《微生物与免疫学》课程教学资源（书籍教材）Janeway's Immunobiology，8th edition，Kenneth Murphy.pdf_P26-P30

activates a given B cell becomes the target of the antibodies produced by that cell's progeny. Antibody molecules as a class are known as immunoglobulins (lg), and so the antigen receptor of B lymphocytes is also known as membrane immunoglobulin (mig) or surface immunoglobulin (slg). The T-cell antigen receptor, or T-cell receptor (TCR), is related to immunoglobulin but is quite distinct in its structure and recognition properties. After aT cell has been activated by its first encounter with antigen, it proliferates and differentiates into one of several different functional types of effector T lymphocytes. Effector T-cell functions fall into three broad classes: killing, activation, and regulation. Cytotoxic T cells kill cells that are infected with viruses or other intracellular pathogens. HelperT cells provide essential additional signals that influence the behavior and activity of other cells. Helper T cells provide signals to antigen-stimulated B cells that influence their production of antibody, and to macrophages that allow them to become more efficient at killing engulfed pathogens. We return to the functions of cytotoxic and helper T cells later in this chapter, and their actions are described in detail in Chapters 9 and 11. Regulatory T cells suppress the activity of other lymphocytes and help to control immune responses; they are discussed in Chapters 9, 11, 12, and 15. During the course of an immune response, some of the B cells and T cells activated by antigen differentiate into memory cells, the lymphocytes that are responsible for the long-lasting immunity that can follow exposure to disease or vaccination. Memory cells will readily differentiate into effector cells on a second exposure to their specific antigen. Immunological memory is described in Chapter 11. 1-5 Lymphocytes mature in the bone marrow or the thymus and then congregate in lymphoid tissues throughout the body. Lymphocytes circulate in the blood and the lymph and are also found in large numbers in lymphoid tissues or lymphoid organs, which are organized aggregates of lymphocytes in a framework of nonlymphoid cells. Lymphoid organs can be divided broadly into the central or primary lymphoid organs, where lymphocytes are generated, and the peripheral or secondary lymphoid organs, where mature naive lymphocytes are maintained and adaptive immune responses are initiated. The central lymphoid organs are the bone marrow and the thymus, an organ in the upper chest. The peripheral lymphoid organs comprise the lymph nodes, the spleen, and the mucosal lymphoid tissues of the gut, the nasal and respiratory tract, the urogenital tract, and other mucosa. The location of the main lymphoid tissues is shown schematically in Fig. 1.8, and we describe the individual peripheral lymphoid organs in more detail later in the chapter. Lymph nodes are interconnected by a system of lymphatic vessels, which drain extracellular fluid from tissues, through the lymph nodes, and back into the blood. Both B and T lymphocytes originate in the bone marrow, but only the B lymphocytes mature there. The precursor T lymphocytes migrate to the thymus, from which they get their name, and mature there. The 'B' in B lymphocytes originally stood for the bursa of Fabricius, a lymphoid organ in young chicks in which lymphocytes mature; fortunately, it can stand equally well for bone marrow derived. Once they have completed maturation, both types of lymphocytes enter the bloodstream as mature naive lymphocytes. They circulate through the peripheral lymphoid tissues, in which an adaptive immune response is initiated if a lymphocyte meets its corresponding antigen. Before this, however, an innate immune response to the infection has usually occurred, and we now look at how this alerts the rest of the immune system to the presence of a pathogen. Principles of innate and adaptive immunity E Fig. 1. 7 Lymphocytes are mostly small and inactive cells. The upper panel shows a light micrograph of a small lymphocyte in which the nucleus has been stained purple by the hematoxylin and eosin dye, surrounded by red blood cells (which have no nuclei). Note the darker purple patches of condensed chromatin of the lymphocyte nucleus, indicating little transcriptional activity, the relative absence of cytoplasm, and the small size. The lower panel shows a transmission electron micrograph of a small lymphocyte. Again, note the evidence of functional inactivity: the condensed chromatin, the scanty cytoplasm, and the absence of rough endoplasmic reticulum. Photographs courtesy of N. Rooney

� Chapter 1: Basic Concepts in Immunology Fig. 1.8 The distribution of lymphoid tissues in the body. Lymphocytes arise from stem cells in bone marrow and differentiate in the central lymphoid organs (yellow)-8 cells in the bone marrow and T cells in the thymus. They migrate from these tissues and are carried in the bloodstream to the peripheral lymphoid organs (blue). These include lymph nodes, spleen, and lymphoid tissues associated with mucosa, such as the gut-associated tonsils, Peyer's patches, and appendix. The peripheral lymphoid organs are the sites of lymphocyte activation by antigen, and lymphocytes recirculate between the blood and these organs until they encounter their specific antigen. Lymphatics drain extracellular fluid from the peripheral tissues, through the lymph nodes and into the thoracic duct, which empties into the left subclavian vein. This fluid, known as lymph, carries antigen taken up by dendritic cells and macrophages to the lymph nodes, as well as recirculating lymphocytes from the lymph nodes back into the blood. Lymphoid tissue is also associated with other mucosa such as the bronchial linings (not shown). adenoid tonsil right subclavian vein lymph node kidney appendix lymphatics -. .;.�1'11! - - left subclavian vein -'t- thymus f-1- heart 1 -\-�r- spleen """_.,., +-_,r-+- Peyer's patch in ":7::._-+-T-'r- small intestine large intestine 1-6 Most infectious agents activate the innate immune system and induce an inflammatory response. The skin and the mucosal epithelia lining the airways and gut are the first defense against invading pathogens, forming a physical and chemical barrier against infection. Microorganisms that breach these defenses are met by cells and molecules that mount an immediate innate immune response. Macrophages resident in the tissues, for example, can recognize bacteria by means of receptors that bind common constituents of many bacterial surfaces. Engagement of these receptors triggers the macrophage both to engulf the bacterium and degrade it internally, and to secrete proteins called cytokines and chemokines that convey important signals to other immune cells. Similar responses occur to viruses, fungi, and parasites. Cytokine is a general name for any protein that is secreted by cells and affects the behavior of nearby cells bearing appropriate receptors. Chemokines are secreted proteins that act as chemoattractants (hence the name 'chemokine'), attracting cells bearing chemokine receptors, such as neutrophils and monocytes, out of the bloodstream and into infected tissue (Fig. 1.9). The cytokines and chemokines released by activated macrophages initiate the process known as inflammation. Inflammation is beneficial to combating infection by recruiting proteins and cells from the blood into infected tissues that help to directly destroy the pathogen. In addition, inflammation increases the flow of lymph carrying microbes and antigen-presenting cells from the infected tissue to nearby lymphoid tissues, where they activate lymphocytes and initiate the adaptive immune response. Once adaptive immunity has been triggered, inflammation also recruits the effector components of the adaptive immune system-antibody molecules and effector T cells-to the site of infection

Bacteria trigger macrophages to release cytokines and chemokines Vasodilation and increased vascular permeability cause redness, heat, and swelling Inflammatory cells migrate Into tissue, releasing Inflammatory mediators that cause pain Local inflammation and the phagocytosis of invading bacteria can also be triggered as a result of the activation of a group of plasma proteins known collectively as complement. Activation of the complement system by bacterial surfaces leads to a cascade of proteolytic reactions that coats microbes, but not the body's own cells, with complement fragments. Complement-coated microbes are recognized and bound by specific complement receptors on macrophages, taken up by phagocytosis, and destroyed. Inflammation is described clinically by the Latin words calor, dolor, rubor, and tumor, meaning heat, pain, redness, and swelling. Each of these features reflects an effect of cytokines or other inflammatory mediators on the local blood vessels. Heat, redness, and swelling result from the dilation and increased permeability of blood vessels during inflammation, leading to increased local blood flow and leakage of fluid and blood proteins into the tissues. Cytokines and complement fragments have important effects on the endothelium that lines blood vessels; the endothelial cells themselves also produce cytokines in response to infection. The pro-inflammatory cytokines produce changes in the adhesive properties of the endothelial cells, in turn causing circulating leukocytes to stick to the endothelial cells and migrate between them into the site of infection, to which they are attracted by chemokines. The migration of cells into the tissue and their local actions account for the pain. The main cell types seen in the initial phase of an inflammatory response are macrophages and neutrophils, the latter being recruited into the inflamed, infected tissue in large numbers. Macrophages and neutrophils are thus also known as inflammatory cells. Like macrophages, neutrophils have surface receptors for common bacterial constituents and for complement, and they are the principal cells that engulf and destroy the invading microorganisms. The influx of neutrophils is followed a short time later by the increased entry of monocytes, which rapidly differentiate into macro phages, thus reinforcing and sustaining the innate immune response. Later, if the inflammation continues, eosinophils also migrate into inflamed tissues and contribute to the destruction of the invading microorganisms. 1-7 Pattern recognition receptors of the innate immune system provide an initial discrimination between self and nonself. The defense systems of innate immunity are effective in combating many pathogens, but rely on a limited number of invariant receptors that recognize microorganisms. The pathogen-recognition receptors of macrophages, neutrophils, and dendritic cells recognize simple molecules and regular patterns of molecular structure known as pathogen-associated molecular patterns (PAMPs) that are present on many microorganisms but not on the Principles of innate and adaptive immunity � Fig. 1.9 Infection triggers an inflammatory response. Macrophages encountering bacteria or other types of microorganisms in tissues are triggered to release cytokines that increase the permeability of blood vessels, allowing fluid and proteins to pass into the tissues. They also produce chemokines, which direct the migration of neutrophils to the site of infection. The stickiness of the endothelial cells of the blood vessel wall is also changed, so that cells adhere to the wall and are able to crawl through it; first neutrophils and then monocytes are shown entering the tissue from a blood vessel. The accumulation of fluid and cells at the site of infection causes the redness, swelling, heat, and pain known collectively as inflammation. Neutrophils and macrophages are the principal inflammatory cells. Later in an immune response, activated lymphocytes can also contribute to inflammation

� Chapter 1: Basic Concepts in Immunology Macrophages express receptors for many microbial constituents 0 • TLR-4 TLR-2 • • • glucan receptor Fig. 1.10 Macrophages express a number of receptors that allow them to recognize different pathogens. Macrophages express a variety of receptors, each of which is able to recognize specific components of microbes. Some, like the mannose and glucan receptors and the scavenger receptor, bind cell-wall carbohydrates of bacteria, yeast, and fungi. The Toll-like receptors (TLRs) are an important family of pattern recognition receptors present on macrophages and other immune cells, and they are able to bind different microbial components; for example, TLR-2 binds cell-wall components of Gram-negative bacteria, whereas TLR-4 binds cell-wall components of Gram-positive bacteria. LPS, lipopolysaccharide. body's own cells. The receptors that recognize PAMPs are known generally as pattern recognition receptors (PRRs), and they recognize structures such as mannose-rich oligosaccharides, peptidoglycans, and lipopolysaccharides in the bacterial cell wall, and unmethylated CpG DNA, which are common to many pathogens and have been conserved during evolution, making them excellent targets for recognition because they do not change (Fig. 1.10). We consider this system of innate recognition in detail in Chapter 3. Much of our knowledge of innate recognition has emerged only within the past lO years, and this is one of the most exciting areas in modern immunology. The pattern recognition receptors allow the innate immune system to distinguish self (the body) from nonself (pathogen). Detection of nonself activates innate cells and initiates adaptive immunity: macrophages are triggered to engulf microbes; immature dendritic cells are triggered to activate naive T lymphocytes. The molecules recognized by pattern recognition receptors are quite distinct from the individual pathogen-specific antigens recognized by lymphocytes. The fact that microbial constituents were needed to stimulate immune responses against purified proteins highlights the requirement that an innate response must precede the initiation of an adaptive response (see Appendix I, Sections A-1-A-4). This requirement was recognized long before the discovery of dendritic cells and their mode of activation. It was known that purified antigens such as proteins often did not evoke an immune response in an experimental immunization-that is, they were not immunogenic. To obtain adaptive immune responses to purified antigens, killed bacteria or bacterial extracts had to be mixed with the antigen. This additional material was termed an adjuvant, because it helped the response to the immunizing antigen (adjuvare is Latin for 'to help' ). We know now that adjuvants are needed, at least in part, to activate dendritic cells to full antigen-presenting status in the absence of an infection. Finding suitable adjuvants is still an important part of vaccine preparation, as we discuss in Chapter 16. 1-8 Adaptive immune responses are initiated by antigen and antigenpresenting cells in secondary lymphoid tissues. Adaptive immune responses are initiated when antigens or antigenpresenting cells, particularly dendritic cells bearing antigens picked up at sites of infection, reach the secondary lymphoid organs. Like the neutrophils and macrophages described earlier, dendritic cells have pattern recognition receptors that recognize molecular patterns common to microorganisms, such as bacterial lipopolysaccharide. Microbial components binding to these receptors stimulate the immature dendritic cell to engulf the pathogen and degrade it intracellularly. Immature dendritic cells also take up extracellular material, including virus particles and bacteria, by receptor-independent macropinocytosis, and thus internalize and degrade pathogens that their cell-surface receptors do not detect. In addition to the display of antigens that activates the antigen-receptors of lymphocytes, mature dendritic cells also express cell-surface proteins called co-stimulatory molecules, which provide signals that act together with antigen to stimulate the T lymphocyte to proliferate and differentiate into its final fully functional form (Fig. 1.11). Free antigens can also stimulate the antigen receptors of B cells, but most B cells require 'help' from activated helper T cells for optimal antibody responses. The activation of naive T lymphocytes is therefore an essential first stage in virtually all adaptive immune responses. 1-9 Lymphocytes activated by antigen give rise to clones of antigenspecific effector cells that mediate adaptive immunity. Cells of the innate immune system express many different pattern recognition receptors, each recognizing a different feature shared by many pathogens

Immature dendritic cells reside In peripheral tissues � � macropinosome Dendritic cells migrate via lymphatic vessels to regional lymph nodes Mature dendritic cells activate naive T cells In lymphoid organs such as lymph nodes 0 naive 0 0 Tcells 0 � � activated Tcells *mature dendritic cell Lymph node medulla In contrast, lymphocyte antigen receptor expression is 'clonal'-in other words, each mature lymphocyte emerging from the central lymphoid organs differs from the others in the specificity of its antigen receptor. When that lymphocyte proliferates it forms a clone of identical cells bearing identical antigen receptors. The diversity in antigen receptors is generated by a unique genetic mechanism that operates during lymphocyte development in the bone marrow and the thymus to generate millions of different variants of the genes encoding the receptor molecules. This ensures that the lymphocytes in the body collectively carry millions of different antigen receptor specificities-the lymphocyte receptor repertoire of the individual. Lymphocytes are continually undergoing a process akin to natural selection; only those lymphocytes that encounter an antigen to which their receptor binds will be activated to proliferate and differentiate into effector cells. This selective mechanism was first proposed in the 1950s by Macfarlane Burnet to explain why a person produces antibodies against only those antigens to which he or she has been exposed. Burnet postulated the preexistence in the body of many different potential antibody-producing cells, each having the ability to make antibody of a different specificity and displaying on its surface a membrane-bound version of the antibody: this serves as a receptor for the antigen. On binding antigen, the cell is activated to divide and to produce many identical progeny, a process known as clonal expansion; this clone of identical cells can now secrete clonotypic antibodies with a specificity identical to that of the surface receptor that first triggered activation and clonal expansion (Fig. 1.12). Burnet called this the clonal selection theory of antibody production. 1-10 Clonal selection of lymphocytes is the central principle of adaptive immunity. Remarkably, at the time that Burnet formulated his theory, nothing was known of the antigen receptors of lymphocytes; indeed, the function of lymphocytes themselves was still obscure. Lymphocytes did not take center stage until the early 1960s, when James Gowans discovered that removal of the small lymphocytes from rats resulted in the loss of all known adaptive immune responses. These immune responses were restored when the small lymphocytes were replaced. This led to the realization that lymphocytes must be the units of clonal selection, and their biology became the focus of the new field of cellular immunology. Clonal selection of lymphocytes with diverse receptors elegantly explained adaptive immunity, but it raised one significant conceptual problem. If the antigen receptors of lymphocytes are generated randomly during the lifetime of an individual, how are lymphocytes prevented from recognizing antigens Principles of innate and adaptive immunity � Fig. 1.11 Dendritic cells initiate adaptive immune responses. Immature dendritic cells resident in a tissue take up pathogens and their antigens by macropinocytosis and by receptormediated endocytosis. They are stimulated by recognition of the presence of pathogens to migrate through the lymphatics to regional lymph nodes, where they arrive as fully mature nonphagocytic dendritic cells that express both antigen and the co-stimulatory molecules necessary to activate a naive T cell that recognizes the antigen, stimulating lymphocyte proliferation and differentiation