Chapter 1:Basic Concepts in Immunology virtually any antigen a person is likely to be exposed to.In this way,adap activated lyn oroduced by an adaptive immune res se can alsc persist ed.They elp to preven many years later. 1-2 The cells of the immune system derive from precursors in the bone marrow. Both i te and adaptive immun e rest n the activities of develop and mature there. Once mature. they migrate tem of vessels an eventually All the cellular ele nents of blood,including the red blood cells that transport ting in damaged cells of the bone marrow.Because these stem cells can give rise to all the diff. own as pluripotent h itors ofred blood cells nlatelet and the tw lls,the lymphoid and myeloid lineages The cells and their lineage relationships are summarized 13 henmegygnage6ompisesmostothe6ahohetma uhe common myelod proge th precursor of the macrophages,gran ytes and red blood cells whiche with here.The cells of the myeloid lineage are shown in Fig 1.4. not b Fig.1.3 All the cellular elements of the blood,including leukocytes are the me ytes,the dendritic cells,and the ,ase from pluripoten nd basophils.The last e of thes divide to produce two types of stemcells. of the cytoplasmic granules whosestaning gives these A common lymphoid progenitor gives nse to the lymphoid distinctive appearance in blood smears,or polymorphonuclear common myeloid progenitor gives rise to the myeloid lineage enter the tissues:they mature after they have enc tered a (pink and yell pathogen.Ihe commo give this developmental not been.However clotting.Tand B lymphocytes are distinguished from the other as there are more mon myeloid rogenitor cel f the each other by t an re bone marrow.respectively.After encounter with antigen,B cells nbody-secr sma cell that gives r 【o mast c maturation there
� Chapter 1: Basic Concepts in Immunology virtually any antigen a person is likely to be exposed to. In this way, adaptive immunity can more effectively focus its resources to overcome pathogens that have evaded or overwhelmed innate immunity. Antibodies and activated lymphocytes produced by an adaptive immune response can also persist after the original infection has been eliminated. They help to prevent immediate reinfection and also provide for long-lasting immunity, allowing a faster and more intense response to a second exposure even when it occurs many years later. 1-2 The cells of the immune system derive from precursors in the bone marrow. Both innate and adaptive immune responses depend upon the activities of white blood cells or leukocytes. These cells all originate in the bone marrow, and many of them also develop and mature there. Once mature, they migrate to guard the peripheral tissues: some of them reside within tissues, while others circulate in the bloodstream and in a specialized system of vessels called the lymphatic system, which drains extracellular fluid and free cells from tissues, transports them through the body as lymph, and eventually empties back into the blood system. All the cellular elements of blood, including the red blood cells that transport oxygen, the platelets that trigger blood clotting in damaged tissues, and the white blood cells of the immune system, derive from the hematopoietic stem cells of the bone marrow. Because these stem cells can give rise to all the different types of blood cells, they are often known as pluripotent hematopoietic stem cells. They give rise to cells of more limited developmental potential, which are the immediate progenitors of red blood cells, platelets, and the two main categories of white blood cells, the lymphoid and myeloid lineages. The different types of blood cells and their lineage relationships are summarized in Fig. 1.3. 1-3 The myeloid lineage comprises most of the cells of the innate immune system. The common myeloid progenitor is the precursor of the macro phages, granulocytes, mast cells, and dendritic cells of the innate immune system, and also of megakaryocytes and red blood cells, which we will not be concerned with here. The cells of the myeloid lineage are shown in Fig. 1.4. Fig. 1.3 All the cellular elements of the blood, including leukocytes are the monocytes, the dendritic cells, and the neutrophils, eosinophils, and basophils. The last three of these circulate in the blood and are termed granulocytes, because the cells of the immune system, arise from pluripotent hematopoietic stem cells in the bone marrow. These pluripotent cells divide to produce two types of stem cells. A common lymphoid progenitor gives rise to the lymphoid lineage (blue background) of white blood cells or leukocytesthe natural killer (NK) cells and the T and B lymphocytes. A common myeloid progenitor gives rise to the myeloid lineage (pink and yellow backgrounds), which comprises the rest of the leukocytes, the erythrocytes (red blood cells), and the megakaryocytes that produce platelets important in blood clotting. T and B lymphocytes are distinguished from the other leukocytes by the possession of antigen receptors, and from each other by their sites of differentiation-the thymus and bone marrow, respectively. After encounter with antigen, B cells differentiate into antibody-secreting plasma cells, while T cells differentiate into effector T cells with a variety of functions. Unlike T and B cells, NK cells lack antigen specificity. The remaining of the cytoplasmic granules whose staining gives these cells a distinctive appearance in blood smears, or polymorphonuclear leukocytes, because of their irregularly shaped nuclei. Immature dendritic cells (yellow background) are phagocytic cells that enter the tissues; they mature after they have encountered a potential pathogen. The common lymphoid progenitor also gives rise to a minor subpopulation of dendritic cells, but for simplicity this developmental pathway has not been illustrated. However, as there are more common myeloid progenitor cells than there are common lymphoid progenitors, the majority of the dendritic cells in the body develop from common myeloid progenitors. Monocytes enter tissues, where they differentiate into phagocytic macrophages. The precursor cell that gives rise to mast cells is still unknown. Mast cells also enter tissues and complete their maturation there
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Principles of innate and adaptive immunity E Macrophages are resident in almost all tissues and are the mature form of monocytes, which circulate in the blood and continually migrate into tissues, where they differentiate. Together, monocytes and macrophages make up one of the three types of phagocytes in the immune system: the others are the granulocytes (the collective term for the white blood cells called neutrophils, eosinophils, and basophils) and the dendritic cells. Macrophages are relatively long-lived cells and perform several different functions throughout Bcell common lymphoid progenitor Tcell Bone marrow pluripotent hematopoietic stem cell @ Bone marrow @ Granulocytes (or polymorphonuclear leukocytes) @ megakaryocyte/ erythrocyte progenitor Q��� @8 immature unknown NK cell dendritic cell neutrophil eosinophil basophil precursor monocyte of mast cell Lymph nodes Tissues , �, ·�··' platelets �' Q � iX � � mature immature Bcell Tcell NKcell dendritic cell dendritic cell mast cell macrophage Effector cells of/Jv� Q � . activated activated plasma cell Tcell NKcell 0 erythrocyte
6 Chapter 1:Basic Concepts in Immunology the innate immune response and the subsequent adaptive immune response. inhaacoe of pathogens and infected cells targered by an adaptive immune response imps to Cell Macrophage Eosinophil Dendritic cell Basophil Neutrophi Mast cell 复 1.4M the left.A ninent aranules u actvationvaant hils are primarily p agocytic cell -coated parasites such are tis that ure and ca after matu unction act on local blood ves nfom they
3 Chapter 1: Basic Concepts in Immunology the innate immune response and the subsequent adaptive immune response. One is to engulf and kill invading microorganisms. In this phagocytic role they are an important first defense in innate immunity and also dispose of pathogens and infected cells targeted by an adaptive immune response. Both monocytes and macro phages are phagocytic, but most infections occur in the tissues, and so it is primarily macrophages that perform this important protective function. An additional and crucial role of macro phages is to Cell Macrophage Dendritic cell Neutrophil Activated function Phagocytosis and activation of bactericidal mechanisms Antigen presentation Antigen uptake in peripheral sites Antigen presentation Phagocytosis and activation of bactericidal mechanisms Fig. 1.4 Myeloid cells in innate and adaptive immunity. Cells of the myeloid lineage perform various important functions in the immune response. In the rest of the book, these cells will be represented in the schematic form shown on the left. A photomicrograph of each cell type is shown in the center panels. Macrophages and neutrophils are primarily phagocytic cells that engulf pathogens and destroy them in intracellular vesicles, a function they perform in both innate and adaptive immune responses. Dendritic cells are phagocytic when they are immature and can take up pathogens; after maturing, they function as specialized cells that present pathogen antigens toT lymphocytes in a form they can recognize, thus activating T lymphocytes and Cell Eosinophil Basophil Mast cell Activated function Killing of antibody-coated parasites Promotion of allergic responses and augmentation of anti-parasitic immunity Release of granules containing histamine and active agents initiating adaptive immune responses. Macrophages can also present antigens toT lymphocytes and can activate them. The other myeloid cells are primarily secretory cells that release the contents of their prominent granules upon activation via antibody during an adaptive immune response. Eosinophils are thought to be involved in attacking large antibody-coated parasites such as worms; basophils are also thought to be involved in antiparasite immunity. Mast cells are tissue cells that trigger a local inflammatory response to antigen by releasing substances that act on local blood vessels. Mast cells, eosinophils, and basophils are also important in allergic responses. Photographs courtesy of N. Rooney, R. Steinman, and D. Friend
Principles of innate and adaptive immunity 7 egranulocytes are so called because they have densely staining granules asm;they are s because staining properties ofthe granules.In comparison with macrophages they are Ior on ave the ood to migrate to sites of infection or inflammation.The phagocytic neutrophils are destroy the antimicrobial substances stored in their cytoplasmic granules.Their role is in Chapter reditaryd un Eosinophils and basophils are less abundant than neutrophils,but like neut and toxic proteins ohils.They can also contribute am nwhic role in allergic inflammation in Chapter 14. e blood-bo ell defi Alth gic responses,which is discussed in Chapter 14,they are believed to play a mie2enghentemalicesofthehotyaenstpahogemsal I kinds of dendritic cells processes,like the dendrites of nerve cells,which give them their name Immature dendr m ethrough bloodstream from the bone of the ytosis.Like macrophages and neutrophils hey degrad e pathogens y take up,but their man le in the immun a particular class of lymphocytes- the T lymphocytes which are dese tion ed ure ath the antigen receptor of a T lymphocyte.They also provide other signals that ls (APCs).As such.dendritic cells form between the innate immune response and the adaptive immune response ig)n certain macrophages can also act as antigen-pre tive immune ponses.We describe the types and functions of dendritic cells in Chapters6,9,11,and 12
orchestrate immune responses: they help induce inflammation, which, as we shall see, is a prerequisite to a successful immune response, and they secrete signaling proteins that activate other immune-system cells and recruit them into an immune response. In addition to their specialized role in the immune system, macro phages act as general scavenger cells in the body, clearing dead cells and cell debris. The granulocytes are so called because they have densely staining granules in their cytoplasm; they are also called polymorphonuclear leukocytes because of their oddly shaped nuclei. There are three types of granulocytes-neutrophils, eosinophils, and basophils-which are distinguished by the different staining properties of the granules. In comparison with macro phages they are all relatively short -lived, surviving for only a few days, and are produced in increased numbers during immune responses, when they leave the blood to migrate to sites of infection or inflammation. The phagocytic neutrophils are the most numerous and most important cells in innate immune responses: they take up a variety of microorganisms by phagocytosis and efficiently destroy them in intracellular vesicles using degradative enzymes and other antimicrobial substances stored in their cytoplasmic granules. Their role is discussed in more detail in Chapter 3. Hereditary deficiencies in neutrophil function lead to overwhelming bacterial infection, which is fatal if untreated. Eosinophils and basophils are less abundant than neutrophils, but like neutrophils they have granules containing a variety of enzymes and toxic proteins, which are released when the cells are activated. Eosinophils and basophils are thought to be important chiefly in defense against parasites, which are too large to be ingested by macrophages or neutrophils. They can also contribute to allergic inflammatory reactions, in which their effects are damaging rather than protective. We discuss the functions of these cells in Chapter 10 and their role in allergic inflammation in Chapter 14. Mast cells, whose blood-borne precursors are not well defined, differentiate in the tissues. Although best known for their role in orchestrating allergic responses, which is discussed in Chapter 14, they are believed to play a part in protecting the internal surfaces of the body against pathogens, and are involved in the response to parasitic worms. They have large granules in their cytoplasm that are released when the mast cell is activated; these help induce inflammation. There are several kinds of dendritic cells, which form the third class of phagocytic cell of the immune system. Most dendritic cells have long fingerlike processes, like the dendrites of nerve cells, which give them their name. Immature dendritic cells migrate through the bloodstream from the bone marrow to enter tissues. They take up particulate matter by phagocytosis and also continually ingest large amounts of the extracellular fluid and its contents by a process known as macropinocytosis. Like macro phages and neutrophils, they degrade the pathogens they take up, but their main role in the immune system is not the clearance of microorganisms. Instead, the encounter with a pathogen stimulates dendritic cells to mature into cells that can activate a particular class of lymphocytes-the T lymphocytes-which are described in Section 1-4. Mature dendritic cells activate T lymphocytes by displaying antigens derived from the pathogen on their surface in a way that activates the antigen receptor of aT lymphocyte. They also provide other signals that are necessary to activate T lymphocytes that are encountering their specific antigen for the first time, and for this reason dendritic cells are also called antigen-presenting cells (APCs). As such, dendritic cells form a crucial link between the innate immune response and the adaptive immune response (Fig. 1.5). In certain situations, macrophages can also act as antigen-presenting cells, but dendritic cells are the cells that are specialized in initiating adaptive immune responses. We describe the types and functions of dendritic cells in Chapters 6, 9, 11, and 12. Principles of innate and adaptive immunity E
8Chapter 1:Basic Concepts in Immunology Dendritic cells form the bridae between innate and adaptive immune responses system pathogen n es,and are r po dritic n the tissues are in a fom that tivated de 1-4 une system and th The common lymphoid progenitor in the bone marrow gives rise to the anti- gen-specific lymphocytes of the adaptive immune system and also toa type This latte er is a large cell with a distinctive granular cytoplasm and is called a natural kille rce(NKcell)(Fig16).These e cells can recognize and kill some viruses.and are thought to be important in holding viral infections in check We come finally to the key components of adaptive immunity,the antigen specific lymphocytes.Unless indicated otherwise,we shall use the term lym Natural killer (NK)cell the antigen-specific lymphocytes only.Th the wide variery of different pathogens a person is likely to encounter dur ing their lifetime mpnocyes colectvely make this possible tho are highly diverse heir antigen-binding with w cy sh by its 17) pcof加teclryhe一 books described these c the cen that have not yet been activated by antigen are known as naive mphocytes: r lymphocytes Fig.1.6 Natural killer (NK) There are two types of lymphocyte B lymphocytes (B cells. )and T lym ns in inn phocytes(Tcel acn with quite a erent roles I he immt unity erstem and cells.Unlike re or.or B-ere proliferate and differentiate into plasma cells.These are the eff tor form of Photograph courtesy of B.Smith B-cell
3 Chapter 1: Basic Concepts in Immunology Fig. 1.5 Dendritic cells form a key link between the innate immune system and the adaptive immune system. Like the other cells of innate immunity, dendritic cells recognize pathogens via invariant cell-surface receptors for pathogen molecules, and are activated by these stimuli early in an infection. Dendritic cells in the tissues are phagocytic and are specialized to ingest a wide range of pathogens and to display their antigens at the dendritic cell surface in a form that can be recognized by T cells. As described later in the chapter, activated dendritic cells also produce molecules that enable T cells to be activated by antigen. Natural killer (NK) cell g . . . . . Releases lytic granules that kill some virus-infected cells Fig. 1.6 Natural killer (NK) cells. These are large granular lymphoid-like cells with important functions in innate immunity, especially against intracellular infections, being able to kill other cells. Unlike lymphocytes, they lack antigen-specific receptors. Photograph courtesy of B. Smith. neutrophil DendrHic cells form the bridge between innate and adaptive immune responses Innate immunity eosinophil basophil monocyte dendritic cell Adaptive immunity Bcell Tcell 1-4 The lymphoid lineage comprises the lymphocytes of the adaptive immune system and the natural killer cells of innate immunity. The common lymphoid progenitor in the bone marrow gives rise to the antigen-specific lymphocytes of the adaptive immune system and also to a type of lymphocyte that responds to the presence of infection but is not specific for antigen, and is thus considered to be part of the innate immune system. This latter is a large cell with a distinctive granular cytoplasm and is called a natural killer cell (NK cell) (Fig. 1.6). These cells can recognize and kill some abnormal cells, for example some tumor cells and cells infected with herpesviruses, and are thought to be important in holding viral infections in check before the adaptive immune response kicks in. Their functions in innate immunity are described in Chapter 3. We come finally to the key components of adaptive immunity, the antigenspecific lymphocytes. Unless indicated otherwise, we shall use the term lymphocyte from now on to refer to the antigen-specific lymphocytes only. The immune system must be able to mount an immune response against any of the wide variety of different pathogens a person is likely to encounter during their lifetime. Lymphocytes collectively make this possible through the highly variable antigen receptors on their surface, by which they recognize and bind antigens. Each lymphocyte matures bearing a unique variant of a prototype antigen receptor, so that the population of lymphocytes expresses a huge repertoire of receptors that are highly diverse in their antigen-binding sites. Among the billion or so lymphocytes circulating in the body at any one time there will always be some that can recognize a given foreign antigen. In the absence of an infection, most lymphocytes circulating in the body are small, featureless cells with few cytoplasmic organelles and much of the nuclear chromatin inactive, as shown by its condensed state (Fig. 1.7). This appearance is typical of inactive cells. It is hardly surprising that until the 1960s, textbooks described these cells, now the central focus of immunology, as having no known function. Indeed, these small lymphocytes have no functional activity until they encounter their specific antigen. Lymphocytes that have not yet been activated by antigen are known as naive lymphocytes; those that have met their antigen, become activated, and have differentiated further into fully functional lymphocytes are known as effector lymphocytes. There are two types of lymphocytes-B lymphocytes (B cells) and T lymphocytes (T cells)-each with quite different roles in the immune system and distinct types of antigen receptors. After antigen binds to a B-cell antigen receptor, orB-cell receptor (BCR), on the B-cell surface, the lymphocyte will proliferate and differentiate into plasma cells. These are the effector form of B lymphocytes and they produce antibodies, which are a secreted form of the B-cell receptor and have an identical antigen specificity. Thus the antigen that