Apoptosis For every cell, there is a time to live and a time to die. There are two ways in which cells die: they are killed by injurious agents they are induced to commit suicide Death by injury Cells that are damaged by injury, such as by mechanical damage exposure to toxic chemicals undergo a characteristic series of changes: they (and their organelles like mitochondria) swell (because the ability of the plasma membrane to control the passage of ions and water is disrupted) the cell contents leak out, leading to inflammation of surrounding tissues Death by suicide
Caspase 9 is one of a family of over a dozen caspases. They are all proteases. They get their name because they cleave proteins - mostly each other - at aspartic acid (Asp) residues). Caspase 9 cleaves and, in so doing, activates other caspases. The sequential activation of one caspase by another creates an expanding cascade of proteolytic activity (rather like that in blood clotting and complement activation) which leads to digestion of structural proteins in the cytoplasm degradation of chromosomal DNA and phagocytosis of the cell 2. Apoptosis triggered by external signals: the extrinsic or death receptor pathway Fas and the TNF receptor are integral membrane proteins with their receptor domains exposed at the surface of the cell binding of the complementary death activator (FasL and TNF respectively) transmits a signal to the cytoplasm that leads to activation of caspase 8 caspase 8 (like caspase 9) initiates a cascade of caspase activation leading to phagocytosis of the cell. Example (right): When cytotoxic T cells recognize (bind to) their target, they produce more FasL at their surface. This binds with the Fas on the surface of the target cell leading to its death by apoptosis. The early steps in apoptosis are reversible - at least in C. elegans. In some cases, final destruction of the cell is guaranteed only with its engulfment by a phagocyte. 3. Apoptosis-Inducing Factor (AIF) Neurons, and perhaps other cells, have another way to self-destruct that - unlike the two paths described above - does not use caspases. Apoptosis-inducing factor (AIF) is a protein that is normally located in the intermembrane space of mitochondria. When the cell receives a signal telling it that it is time to die, AIF is released from the mitochondria (like the release of cytochrome c in the first pathway) migrates into the nucleus binds to DNA, which triggers the destruction of the DNA and cell death. Apoptosis and Cancer Some cancer-causing viruses use tricks to prevent apoptosis of the cells they have transformed. Several human papilloma viruses (HPV) have been implicated in causing cervical cancer. One of them produces a protein (E6) that binds and inactivates the apoptosis promoter p53. Epstein-Barr Virus (EBV), the cause of mononucleosis and a cause of Burkitt's lymphoma produces a protein similar to Bcl-2 produces another protein that causes the cell to increase its own production of Bcl-2. Both these actions make the cell more resistant to apoptosis (thus enabling the cancer cell to continue to proliferate). Even cancer cells produced without the participation of viruses may have tricks to avoid apoptosis. Some B-cell leukemias and lymphomas express high levels of Bcl-2, thus blocking apoptotic signals they may receive. The high levels result from a translocation of the BCL-2 gene into an enhancer region for antibody production. [Discussion]. Melanoma (the most dangerous type of skin cancer) cells avoid apoptosis by inhibiting the expression of the gene encoding Apaf-1. Some cancer cells, especially lung and colon cancer cells, secrete elevated levels of a soluble "decoy" molecule that binds to FasL, plugging it up so it cannot bind Fas. Thus, cytotoxic T cells (CTL) cannot kill the cancer cells by the mechanism shown above. Other cancer cells express high levels of FasL, and can kill any cytotoxic T cells (CTL) that try to kill them because CTL also express Fas (but are protected from their own FasL). Apoptosis and AIDS The hallmark of AIDS (acquired immunodeficiency syndrome) is the decline in the number of the patient's CD4+ T cells (normally about 1000 per microliter (µl) of blood). CD4+ T cells are responsible, directly or indirectly (as helper cells), for all immune responses. When their number declines below about 200 per µl, the patient is no longer able to mount effective immune responses and begins to suffer a series of dangerous infections. What causes the disappearance of CD4+ T cells? HIV (human immunodeficiency virus) invades CD4+ and one might assume that it this infection by HIV that causes the great dying-off of CD4+ T cells. However, that appears not to the main culprit. Fewer than 1 in 100,000 CD4+ T cells in the blood of AIDS patients are actually infected with the virus. So what kills so many uninfected CD4+ cells? The answer is clear: apoptosis. The mechanism is not clear. There are several possibilities. One of them: All T cells, both infected and uninfected, express Fas. Expression of a HIV gene (called Nef) in a HIV-infected cell causes the cell to express high levels of FasL at its surface while preventing an interaction with its own Fas from causing it to self-destruct. However, when the infected T cell encounters an uninfected one (e.g. in a lymph node), the interaction of FasL with Fas on the uninfected cell kills it by apoptosis. Apoptosis and Organ Transplants For many years it has been known that certain parts of the body the anterior chamber of the eye the testes are "immunologically privileged sites". Antigens within these sites fail to elicit an immune response. It turns out that cells in these sites differ from the other cells of the body in that they express high levels of FasL at all times. Thus antigen-reactive T cells, which express Fas, would be killed when they enter these sites.
This finding raises the possibility of a new way of preventing graft rejection. If at least some of the cells on a transplanted kidney, liver, heart, etc. could be made to express high levels of FasL, that might protect the graft from attack by the T cells of the host's cell-mediated immune system. If so, then the present need for treatment with immunosuppressive drugs for the rest of the transplant recipient's life would be reduced or eliminated. So far, the results in animal experiments have been mixed. Allografts engineered to express FasL have shown increased survival for kidneys but not for hearts or islets of Langerhans.
