《免疫学》（英文版） Chapter 02 Cells and organs of the Immune system

8536d_ ch02024-056 9/6/029: 00 PM Page 24 mac85 Mac 85: 365 smm poldsby et al./Immunology 5e: Cells and Organs of the chapter 2 Immune System HE IMMUNE SYSTEM CONSISTS OF MANY DIFFERENT organs and tissues that are found throughout the body. These organs can be classified functionall nto two main groups. The primary lymphoid organs provide appropriate microenvironments for the development and maturation of lymphocytes. The secondary lymphoid organs trap antigen from defined tissues or vascular spaces and are sites where mature lymphocytes can interact effectively with that antigen. Blood vessels and lymphatic systems connect these organs, uniting them into a functional whole Carried within the blood and lymph and populating the Macrophage Interacting with Bacteria uphold various white blood cells, or leuko- cytes, that participate in the immune response. Of these a Hematopoiesis cells, only the lymphocytes possess the attributes of diversity specificity, memory, and self/nonself recognition, the hall- Cells of the Immune System marks of an adaptive immune response. All the other cells a Organs of the Immune System play accessory roles in adaptive immunity, serving to activate lymphocytes, to increase the effectiveness of antigen clear- a Systemic Function of the Immune System ance by phagocytosis, or to secrete various immune-effector a Lymphoid Cells and Organs-Evolutionary molecules. Some leukocytes, especially T lymphocytes, se- Compariso rete various protein molecules called cytokines. These mol ecules act as immunoregulatory hormones and pla important roles in the regulation of immune responses. Th chapter describes the formation of blood cells, the properties contrast to a unipotent cell, which differentiates into a single of the various immune-system cells, and the functions of the cell type, a hematopoietic stem cell is multipotent, or pluripo- lymphoid organs. ent, able to differentiate in various ways and thereby generate erythrocytes, granulocytes, monocytes, mast cells, lympho- cytes, and megakaryocytes. These stem cells are few, normally Hematopoiesis fewer than one HSC per 5 X 10" cells in the bone marrow The study of hematopoietic stem cells is difficult both be All blood cells arise from a type of cell called the hematopoi- cause of their scarcity and because they are hard to grow in etic stem cell(HSC). Stem cells are cells that can differentiate vitro. As a result, little is known about how their proliferation into other cell types; they are self-renewing-they maintain and differentiation are regulated. By virtue of their capacity heir population level by cell division. In humans, for self-renewal, hematopoietic stem cells are maintained at hematopoiesis, the formation and development of red and stable levels throughout adult life; however, when there is an white blood cells, begins in the embryonic yolk sac during the increased demand for hematopoiesis, HSCs display an enor- first weeks of development. Here, yolk-sac stem cells differen- mous proliferative capacity. This can be demonstrated in tiate into primitive erythroid cells that contain embryonic mice whose hematopoietic systems have been completely de hemoglobin In the third month of gestation, hematopoietic stroyed by a lethal dose of x-rays(950 rads; one rad repre- stem cells migrate from the yolk sac to the fetal liver and then sents the absorption by an irradiated target of an amount of to the spleen; these two organs have major roles in radiation corresponding to 100 ergs/gram of target). Such ir hematopoiesis from the third to the seventh months of gesta- radiated mice will die within 10 days unless they are infused tion. After that, the differentiation of HSCs in the bone mar bone-marrow cells from a syngeneic(genetically row becomes the major factor in hematopoiesis, and by birth identical)mouse. Although a normal mouse has 3 X 10 there is little or no hematopoiesis in the liver and spleen bone-marrow cells, infusion of only 10-10 bone-marrow It is remarkable that every functionally specialized, ma- cells(i. e, 0.01%-0.1% of the normal amount)from a donor ture blood cell is derived from the same type of stem cell In is sufficient to completely restore the hematopoietic system

contrast to a unipotent cell, which differentiates into a single cell type, a hematopoietic stem cell is multipotent, or pluripo￾tent, able to differentiate in various ways and thereby generate erythrocytes, granulocytes, monocytes, mast cells, lympho￾cytes, and megakaryocytes. These stem cells are few, normally fewer than one HSC per 5 104 cells in the bone marrow. The study of hematopoietic stem cells is difficult both be￾cause of their scarcity and because they are hard to grow in vitro. As a result, little is known about how their proliferation and differentiation are regulated. By virtue of their capacity for self-renewal, hematopoietic stem cells are maintained at stable levels throughout adult life; however, when there is an increased demand for hematopoiesis, HSCs display an enor￾mous proliferative capacity. This can be demonstrated in mice whose hematopoietic systems have been completely de￾stroyed by a lethal dose of x-rays (950 rads; one rad repre￾sents the absorption by an irradiated target of an amount of radiation corresponding to 100 ergs/gram of target). Such ir￾radiated mice will die within 10 days unless they are infused with normal bone-marrow cells from a syngeneic (genetically identical) mouse. Although a normal mouse has 3 108 bone-marrow cells, infusion of only 104 –105 bone-marrow cells (i.e., 0.01%–0.1% of the normal amount) from a donor is sufficient to completely restore the hematopoietic system, chapter 2 ■ Hematopoiesis ■ Cells of the Immune System ■ Organs of the Immune System ■ Systemic Function of the Immune System ■ Lymphoid Cells and Organs—Evolutionary Comparisons Cells and Organs of the Immune System T       organs and tissues that are found throughout the body. These organs can be classified functionally into two main groups. The primary lymphoid organs provide appropriate microenvironments for the development and maturation of lymphocytes. The secondary lymphoid organs trap antigen from defined tissues or vascular spaces and are sites where mature lymphocytes can interact effectively with that antigen. Blood vessels and lymphatic systems connect these organs, uniting them into a functional whole. Carried within the blood and lymph and populating the lymphoid organs are various white blood cells, or leuko￾cytes, that participate in the immune response. Of these cells, only the lymphocytes possess the attributes of diversity, specificity, memory, and self/nonself recognition, the hall￾marks of an adaptive immune response. All the other cells play accessory roles in adaptive immunity, serving to activate lymphocytes, to increase the effectiveness of antigen clear￾ance by phagocytosis, or to secrete various immune-effector molecules. Some leukocytes, especially T lymphocytes, se￾crete various protein molecules called cytokines. These mol￾ecules act as immunoregulatory hormones and play important roles in the regulation of immune responses. This chapter describes the formation of blood cells, the properties of the various immune-system cells, and the functions of the lymphoid organs. Hematopoiesis All blood cells arise from a type of cell called the hematopoi￾etic stem cell (HSC). Stem cells are cells that can differentiate into other cell types; they are self-renewing—they maintain their population level by cell division. In humans, hematopoiesis, the formation and development of red and white blood cells, begins in the embryonic yolk sac during the first weeks of development. Here, yolk-sac stem cells differen￾tiate into primitive erythroid cells that contain embryonic hemoglobin. In the third month of gestation, hematopoietic stem cells migrate from the yolk sac to the fetal liver and then to the spleen; these two organs have major roles in hematopoiesis from the third to the seventh months of gesta￾tion. After that, the differentiation of HSCs in the bone mar￾row becomes the major factor in hematopoiesis, and by birth there is little or no hematopoiesis in the liver and spleen. It is remarkable that every functionally specialized, ma￾ture blood cell is derived from the same type of stem cell. In Macrophage Interacting with Bacteria 8536d_ch02_024-056 9/6/02 9:00 PM Page 24 mac85 Mac 85:365_smm:Goldsby et al. / Immunology 5e:

8536d_cho2024-056 8/5/02 4: 02 PM Page 25 mac79 Mac 79: 45_BW: Go dsby et al./Immunology se Cells and Organs of the Immune System CHAPTER 2 which demonstrates the enormous proliferative and differ- progenitor cell( Figure 2-1). The types and amounts of entitative capacity of the stem cell growth factors in the microenvironment of a particular stem Early in hematopoiesis, a multipotent stem cell differenti- cell or progenitor cell control its differentiation. During the ates along one of two pathways, giving rise to either a com- development of the lymphoid and myeloid lineages, stem mon lymphoid progenitor cell or a common myeloid cells differentiate into progenitor cells, which have lost the VISUALIZING CONCEPTS Hematopoictic stem cell g progenitor (NK)cell ② TH helper cell cutrophill T-cell monocyte progenitor 像 B cell Erythrocyte Erythroid progenitor FICURE2-1Hematopoiesis. Self-renewing hematopoietic of the myeloid lineage arise from myeloid progenitors. Note that tem cells give rise to lymphoid and myeloid progenitors. All lym- some dendritic cells come from lymphoid progenitors, others phoid cells descend from lymphoid progenitor cells and all cells from myeloid precursors

Cells and Organs of the Immune System CHAPTER 2 25 which demonstrates the enormous proliferative and differ￾entiative capacity of the stem cells. Early in hematopoiesis, a multipotent stem cell differenti￾ates along one of two pathways, giving rise to either a com￾mon lymphoid progenitor cell or a common myeloid progenitor cell (Figure 2-1). The types and amounts of growth factors in the microenvironment of a particular stem cell or progenitor cell control its differentiation. During the development of the lymphoid and myeloid lineages, stem cells differentiate into progenitor cells, which have lost the TH helper cell TC cytotoxic T cell Natural killer (NK) cell Myeloid progenitor Lymphoid progenitor Hematopoietic stem cell Self￾renewing B cell Dendritic cell T-cell progenitor B-cell progenitor Eosinophil Monocyte Neutrophil Basophil Platelets Erythrocyte Erythroid progenitor Megakaryocyte Eosinophil progenitor Granulocyte￾monocyte progenitor Basophil progenitor Macrophage Dendritic cell VISUALIZING CONCEPTS FIGURE 2-1 Hematopoiesis. Self-renewing hematopoietic stem cells give rise to lymphoid and myeloid progenitors. All lym￾phoid cells descend from lymphoid progenitor cells and all cells of the myeloid lineage arise from myeloid progenitors. Note that some dendritic cells come from lymphoid progenitors, others from myeloid precursors. 8536d_ch02_024-056 8/5/02 4:02 PM Page 25 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:

8536d_ch02_024-0568/5/02 4: 02 PM Page 26 mac79 Mac 79: 45_BW: Godsby et al. /Immunology 5e apacity for self-renewal and are committed to a particular cell possible to identify many hematopoietic growth factors. In neage. Common lymphoid progenitor cells give rise to B, T, these in vitro systems, bone-marrow stromal cells are cul- and nk(natural killer)cells and some dendritic cells. Myeloid tured to form a layer of cells that adhere to a petri dish stem cells generate progenitors of red blood cells(erythro- freshly isolated bone-marrow hematopoietic cells placed on ytes), many of the various white blood cells(neutrophils, this layer will grow, divide, and produce large visible colonies eosinophils, basophils, monocytes, mast cells, dendritic cells),(Figure 2-2). If the cells have been cultured in semisolid agar, nd platelets Progenitor commitment depends on the acquisi- their progeny will be immobilized and can be analyzed for tion of responsiveness to particular growth factors and cy- cell types. Colonies that contain stem cells can be replated to tokines. When the appropriate factors and cytokines are produce mixed colonies that contain different cell types, in present, progenitor cells proliferate and differentiate into the cluding progenitor cells of different cell lineages. In contrast, corresponding cell type, either a mature erythrocyte, a partic- progenitor cells, while capable of division, cannot be replated ular type of leukocyte, or a platelet-generating cell(the and produce lineage-restricted colonies. megakaryocyte). Red and white blood cells pass into bone Various growth factors are required for the survival, pro- marrow channels, from which they enter the circulation liferation, differentiation, and maturation of hematopoietic In bone marrow, hematopoietic cells grow and mature on cells in culture. These growth factors, the hematopoietic a meshwork of stromal cells, which are nonhematopoietic cytokines, are identified by their ability to stimulate the for- cells that support the growth and differentiation of hema- mation of hematopoietic cell colonies in bone-marrow topoietic cells Stromal cells include fat cells, endothelial cells, cultures. Among the cytokines detected in this way was a ibroblasts, and macrophages Stromal cells influence the dif- family of acidic glycoproteins, the colony-stimulating fac- ferentiation of hematopoietic stem cells by providing a tors(CSFs), named for their ability to induce the formation hematopoietic-inducing microenvironment(HIM)con- of distinct hematopoietic cell lines. Another importan sisting of a cellular matrix and factors that promote growth hematopoietic cytokine detected by this method was the gly- and differentiation. Many of these hematopoietic growth coprotein erythropoietin(EPO). Produced by the kidney, factors are soluble agents that arrive at their target cells by this cytokine induces the terminal development of erythro diffusion, others are membrane-bound molecules on the cytes and regulates the production of red blood cells. Fur surface of stromal cells that require cell-to-cell contact be- ther studies showed that the ability of a given cytokine to tween the responding cells and the stromal cells. During in- signal growth and differentiation is dependent upon the fection, hematopoiesis is stimulated by the production of presence of a receptor for that cytokine on the surface of the hematopoietic growth factors by activated macrophages and target cell--commitment of a progenitor cell to a particular Tcells differentiation pathway is associated with the expression of membrane receptors that are specific for particular cy Hematopoiesis Can Be Studied In Vitro tokines. Many cytokines and their receptors have since been shown to play essential roles in hematopoiesis. This topic is Cell-culture systems that can support the growth and differ- explored much more fully in the chapter on cytokines entiation of lymphoid and myeloid stem cells have made it Chapter 11) Adherent layer of marrow cells Culture in semioli Visible colonies of bone-marrow cells ∠s8、g 發 FIGURE2-2(a) Experimental scheme for culturing hematopoietic in long-term culture of human bone marrow.[Photograph from ells Adherent bone-marrow stromal cells form a matrix on which M.J. Cline and D. W. Golde, 1979, Nature 277: 180; reprinted by the hematopoietic cells proliferate. Single cells can be transferred permission;@ 1979 Macmillan Magazines Ltd, micrograph cour. to semisolid agar for colony growth and the colonies analyzed for tesy of S. quan J differentiated cell types. (b) Scanning electron micrograph of cells

26 PART I Introduction capacity for self-renewal and are committed to a particular cell lineage. Common lymphoid progenitor cells give rise to B, T, and NK (natural killer) cells and some dendritic cells. Myeloid stem cells generate progenitors of red blood cells (erythro￾cytes), many of the various white blood cells (neutrophils, eosinophils, basophils, monocytes, mast cells, dendritic cells), and platelets. Progenitor commitment depends on the acquisi￾tion of responsiveness to particular growth factors and cy￾tokines. When the appropriate factors and cytokines are present, progenitor cells proliferate and differentiate into the corresponding cell type, either a mature erythrocyte, a partic￾ular type of leukocyte, or a platelet-generating cell (the megakaryocyte). Red and white blood cells pass into bone￾marrow channels, from which they enter the circulation. In bone marrow, hematopoietic cells grow and mature on a meshwork of stromal cells, which are nonhematopoietic cells that support the growth and differentiation of hema￾topoietic cells. Stromal cells include fat cells, endothelial cells, fibroblasts, and macrophages. Stromal cells influence the dif￾ferentiation of hematopoietic stem cells by providing a hematopoietic-inducing microenvironment (HIM) con￾sisting of a cellular matrix and factors that promote growth and differentiation. Many of these hematopoietic growth factors are soluble agents that arrive at their target cells by diffusion, others are membrane-bound molecules on the surface of stromal cells that require cell-to-cell contact be￾tween the responding cells and the stromal cells. During in￾fection, hematopoiesis is stimulated by the production of hematopoietic growth factors by activated macrophages and T cells. Hematopoiesis Can Be Studied In Vitro Cell-culture systems that can support the growth and differ￾entiation of lymphoid and myeloid stem cells have made it possible to identify many hematopoietic growth factors. In these in vitro systems, bone-marrow stromal cells are cul￾tured to form a layer of cells that adhere to a petri dish; freshly isolated bone-marrow hematopoietic cells placed on this layer will grow, divide, and produce large visible colonies (Figure 2-2). If the cells have been cultured in semisolid agar, their progeny will be immobilized and can be analyzed for cell types. Colonies that contain stem cells can be replated to produce mixed colonies that contain different cell types, in￾cluding progenitor cells of different cell lineages. In contrast, progenitor cells, while capable of division, cannot be replated and produce lineage-restricted colonies. Various growth factors are required for the survival, pro￾liferation, differentiation, and maturation of hematopoietic cells in culture. These growth factors, the hematopoietic cytokines, are identified by their ability to stimulate the for￾mation of hematopoietic cell colonies in bone-marrow cultures. Among the cytokines detected in this way was a family of acidic glycoproteins, the colony-stimulating fac￾tors (CSFs), named for their ability to induce the formation of distinct hematopoietic cell lines. Another important hematopoietic cytokine detected by this method was the gly￾coprotein erythropoietin (EPO). Produced by the kidney, this cytokine induces the terminal development of erythro￾cytes and regulates the production of red blood cells. Fur￾ther studies showed that the ability of a given cytokine to signal growth and differentiation is dependent upon the presence of a receptor for that cytokine on the surface of the target cell—commitment of a progenitor cell to a particular differentiation pathway is associated with the expression of membrane receptors that are specific for particular cy￾tokines. Many cytokines and their receptors have since been shown to play essential roles in hematopoiesis. This topic is explored much more fully in the chapter on cytokines (Chapter 11). FIGURE 2-2 (a) Experimental scheme for culturing hematopoietic cells. Adherent bone-marrow stromal cells form a matrix on which the hematopoietic cells proliferate. Single cells can be transferred to semisolid agar for colony growth and the colonies analyzed for differentiated cell types. (b) Scanning electron micrograph of cells Add fresh bone￾marrow cells Culture in semisolid agar Adherent layer of stromal cells Visible colonies of bone-marrow cells (a) (b) in long-term culture of human bone marrow. [Photograph from M. J. Cline and D. W. Golde, 1979, Nature 277:180; reprinted by permission; © 1979 Macmillan Magazines Ltd., micrograph cour￾tesy of S. Quan.] 8536d_ch02_024-056 8/5/02 4:02 PM Page 26 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:

8536d_cho2024-056 8/5/02 4: 02 PM Page 27 mac79 Mac 79: 45_BW: Go dsby et al./Immunology se Cells and Organs of the Immune System CHAPTER 2 Hematopoiesis Is Regulated at the numbers of B, T, and NK cells, their production of erythro Genetic Level cytes, granulocytes, and other cells of the myeloid lineage is unimpaired. Ikaros knockout mice survive embryonic devel- The development of pluripotent hematopoietic stem cells opment, but they are severely compromised immunologi into different cell types requires the expression of different cally and die of infections at an early age sets of lineage-determining and lineage-specific genes at ap propriate times and in the correct order. The proteins speci- Hematopoietic Homeostasis Involves fied by these genes are critical components of regulatory Many Factors its descendants. Much of what we know about the depen- Hematopoiesis is a continuous process that generally main- dence of hematopoiesis on a particular gene comes from tains a steady state in which the production of mature blood studies of mice in which a gene has been inactivated or cells equals their loss(principally from aging). The average "knocked out"by targeted disruption, which blocks the pro- erythrocyte has a life span of 120 days before it is phagocytosed duction of the protein that it encodes(see Targeted Disrup- and digested by macrophages in the spleen. The various white tion of Genes, in Chapter 23). If mice fail to produce red cells blood cells have life spans ranging from a few days, for neu or particular white blood cells when a gene is knocked out, trophils, to as long as 20-30 years for some Tlymphocytes. To we conclude that the protein specified by the gene is neces- maintain steady-state levels, the average human being must sary for development of those cells. Knockout technology is produce an estimated 3.7 X 10 white blood cells per day one of the most powerful tools available for determining the Hematopoiesis is regulated by complex mechanisms that roles of particular genes in a broad range of processes and it affect all of the individual cell types. These regulatory mech has made important contributions to the identification of anisms ensure steady-state levels of the various blood cells, many genes that regulate hematopoiesis they have enough built-in flexibility so that production of Although much remains to be done, targeted disruption blood cells can rapidly increase tenfold to twentyfold in re- hematopoiesis.Some of these transcription factors affect cude. o hemorrhage or infection. Steady-state regulation of and other approaches have identified a number of transcrip- sponse to tion factors (Table 2-1)that play important roles in hematopoiesis is accomplished in various ways, which in many different hematopoietic lineages, and others affect only Control of the levels and types of cytokines produced by a single lineage, such as the developmental pathway that leads bone-marrow stromal cells to lymphocytes. One transcription factor that affects multi ple lineages is GATA-2, a member of a family of transcription The production of cytokines with hematopoietic activity factors that recognize the tetranucleotide sequence GATA, a by other cell types, such as activated T cells and nucleotide motif in target genes. A functional GATA-2 gene, which specifies this transcription factor, is essential for the The regulation of the expression of receptors for eages. As might be expected, animals in which this gene is hematopoietically active cytokines in stem cells and cell disrupted die during embryonic development. In contrast to GATA-2, another transcription factor, Ikaros, is required The removal of some cells by the controlled induction of only for the development of cells of the lymphoid lineage cell death though Ikaros knockout mice do not produce significant A failure in one or a combination of these regulatory mecha- nisms can have serious consequences. For example, abnormal- ities in the expression of hematopoietic cytokines or their TABLE 2.1 Some transcription factors essential for hematopoietic lineages e ceptors could lead to unregulated cellular proliferation and may contribute to the development of some leukemias. Ulti- mately, the number of cells in any hematopoietic lineage is set Factor Dependent lineage a balance between the number of cells removed by cell death and the number that arise from division and differentiation GATA-1 Erythroid Any one or a combination of regulatory factors can affect rates GATA-2 Erythroid, myeloid, lymphoid f cell reproduction and differentiation. These factors can also PU. 1 Erythroid (maturational stages), myeloid(later determine whether a hematopoietic cell is induced to die. tages), lymphoid Programmed Cell Death Is an Essential Homeostatic Mechanism B lymphoid (differentiation of B cells into plasma Programmed cell death, an induced and ordered process in which the cell actively participates in bringing about its own demise, is a critical factor in the homeostatic regulation of

Cells and Organs of the Immune System CHAPTER 2 27 Hematopoiesis Is Regulated at the Genetic Level The development of pluripotent hematopoietic stem cells into different cell types requires the expression of different sets of lineage-determining and lineage-specific genes at ap￾propriate times and in the correct order. The proteins speci￾fied by these genes are critical components of regulatory networks that direct the differentiation of the stem cell and its descendants. Much of what we know about the depen￾dence of hematopoiesis on a particular gene comes from studies of mice in which a gene has been inactivated or “knocked out” by targeted disruption, which blocks the pro￾duction of the protein that it encodes (see Targeted Disrup￾tion of Genes, in Chapter 23). If mice fail to produce red cells or particular white blood cells when a gene is knocked out, we conclude that the protein specified by the gene is neces￾sary for development of those cells. Knockout technology is one of the most powerful tools available for determining the roles of particular genes in a broad range of processes and it has made important contributions to the identification of many genes that regulate hematopoiesis. Although much remains to be done, targeted disruption and other approaches have identified a number of transcrip￾tion factors (Table 2-1) that play important roles in hematopoiesis. Some of these transcription factors affect many different hematopoietic lineages, and others affect only a single lineage, such as the developmental pathway that leads to lymphocytes. One transcription factor that affects multi￾ple lineages is GATA-2, a member of a family of transcription factors that recognize the tetranucleotide sequence GATA, a nucleotide motif in target genes. A functional GATA-2 gene, which specifies this transcription factor, is essential for the development of the lymphoid, erythroid, and myeloid lin￾eages. As might be expected, animals in which this gene is disrupted die during embryonic development. In contrast to GATA-2, another transcription factor, Ikaros, is required only for the development of cells of the lymphoid lineage. Al￾though Ikaros knockout mice do not produce significant numbers of B, T, and NK cells, their production of erythro￾cytes, granulocytes, and other cells of the myeloid lineage is unimpaired. Ikaros knockout mice survive embryonic devel￾opment, but they are severely compromised immunologi￾cally and die of infections at an early age. Hematopoietic Homeostasis Involves Many Factors Hematopoiesis is a continuous process that generally main￾tains a steady state in which the production of mature blood cells equals their loss (principally from aging). The average erythrocyte has a life span of 120 days before it is phagocytosed and digested by macrophages in the spleen. The various white blood cells have life spans ranging from a few days, for neu￾trophils, to as long as 20–30 years for some T lymphocytes. To maintain steady-state levels, the average human being must produce an estimated 3.7 1011 white blood cells per day. Hematopoiesis is regulated by complex mechanisms that affect all of the individual cell types. These regulatory mech￾anisms ensure steady-state levels of the various blood cells, yet they have enough built-in flexibility so that production of blood cells can rapidly increase tenfold to twentyfold in re￾sponse to hemorrhage or infection. Steady-state regulation of hematopoiesis is accomplished in various ways, which in￾clude: ■ Control of the levels and types of cytokines produced by bone-marrow stromal cells ■ The production of cytokines with hematopoietic activity by other cell types, such as activated T cells and macrophages ■ The regulation of the expression of receptors for hematopoietically active cytokines in stem cells and progenitor cells ■ The removal of some cells by the controlled induction of cell death A failure in one or a combination of these regulatory mecha￾nisms can have serious consequences. For example, abnormal￾ities in the expression of hematopoietic cytokines or their receptors could lead to unregulated cellular proliferation and may contribute to the development of some leukemias. Ulti￾mately, the number of cells in any hematopoietic lineage is set by a balance between the number of cells removed by cell death and the number that arise from division and differentiation. Any one or a combination of regulatory factors can affect rates of cell reproduction and differentiation. These factors can also determine whether a hematopoietic cell is induced to die. Programmed Cell Death Is an Essential Homeostatic Mechanism Programmed cell death, an induced and ordered process in which the cell actively participates in bringing about its own demise, is a critical factor in the homeostatic regulation of TABLE 2-1 Some transcription factors essential for hematopoietic lineages Factor Dependent lineage GATA-1 Erythroid GATA-2 Erythroid, myeloid, lymphoid PU.1 Erythroid (maturational stages), myeloid (later stages), lymphoid BM11 Myeloid, lymphoid Ikaros Lymphoid Oct-2 B lymphoid (differentiation of B cells into plasma cells) 8536d_ch02_024-056 8/5/02 4:02 PM Page 27 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:

8536d_ch02_024-0569/6/02 9: 00 PM Page 28 macas Mac 85: 365_smm pldsby et al./ Immunology Se mema su stem popuauons, Incuding those of tne leasing t creseosand possiBly triggering a damaging in Cells undergoing programmed cell death often exhibit Each of the leukocytes produced by hematopoiesis has distinctive morphologic changes, collectively referred to characteristic life span and then dies by programmed ce as apoptosis(Figures 2-3, 2-4). These changes include a death. In the adult human, for example, there are about pronounced decrease in cell volume, modification of the cy- 5 X 10 neutrophils in the circulation. These cells have a toskeleton that results in membrane blebbing, a condensa- life span of only a few days before programmed cell death tion of the chromatin, and degradation of the DNA into is initiated. This death, along with constant neutrophil smaller fragments. Following these morphologic changes, an production, maintains a stable number of these cells. If apoptotic cell sheds tiny membrane-bounded apoptotic bod- programmed cell death fails to occur, a leukemic state may s containing intact organelles. Macrophages quickly phago- develop Programmed cell death also plays a role in main cytose apoptotic bodies and cells in the advanced stages of taining proper numbers of hematopoietic progenitor cell apoptosis. This ensures that their intracellular contents, in- For example, when colony-stimulating factors are re- cluding proteolytic and other lytic enzymes, cationic pro- moved, progenitor cells undergo apoptosis. Beyond teins, and oxidizing molecules are not released into the hematopoiesis, apoptosis is important in such immuno- urrounding tissue. In this way, apoptosis does not induce a logical processes as tolerance and the killing of target cells local inflammatory response. Apoptosis differs markedly by cytotoxic T cells or natural killer cells. Details of th from necrosis, the changes associated with cell death arising mechanisms underlying apoptosis are emerging; Chapte from injury. In necrosis the injured cell swells and bursts, re- 13 describes them in detail NECROSIS APOPTOSIS Chromatin clumping Mild convolution tion Flocculent mitochondria nd segregation Condensation Blebbing Apoptotic Disintegration Phagocytosis Release of intracellular Phagocytic nflammation FIGURE 2-3 Comparison of morphologic changes that occur in tory response. In contrast, necrosis, the process that leads to death poptosis and necrosis. Apoptosis, which results in the programmed of injured cells, results in release of the cells'contents, which may in- ell death of hematopoietic cells, does not induce a local inflamma- duce a local inflammatory response Gotowww.whfreeman.com/immun② Cell Death

28 PART I Introduction many types of cell populations, including those of the hematopoietic system. Cells undergoing programmed cell death often exhibit distinctive morphologic changes, collectively referred to as apoptosis (Figures 2-3, 2-4). These changes include a pronounced decrease in cell volume, modification of the cy￾toskeleton that results in membrane blebbing, a condensa￾tion of the chromatin, and degradation of the DNA into smaller fragments. Following these morphologic changes, an apoptotic cell sheds tiny membrane-bounded apoptotic bod￾ies containing intact organelles. Macrophages quickly phago￾cytose apoptotic bodies and cells in the advanced stages of apoptosis. This ensures that their intracellular contents, in￾cluding proteolytic and other lytic enzymes, cationic pro￾teins, and oxidizing molecules are not released into the surrounding tissue. In this way, apoptosis does not induce a local inflammatory response. Apoptosis differs markedly from necrosis, the changes associated with cell death arising from injury. In necrosis the injured cell swells and bursts, re￾leasing its contents and possibly triggering a damaging in￾flammatory response. Each of the leukocytes produced by hematopoiesis has a characteristic life span and then dies by programmed cell death. In the adult human, for example, there are about 5 1010 neutrophils in the circulation. These cells have a life span of only a few days before programmed cell death is initiated. This death, along with constant neutrophil production, maintains a stable number of these cells. If programmed cell death fails to occur, a leukemic state may develop. Programmed cell death also plays a role in main￾taining proper numbers of hematopoietic progenitor cells. For example, when colony-stimulating factors are re￾moved, progenitor cells undergo apoptosis. Beyond hematopoiesis, apoptosis is important in such immuno￾logical processes as tolerance and the killing of target cells by cytotoxic T cells or natural killer cells. Details of the mechanisms underlying apoptosis are emerging; Chapter 13 describes them in detail. NECROSIS APOPTOSIS Chromatin clumping Swollen organelles Flocculent mitochondria Mild convolution Chromatin compaction and segregation Condensation of cytoplasm Nuclear fragmentation Blebbing Apoptotic bodies Phagocytosis Phagocytic cell Apoptotic body Disintegration Release of intracellular contents Inflammation FIGURE 2-3 Comparison of morphologic changes that occur in apoptosis and necrosis. Apoptosis, which results in the programmed cell death of hematopoietic cells, does not induce a local inflamma￾tory response. In contrast, necrosis, the process that leads to death of injured cells, results in release of the cells’ contents, which may in￾duce a local inflammatory response. Go to www.whfreeman.com/immunology Animation Cell Death 8536d_ch02_024-056 9/6/02 9:00 PM Page 28 mac85 Mac 85:365_smm:Goldsby et al. / Immunology 5e: