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 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 condensation of the chromatin, and degradation of the DNA into smaller fragments. Following these morphologic changes, an apoptotic cell sheds tiny membrane-bounded apoptotic bodies containing intact organelles. Macrophages quickly phagocytose apoptotic bodies and cells in the advanced stages of apoptosis. This ensures that their intracellular contents, including proteolytic and other lytic enzymes, cationic proteins, 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 inflammatory 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 X 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 maintaining proper numbers of hematopoietic progenitor cells. For example, when colony-stimulating factors are removed, 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

Chromatin clumping Swollen organelles Flocculent mitochondria

NECROSIS

Chromatin clumping Swollen organelles Flocculent mitochondria

Clumping Nuclear Chromatin

APOPTOSIS

Mild convolution Chromatin compaction and segregation Condensation of cytoplasm

APOPTOSIS

Mild convolution Chromatin compaction and segregation Condensation of cytoplasm

Disintegration

Release of intracellular contents

Inflammation

Tunnel Apoptotic Body
Nuclear fragmentation Blebbing Apoptotic bodies

Phagocytosis

Phagocytosis

Steps Exocytosis

tory response. In contrast, necrosis, the process that leads to death of injured cells, results in release of the cells' contents, which may induce a local inflammatory response.

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-

Go to www.whfreeman.com/immunology Cell Death if 1

Animation tory response. In contrast, necrosis, the process that leads to death of injured cells, results in release of the cells' contents, which may induce a local inflammatory response.

Animated ThymusSteps Local Inflamatory Response

Apoptosis. Light micrographs of (a) normal thymocytes (developing T cells in the thymus) and (b) apoptotic thymocytes. Scanning electron micrographs of (c) normal and (d)

apoptotic thymocytes. [From B. A. Osborne and S. Smith, 1997, Journal of NIH Research 9:35; courtesy B. A. Osborne, University of Massachusetts at Amherst.]

FIGURE 2-4

Apoptosis. Light micrographs of (a) normal thymocytes (developing T cells in the thymus) and (b) apoptotic thymocytes. Scanning electron micrographs of (c) normal and (d)

apoptotic thymocytes. [From B. A. Osborne and S. Smith, 1997, Journal of NIH Research 9:35; courtesy B. A. Osborne, University of Massachusetts at Amherst.]

The expression of several genes accompanies apoptosis in leukocytes and other cell types (Table 2-2). Some of the proteins specified by these genes induce apoptosis, others are critical during apoptosis, and still others inhibit apoptosis. For example, apoptosis can be induced in thymocytes by radiation, but only if the protein p53 is present; many cell deaths are induced by signals from Fas, a molecule present on the surface of many cells; and proteases known as caspases take part in a cascade of reactions that lead to apoptosis. On the other hand, members of the bcl-2 (B-cell lymphoma 2) family of genes, bcl-2 and bcl-XL encode protein products that inhibit apoptosis. Interestingly, the first member of this gene family, bcl-2, was found in studies that were concerned not with cell death but with the uncontrolled proliferation of B cells in a type of cancer known as B-lymphoma. In this case, the bcl-2 gene was at the breakpoint of a chromosomal translocation in a human B-cell lymphoma. The translocation moved the bcl-2 gene into the immunoglobulin heavy-chain locus, resulting in tran scriptional activation of the bcl-2 gene and overproduction of the encoded Bcl-2 protein by the lymphoma cells. The resulting high levels of Bcl-2 are thought to help transform lymphoid cells into cancerous lymphoma cells by inhibiting the signals that would normally induce apoptotic cell death.

Bcl-2 levels have been found to play an important role in regulating the normal life span of various hematopoietic cell lineages, including lymphocytes. A normal adult has about 5 L of blood with about 2000 lymphocytes/mm3 for a total of about 1010 lymphocytes. During acute infection, the lymphocyte count increases 4- to 15-fold, giving a total lymphocyte count of 40-50 X 109. Because the immune system cannot sustain such a massive increase in cell numbers for an extended period, the system needs a means to eliminate un-needed activated lymphocytes once the antigenic threat has passed. Activated lymphocytes have been found to express lower levels of Bcl-2 and therefore are more susceptible to the induction of apoptotic death than are naive lymphocytes or

TABLE 2-2 |

Genes that regulate apoptosis

Gene

Function

Role in apoptosis

bcl-2

Prevents apoptosis

Inhibits

bax

Opposes bcl-2

Promotes

bcl-XL (bcl-Long)

Prevents apoptosis

Inhibits

bcl-XS (bcl-Short)

Opposes bcl-XL

Promotes

caspase (several different ones)

Protease

Promotes

fas

Induces apoptosis

Initiates

memory cells. However, if the lymphocytes continue to be activated by antigen, then the signals received during activation block the apoptotic signal. As antigen levels subside, so does activation of the block and the lymphocytes begin to die by apoptosis (Figure 2-5).

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