages, which can develop from circulating monocytes and live in tissues much longer than neutrophils do. Macrophages are not only sentinels and destroyers of microbes, they also help to repair damaged tissues. Because the sentinels and phagocytes are primarily cells of innate immunity, they are described in Chapter 2 .
Lymphocytes , including B and T cells, circulate through lymphoid organs and nonlymphoid tissues. They recognize foreign antigens and carry out adaptive immune responses. They are described further later in this chapter.
Types of Adaptive Immunity
The two types of adaptive immunity, called humoral immunity and cell-mediated immunity, are mediated by different cells and molecules and provide defense against extracellular microbes and intracellular microbes, respectively ( Fig. 1.4 ).
Humoral immunity is mediated by proteins called antibodies, which are produced by cells called B lymphocytes. Secreted antibodies enter the circulation, extracellular tissue fluids, and the lumens of mucosal organs such as the gastrointestinal and respiratory tracts. The antibodies defend against microbes present in these locations by preventing them from invading tissue cells and by neutralizing toxins made by the microbes. Microbes that live and divide outside cells but are readily killed once ingested by phagocytes are called extracellular microbes, and antibodies can enhance the uptake of these microbes into phagocytes. However, many microbes, often called intracellular microbes, can live and divide inside infected cells, including phagocytes. Although antibodies can prevent such microbes from infecting tissue cells, they are not effective after the microbes have entered the cells.
Defense against microbes that have already entered host cells is called cell-mediated immunity because it is mediated by cells, which are called T lymphocytes. Cell-mediated immunity is especially important to defend against intracellular organisms that can survive and replicate inside cells. Some T lymphocytes activate phagocytes to destroy microbes that have been ingested and live within intracellular vesicles of these phagocytes. Other T lymphocytes kill any type of host cells (including non-phagocytic cells) that harbor infectious microbes in the cytoplasm or nucleus. In both cases, the T cells recognize microbial antigens that are displayed on host cell surfaces, which indicates there is a microbe inside the cell. Some T lymphocytes also help to defend against extracellular microbes by recruiting large numbers of phagocytes to sites of infection, and the phagocytes ingest and destroy the microbes.
The specificities of B and T lymphocytes differ in important respects. Most T cells recognize only peptide fragments of protein antigens presented on cell surfaces, whereas B cells and antibodies are able to recognize many different types of molecules, including proteins, carbohydrates, nucleic acids, and lipids. These and other differences are discussed in more detail later.
Immunity may be induced in an individual by infection or vaccination (active immunity) or conferred on an individual by transfer of antibodies or lymphocytes from an actively immunized individual (passive immunity) .
In active immunity, an individual exposed to the antigens of a microbe mounts a response to eradicate the infection and develops resistance to later infection by that microbe. Such an individual is said to be immune to that microbe, in contrast with a naive individual who has not previously been exposed to that microbe’s antigens.
In passive immunity, a naive individual receives antibodies or cells (e.g., lymphocytes) from another individual already immune to an infection or protective antibodies that have been synthesized using modern bioengineering techniques. The recipient acquires the ability to combat the infection for as long as the transferred antibodies or cells last. Passive immunity is therefore useful for rapidly conferring immunity even before the individual is able to mount an active response, but it does not induce long-lived resistance to the infection. The only physiologic example of passive immunity is seen in newborns, whose immune systems are not mature enough to respond to many pathogens but who are protected against infections by acquiring antibodies during fetal life from their mothers through the placenta and in the neonatal period from breast milk. Clinically, passive immunity is useful for treating some immunodeficiency diseases with antibodies pooled from multiple donors and for emergency treatment of some viral infections and snakebites using serum from immunized donors. Antibodies and T cells designed to recognize tumors are now widely used for passive immunotherapy of cancers.
Properties of Adaptive Immune Responses
Several properties of adaptive immune responses are crucial for the effectiveness of these responses in combating infections ( Fig. 1.5 ).
Specificity and Diversity
The adaptive immune system is capable of distinguishing millions of different antigens or portions of antigens, a feature that is referred to as specificity . It implies that the total collection of lymphocyte specificities, sometimes called the lymphocyte repertoire, is extremely diverse. The total population of B and T lymphocytes consists of many different clones (each clone made up of cells all derived from one lymphocyte), and all the cells of one clone express identical antigen receptors, which are different from the receptors of all other clones. We now know the molecular basis for the generation of this remarkable diversity of lymphocytes (see Chapter 4 ). The clonal selection hypothesis , formulated in the 1950s, correctly predicted that clones of lymphocytes specific for different antigens develop before an encounter with these antigens, and each antigen elicits an immune response by selecting and activating the lymphocytes of a specific clone ( Fig. 1.6 ).
The diversity of the lymphocyte repertoire, which enables the immune system to respond to a vast number and variety of antigens, also means that before exposure to any one antigen, very few cells, perhaps as few as 1 in 100,000 or 1 in 1,000,000 lymphocytes, are specific for that antigen. Thus, the total number of lymphocytes that can recognize and react against any one antigen ranges from approximately 1,000 to 10,000 cells. To mount an effective defense against microbes, these few cells have to give rise to a large number of lymphocytes capable of destroying the microbes. Each unique lymphocyte that recognizes a single antigen and its progeny constitute an antigen-specific clone. The effectiveness of immune responses is attributable to several features of adaptive immunity, including the marked expansion of the clone of lymphocytes specific for any antigen upon exposure to that antigen, the selection and preservation of the most potent lymphocytes, and numerous positive feedback loops that amplify immune responses. These characteristics of the adaptive immune system are described in later chapters.
The adaptive immune system mounts faster, larger and more effective responses to repeated exposure to the same antigen . This feature of adaptive immune responses implies that the immune system remembers every encounter with antigen, and this property of adaptive immunity is therefore called immunologic memory . The response to the first exposure to antigen, called the primary immune response , is initiated by lymphocytes called naive lymphocytes that are seeing antigen for the first time ( Fig. 1.7 ). The term naive refers to these cells being immunologically inexperienced, not having previously responded to antigens. Subsequent encounters with the same antigen lead to responses called secondary immune responses that usually are more rapid, larger, and better able to eliminate the antigen than primary responses. Secondary responses are the result of the activation of memory lymphocytes, which are long-lived cells that were induced during the primary immune response. Immunologic memory optimizes the ability of the immune system to combat persistent and recurrent infections, because each exposure to a microbe generates more memory cells and activates previously generated memory cells. Immunologic memory is one mechanism by which vaccines confer long-lasting protection against infections.