Apoptosis (programmed cell death) is a regulated process of physiological cell death in which individual cells are triggered to activate intracellular proteins that lead to the death of the cell. Morphologically it is characterized by cell shrinkage, condensation of the nuclear chromatin, fragmentation of the nucleus and cleavage of DNA at internucleosomal sites. It is an important process for maintaining tissue homeostasis in haemopoiesis and lymphocyte development.
Apoptosis results from the action of intracellular cysteine proteases called caspases which are activated following cleavage and lead to endonuclease digestion of DNA and disintegration of the cell skeleton (Fig. 1.9). There are two major pathways by which caspases can be activated. The first is by signalling through membrane proteins such as Fas or TNF receptor via their intracellular death domain. An example of this mechanism is shown by activated cytotoxic T cells expressing Fas ligand which induces apoptosis in target cells. The second pathway is via the release of cytochrome c from mitochondria. Cytochrome c binds to APAF‐1 which then activates caspases. DNA damage induced by irradiation or chemotherapy may act through this pathway. The protein p53 has an importantrole in sensing DNA damage. It activates apoptosis by raising the cell level of BAX which then increases cytochrome c release (Fig. 1.9). P53 also shuts down the cell cycle to stop the damaged cell from dividing (Fig. 1.7). The cellular level of p53 is rigidly controlled by a second protein, MDM2. Following death, apoptotic cells display molecules that lead to their ingestion by macrophages.
As well as molecules that mediate apoptosis there are several intracellular proteins that protect cells from apoptosis. The best characterized example is BCL‐2. BCL‐2 is the prototype of a family of related proteins, some of which are anti‐apoptotic and some, like BAX, pro‐apoptotic. The intracellular ratio of BAX and BCL‐2 determines the relative susceptibility of cells to apoptosis (e.g. determines the lifespan of platelets) and may act through regulation of cytochrome c release from mitochondria. Many of the genetic changes associated with malignant disease lead to a reduced rate of apoptosis and hence prolonged cell survival. The clearest example is the translocation of the BCL‐2 gene to the immunoglobulin heavy chain locus in the t(14;18) translocation in follicular lymphoma (see p. 222). Over- expression of the BCL‐2 protein makes the malignant B cells less susceptible to apoptosis. Apoptosis is the normal fate for most
B cells undergoing selection in the lymphoid germinal centres. Several translocations leading to the generation of fusion proteins, such as t(9;22), t(1;14) and t(15;17), also result in inhibition of apoptosis (see Chapter 11). In addition, genes encoding proteins that are involved in mediating apoptosis following DNA damage, such as p53 and ATM, are also frequently mutated and therefore inactivated in haemopoietic malignancies.
Necrosis is death of cells and adjacent cells due to ischaemia, chemical trauma or hyperthermia. The cells swell, the plasma membrane loses integrity. There is usually an inflammatory infiltrate in response to spillage of cell contents. Autophagy is the digestion of cell organelles by lysosomes. It may be involved in cell death but in some situtions also in maintaining cell survival by recycling nutrients.