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Apoptosis

Apoptosis


Apoptosis
is a pathway of cell death that is induced by a tightly regulated intracellular program in which cells destined to die activate enzymes that degrade the cells' own nuclear DNA and nuclear and cytoplasmic proteins. The cell's plasma membrane remains intact, but its structure is altered in such a way that the apoptotic cell becomes an avid target for phagocytosis. The dead cell is rapidly cleared, before its contents have leaked out, and therefore cell death by this pathway does not elicit an inflammatory reaction in the host. Thus, apoptosis is fundamentally different from necrosis, which is characterized by loss of membrane integrity, enzymatic digestion of cells, and frequently a host reaction (see Fig. 1-9 and Table 1-2 ). However, apoptosis and necrosis sometimes coexist, and they may share some common features and mechanisms.

CAUSES OF APOPTOSIS

Apoptosis was initially recognized in 1972 by its distinctive morphology and named after the Greek designation for "falling off."[42] It occurs normally in many situations, and serves to eliminate unwanted or potentially harmful cells and cells that have outlived their usefulness. It is also a pathologic event when cells are damaged beyond repair, especially when the damage affects the cell's DNA; in these situations, the irreparably damaged cell is eliminated. Apoptosis is responsible for numerous physiologic, adaptive, and pathologic events, listed next.

Apoptosis in Physiologic Situations

Death by apoptosis is a normal phenomenon that serves to eliminate cells that are no longer needed, as, for example, during development, and to maintain a steady number of various cell populations in tissues. It is important in the following physiologic situations:

  

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The programmed destruction of cells during embryogenesis, including implantation, organogenesis, developmental involution and metamorphosis. The term "programmed cell death" was originally coined to denote death of specific cell types at defined times during development.[43] Apoptosis is a generic term for this pattern of cell death, regardless of the context, but it is often used interchangeably with "programmed cell death."

  

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Hormone-dependent involution in the adult, such as endometrial cell breakdown during the menstrual cycle, ovarian follicular atresia in the menopause, the regression of the lactating breast after weaning, and prostatic atrophy after castration.

  

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Cell deletion in proliferating cell populations, such as intestinal crypt epithelia, in order to maintain a constant number.

  

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Death of host cells that have served their useful purpose, such as neutrophils in an acute inflammatory response, and lymphocytes at the end of an immune response. In these situations, cells undergo apoptosis because they are deprived of necessary survival signals, such as growth factors.

  

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Elimination of potentially harmful self-reactive lymphocytes, either before or after they have completed their maturation ( Chapter 6).

  

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Cell death induced by cytotoxic T cells, a defense mechanism against viruses and tumors that serves to eliminate virus-infected and neoplastic cells. The same mechanism is responsible for cellular rejection of transplants ( Chapter 6).

 

Apoptosis in Pathologic Conditions

Death by apoptosis is also responsible for loss of cells in a variety of pathologic states:

  

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Cell death produced by a variety of injurious stimuli.For instance, radiation and cytotoxic anticancer drugs damage DNA, and if repair mechanisms cannot cope with the injury the cell kills itself by apoptosis. In these situations, elimination of the cell may be a better alternative than risking mutations and translocations in the damaged DNA, which may result in malignant transformation. These injurious stimuli, as well as heat and hypoxia, can induce apoptosis if the insult is mild, but large doses of the same stimuli result in necrotic cell death. Endoplasmic reticulum (ER) stress, which is induced by the accumulation of unfolded proteins, also triggers apoptotic death of cells (described later in the chapter).

  

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Cell injury in certain viral diseases, such as viral hepatitis, in which loss of infected cells is largely because of apoptotic death.

  

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Pathologic atrophy in parenchymal organs after duct obstruction, such as occurs in the pancreas, parotid gland, and kidney.

  

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Cell death in tumors, most frequently during regression but also in actively growing tumors.

  

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As we mentioned earlier, even in situations in which cell death is mainly by necrosis, the pathway of apoptosis may contribute. For instance, injurious stimuli that cause increased mitochondrial permeability trigger apoptosis.

 

Before the mechanisms of apoptosis are discussed, we describe the morphologic and biochemical characteristics of this process.

Morphology.

The following morphologic features, some best seen with the electron microscope, characterize cells undergoing apoptosis ( Fig. 1-25).

  

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Cell shrinkage.The cell is smaller in size; the cytoplasm is dense; and the organelles, although relatively normal, are more tightly packed.

  

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Chromatin condensation.This is the most characteristic feature of apoptosis. The chromatin aggregates peripherally, under the nuclear membrane, into dense masses of various shapes and sizes. The nucleus itself may break up, producing two or more fragments.

  

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Formation of cytoplasmic blebs and apoptotic bodies.The apoptotic cell first shows extensive surface blebbing, then undergoes fragmentation into membrane-bound apoptotic bodies composed of cytoplasm and tightly packed organelles, with or without nuclear fragments.

  

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Phagocytosis of apoptotic cells or cell bodies, usually by macrophages.The apoptotic bodies are rapidly degraded within lysosomes, and the adjacent healthy cells migrate or proliferate to replace the space occupied by the now deleted apoptotic cell.

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Figure 1-25  Ultrastructural features of apoptosis. Some nuclear fragments show peripheral crescents of compacted chromatin, whereas others are uniformly dense.  (From Kerr JFR, Harmon BV: Definition and incidence of apoptosis: a historical perspective. In Tomei LD, Cope FO (eds): Apoptosis: The Molecular Basis of Cell Death. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, 1991, pp 5–29.)

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Plasma membranes are thought to remain intact during apoptosis, until the last stages, when they become permeable to normally retained solutes. This classical description is accurate with respect to apoptosis during physiologic conditions such as embryogenesis and deletion of immune cells. However, forms of cell death with features of necrosis as well as of apoptosis are not uncommon after injurious stimuli.[44] Under such conditions, the severity, rather than the specificity, of stimulus determines the form in which death is expressed. If necrotic features are predominant, early plasma membrane damage occurs, and cell swelling, rather than shrinkage, is seen.

On histologic examination, in tissue stained with hematoxylin and eosin, apoptosis involves single cells or small clusters of cells. The apoptotic cell appears as a round or oval mass of intensely eosinophilic cytoplasm with dense nuclear chromatin fragments ( Fig. 1-26). Because the cell shrinkage and formation of apoptotic bodies are rapid and the fragments are quickly phagocytosed, considerable apoptosis may occur in tissues before it becomes apparent in histologic sections. In addition, apoptosis—in contrast to necrosis—does not elicit inflammation, making it more difficult to detect histologically.

Figure 1-26  A, Apoptosis of epidermal cells in an immune-mediated reaction. The apoptotic cells are visible in the epidermis with intensely eosinophilic cytoplasm and small, dense nuclei. H&E stain. B, High power of apoptotic cell in liver in immune-mediated hepatic cell injury.  (Courtesy of Dr. Scott Granter, Brigham and Women's Hospital, Boston, AM.) (Courtesy of Dr. Dhanpat Jain, Yale University, New Haven, CT.)

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BIOCHEMICAL FEATURES OF APOPTOSIS

Apoptotic cells usually exhibit a distinctive constellation of biochemical modifications that underlie the structural changes described above. Some of these features may be seen in necrotic cells also, but other alterations are more specific.

Protein Cleavage.

A specific feature of apoptosis is protein hydrolysis involving the activation of several members of a family of cysteine proteases named caspases.[45] Many caspases are present in normal cells as inactive pro-enzymes, and they need to be activated to induce apoptosis. Active caspases cleave many vital cellular proteins, such as lamins, and thus break up the nuclear scaffold and cytoskeleton; in addition, caspases activate DNAses, which degrade nuclear DNA. These changes underlie the nuclear and cytoplasmic structural alterations seen in apoptotic cells.

DNA Breakdown.

Apoptotic cells exhibit a characteristic breakdown of DNA into large 50- to 300-kilobase pieces.[46] Subsequently, there is internucleosomal cleavage of DNA into oligonucleosomes, in multiples of 180 to 200 base pairs, by Ca2+- and Mg2+-dependent endonucleases. The fragments may be visualized by agarose gel electrophoresis as DNA ladders ( Fig. 1-27). Endonuclease activity also forms the basis for detecting cell death by cytochemical techniques that recognize double-stranded breaks of DNA.[47] However, internucleosomal DNA cleavage is not specific for apoptosis. A "smeared" pattern of DNA fragmentation is thought to be indicative of necrosis, but this may be a late autolytic phenomenon, and typical DNA ladders may be seen in necrotic cells as well.[47]

Figure 1-27  Agarose gel electrophoresis of DNA extracted from culture cells. Ethidium bromide stain; photographed under ultraviolet illumination. Lane A, Control culture. Lane B, Culture of cells exposed to heat showing extensive apoptosis; note ladder pattern of DNA fragments, which represent multiples of oligonucleosomes. Lane C, Culture showing massive necrosis; note diffuse smearing of DNA. The ladder pattern is produced by enzymatic cleavage of nuclear DNA into nucleosome-sized fragments, usually multiples of 180–200 base pairs. These patterns are characteristic of but not specific for apoptosis and necrosis, respectively.  (From Kerr JFR, Harmon BV: Definition and incidence of apoptosis: a historical perspective. In Tomei LD, Cope FO [eds]: Apoptosis: The Molecular Basis of Cell Death. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, 1991, p 13.)

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Phagocytic Recognition.

Apoptotic cells express phosphatidylserine in the outer layers of their plasma membranes, the phospholipid having "flipped" out from the inner layers. (Because of these changes, apoptotic cells can be identified by binding of special dyes, such as Annexin V.) In some types of apoptosis, thrombospondin, an adhesive glycoprotein, is also expressed on the surfaces of apoptotic bodies, and other proteins secreted by phagocytes may bind to apoptotic cells and opsonize the cells for phagocytosis.[48] These alterations permit the early recognition of dead cells by macrophages, resulting in phagocytosis without the release of proinflammatory cellular components.[49] In this way, the apoptotic response disposes of cells with minimal compromise to the surrounding tissue.

MECHANISMS OF APOPTOSIS

Apoptosisis induced by a cascade of molecular events that may be initiated in distinct ways and culminate in the activation of caspases ( Fig. 1-28).[45] Because too much or too little apoptosis is thought to underlie many diseases, such as degenerative diseases and cancer, there is great interest in elucidating the mechanisms of this form of cell death. Tremendous progress has been made in our understanding of apoptosis. One of the remarkable facts to emerge is that the basic mechanisms of apoptosis are conserved in all metazoans.[50] In fact, some of the major breakthroughs came from observations made in the nematode Caenorhabditis elegans, whose development proceeds by a highly reproducible, programmed pattern of cell growth followed by cell death. Studies of mutant worms have allowed the identification of specific genes (called ced genes, for cell death abnormal) that initiate or inhibit apoptosis and for which there are defined mammalian homologues.

Figure 1-28  Mechanisms of apoptosis. Labeled (1) are some of the major inducers of apoptosis. These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand), withdrawal of growth factors or hormones, and injurious agents (e.g., radiation). Some stimuli (such as cytotoxic cells) directly activate execution caspases (right). Others act by way of adapter proteins and initiator caspases, or by mitochondrial events involving cytochrome c. (2) Control and regulation are influenced by members of the Bcl-2 family of proteins, which can either inhibit or promote the cell's death. (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins. This results in a cascade of intracellular degradation, including fragmentation of nuclear chromatin and breakdown of the cytoskeleton. (4) The end result is formation of apoptotic bodies containing intracellular organelles and other cytosolic components; these bodies also express new ligands for binding and uptake by phagocytic cells.

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The process of apoptosis may be divided into an initiation phase, during which caspases become catalytically active, and an execution phase, during which these enzymes act to cause cell death. Initiation of apoptosis occurs principally by signals from two distinct but convergent pathways — the extrinsic, or receptor-initiated, pathway and the intrinsic, or mitochondrial, pathway. Both pathways converge to activate caspases. We will describe these two pathways separately because they involve largely distinct molecular interactions, but it is important to remember that they may be interconnected at numerous steps.

The extrinsic (Death Receptor-Initiated) Pathway.

This pathway is initiated by engagement of cell surface death receptors on a variety of cells.[51] Death receptors are members of the tumor necrosis factor receptor family that contain a cytoplasmic domain involved in protein-protein interactions that is called the death domain because it is essential for delivering apoptotic signals. (Some TNF receptor family members do not contain cytoplasmic death domains; their role in triggering apoptosis is much less established). The best-known death receptors are the type 1 TNF receptor (TNFR1) and a related protein called Fas (CD95), but several others have been described. The mechanism of apoptosis induced by these death receptors is well illustrated by Fas ( Fig. 1-29). When Fas is cross-linked by its ligand, membrane-bound Fas ligand (FasL), three or more molecules of Fas come together, and their cytoplasmic death domains form a binding site for an adapter protein that also contains a death domain and is called FADD (Fas-associated death domain). FADD that is attached to the death receptors in turn binds an inactive form of caspase-8 (and, in humans, caspase-10), again via a death domain. Multiple pro-caspase-8 molecules are thus brought into proximity, and they cleave one another to generate active caspase-8. The enzyme then triggers a cascade of caspase activation by cleaving and thereby activating other pro-caspases, the active enzymes mediate the execution phase of apoptosis (discussed below). This pathway of apoptosis can be inhibited by a protein called FLIP, which binds to pro-caspase-8 but cannot cleave and activate the enzyme because it lacks enzymatic activity.[52] Some viruses and normal cells produce FLIP and use this inhibitor to protect infected and normal cells from Fas-mediated apoptosis. The sphingolipid ceramide has been implicated as an intermediate between death receptors and caspase activation, but the role of this pathway is unclear and remains controversial.[53]

Figure 1-29  The extrinsic (death receptor-initiated) pathway of apoptosis, illustrated by the events following Fas engagement (see text).

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The Intrinsic (Mitochondrial) Pathway.

This pathway of apoptosis is the result of increased mitochondrial permeability and release of pro-apoptotic molecules into the cytoplasm, without a role for death receptors.[54][55] Growth factors and other survival signals stimulate the production of anti-apoptotic members of the Bcl-2 family of proteins.[56] This family is named after Bcl-2, which was identified as an oncogene in a B cell lymphoma and is homologous to the C. elegans protein, Ced-9. There are more than 20 proteins in this family, all of which function to regulate apoptosis; the two main anti-apoptotic ones are Bcl-2 and Bcl-x. These anti-apoptotic proteins normally reside in mitochondrial membranes and the cytoplasm. When cells are deprived of survival signals or subjected to stress, Bcl-2 and/or Bcl-x are lost from the mitochondrial membrane and are replaced by pro-apoptotic members of the family, such as Bak, Bax, and Bim. When Bcl-2/Bcl-x levels decrease, the permeability of the mitochondrial membrane increases, and several proteins that can activate the caspase cascade leak out ( Fig. 1-30). One of these proteins is cytochrome c, well known for its role in mitochondrial respiration. In the cytosol, cytochrome c binds to a protein called Apaf-1 (apoptosis activating factor-1, homologous to Ced-4 in C. elegans), and the complex activates caspase-9.[57] (Bcl-2 and Bcl-x may also directly inhibit Apaf-1 activation, and their loss from cells may permit activation of Apaf-1). Other mitochondrial proteins, such as apoptosis inducing factor (AIF), enter the cytoplasm, where they bind to and neutralize various inhibitors of apoptosis, whose normal function is to block caspase activation.[58] The net result is the initiation of a caspase cascade. Thus, the essence of this intrinsic pathway is a balance between pro-apoptotic and protective molecules that regulate mitochondrial permeability and the release of death inducers that are normally sequestered within the mitochondria.

Figure 1-30  The intrinsic (mitochondrial) pathway of apoptosis. Death agonists cause changes in the inner mitochondrial membrane, resulting in the mitochondrial permeability transition (MPT) and release of cytochrome c and other pro-apoptotic proteins into the cytosol, which activate caspases (see text).

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There is quite a lot of evidence that the intrinsic pathway of apoptosis can be triggered without a role for mitochondria.[59] Apoptosis may be initiated by caspase activation upstream of mitochondria, and the subsequent increase in mitochondrial permeability and release of pro-apoptotic molecules amplify the death signal.[46] However, these pathways of apoptosis involving mitochondria-independent initiation are not well defined. We have described the extrinsic and intrinsic pathways for initiating apoptosis as distinct, but there may be overlaps between them. For instance, in hepatocytes, Fas signaling activates a pro-apoptotic member of the Bcl family called Bid, which then activates the mitochondrial pathway. It is not known if such cooperative interactions between apoptosis pathways are active in most other cell types.

The Execution Phase.

This final phase of apoptosis is mediated by a proteolytic cascade, toward which the various initiating mechanisms converge. The proteases that mediate the execution phase are highly conserved across species and belong to the caspase family, as previously mentioned. They are mammalian homologues of the ced-3 gene in C. elegans.[44] The term caspase is based on two properties of this family of enzymes: the "c" refers to a cysteine protease (i.e., an enzyme with cysteine in its active site), and "aspase" refers to the unique ability of these enzymes to cleave after aspartic acid residues.[60] The caspase family, now including more than 10 members, can be divided functionally into two basic groups—initiator and executioner—depending on the order in which they are activated during apoptosis.[60] Initiator caspases, as we have seen, include caspase-8 and caspase-9. Several caspases, including caspase-3 and caspase-6, serve as executioners.

Like many proteases, caspases exist as inactive pro-enzymes, or zymogens, and must undergo an activating cleavage for apoptosis to be initiated. Caspases have their own cleavage sites that can be hydrolyzed not only by other caspases but also autocatalytically. After an initiator caspase is cleaved to generate its active form, the enzymatic death program is set in motion by rapid and sequential activation of other caspases. Executioner caspases act on many cellular components. They cleave cytoskeletal and nuclear matrix proteins and thus disrupt the cytoskeleton and lead to breakdown of the nucleus.[60] In the nucleus, the targets of caspase activation include proteins involved in transcription, DNA replication, and DNA repair. In particular, caspase-3 activation converts a cytoplasmic DNase into an active form by cleaving an inhibitor of the enzyme; this DNase induces the characteristic internucleosomal cleavage of DNA, described earlier.

Removal of Dead Cells.

At early stages of apoptosis, dying cells secrete soluble factors that recruit phagocytes.[61] This facilitates prompt clearance of apoptotic cells before they undergo secondary necrosis and release their cellular contents (which can result in inflammation). As already alluded to, apoptotic cells and their fragments have marker molecules on their surfaces, which facilitates early recognition by adjacent cells or phagocytes for phagocytic uptake and disposal. Numerous macrophage receptors have been shown to be involved in the binding and engulfment of apoptotic cells. In addition, macrophages can also secrete substances that bind specifically to apoptotic but not live cells and opsonize these cells for phagocytosis. In contrast to markers on apoptotic cells, viable cells appear to prevent their own engulfment by macrophages through expression of certain surface molecules (such as CD31). This process of phagocytosis of apoptotic cells is so efficient that dead cells disappear without leaving a trace, and inflammation is virtually absent.

EXAMPLES OF APOPTOSIS

The signals that induce apoptosis include lack of growth factor or hormone, specific engagement of death receptors, and particular injurious agents. Although the classic example of apoptosis has been programmed death of cells during embryogenesis, we still do not know what triggers apoptosis in this situation. However, many other well-defined examples of apoptosis are known.

Apoptosis After Growth Factor Deprivation.

Hormone-sensitive cells deprived of the relevant hormone, lymphocytes that are not stimulated by antigens and cytokines, and neurons deprived of nerve growth factor die by apoptosis.[62] In all these situations, apoptosis is triggered by the intrinsic (mitochondrial) pathway and is attributable to an excess of pro-apoptotic members of the Bcl family relative to anti-apoptotic members.

DNA Damage-Mediated Apoptosis.

Exposure of cells to radiation or chemotherapeutic agents induces apoptosis by a mechanism that is initiated by DNA damage (genotoxic stress) and that involves the tumor-suppressor gene p53.[63] p53 accumulates when DNA is damaged and arrests the cell cycle (at the G1 phase) to allow time for repair ( Chapter 7). However, if the DNA repair process fails, p53 triggers apoptosis. When p53 is mutated or absent (as it is in certain cancers), it is incapable of inducing apoptosis and it favors cell survival. Thus, p53 seems to serve as a critical "life or death" switch in the case of genotoxic stress. The mechanism by which p53 triggers the distal death effector machinery—the caspases—is complex but seems to involve its well-characterized function in transcriptional activation. Among the proteins whose production is stimulated by p53 are several pro-apoptotic members of the Bcl family, notably Bax and Bak, as well as Apaf-1, mentioned earlier. These proteins activate caspases and cause apoptosis.

Apoptosis Induced by Tumor Necrosis Factor Family of Receptors.

As discussed above, the cell surface receptor Fas (CD95) induces apoptosis when it is engaged by Fas ligand (FasL or CD95L), which is produced by cells of the immune system. This system is important in the elimination of lymphocytes that recognize self-antigens, and mutations in Fas or FasL result in autoimmune diseases in humans and mice ( Chapter 6).[64]

The cytokine TNF is an important mediator of the inflammatory reaction ( Chapter 2), but it is also capable of inducing apoptosis. (The name "tumor necrosis factor" arose not because the cytokine kills tumor cells directly, but because it induces thrombosis of tumor blood vessels, resulting in ischemic death of the tumor.) The binding of TNF to TNFR1 leads to association of the receptor with the adapter protein TRADD (TNF receptor-associated death domain containing protein). TRADD in turn binds to FADD and leads to apoptosis through caspase activation, as with Fas-FasL interactions.[52] The major functions of TNF, however, are mediated not by inducing apoptosis but by activation of the important transcription factor nuclear factor-κB (NF-κB). TNF-mediated signals accomplish this by stimulating degradation of the inhibitor of NF-κB).[65] The NF-κB/IκB transcriptional regulatory system is important for cell survival and, as we shall see in Chapter 2, for a number of inflammatory responses. Since TNF can induce cell death and promote cell survival, what determines this yin and yang of its action? The answer is unclear, but it probably depends on which adapter protein attaches to the TNF receptor after binding of the cytokine. TRADD and FADD favor apoptosis, and other adapter proteins, called TRAFs (TNF receptor associated factors) favor NF-κB activation and survival.

Cytotoxic T-Lymphocyte-Mediated Apoptosis.

Cytotoxic T lymphocytes (CTLs) recognize foreign antigens presented on the surface of infected host cells ( Chapter 6). On recognition, CTLs secrete perforin, a transmembrane pore-forming molecule, which allows entry of the CTL granule serine protease called granzyme B. Granzyme B has the ability to cleave proteins at aspartate residues and is able to activate a variety of cellular caspases.[66] In this way, the CTL kills target cells through bypassing the upstream signaling events and directly induces the effector phase of apoptosis. CTLs also express FasL on their surfaces and kill target cells by ligation of Fas receptors, as described earlier.

Dysregulated apoptosis ("too little or too much") has been postulated to explain components of a wide range of diseases.[67] In essence, two groups of disorders may result from such dysregulation:

  

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Disorders associated with defective apoptosis and increased cell survival.Here, an inappropriately low rate of apoptosis may prolong the survival or reduce the turnover of abnormal cells. These accumulated cells can give rise to: (1) cancers, especially tumors with p53 mutations, or hormone-dependent tumors, such as breast, prostate, or ovarian cancers ( Chapter 7); and (2) autoimmune disorders, which could arise if autoreactive lymphocytes are not eliminated after encounter with self antigens ( Chapter 6).

  

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Disorders associated with increased apoptosis and excessive cell death.These diseases are characterized by a marked loss of normal or protective cells and include: (1) neurodegenerative diseases, manifested by loss of specific sets of neurons, such as in the spinal muscular atrophies ( Chapter 27); (2) ischemic injury, as in myocardial infarction ( Chapter 12) and stroke ( Chapter 28); and (3) death of virus-infected cells, in many viral infections ( Chapter 8).

 

 

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