APOPTOSIS

BY: SAI MANOGNA (MSIWMO14)

Apoptosis or Programmed cell death. It is an induced and ordered mechanism in which the cell is actively involved in bringing about its demise. This is a crucial factor in the homeostatic control of many cell populations, including hematopoietic ones. 

1. Cells undergoing programmed cell death also show distinctive morphological changes, collectively called apoptosis.

2. These changes include a marked decrease in cell volume, cytoskeleton alteration resulting in membrane blebbing, chromatin condensation, and DNA degradation into smaller fragments.

3. Following these morphological changes, an apoptotic cell sheds tiny apoptotic bodies containing intact organs. 

Macrophages rapidly phagocytose apoptotic bodies and cells in advanced apoptosis. This ensures that their intracellular content is not released into the surrounding tissue, including proteolytic and other lytic enzymes, cationic proteins, and oxidizing molecules. Apoptosis causes no local inflammatory response. Apoptosis varies markedly from necrosis, cell death associated with an injury. In necrosis, the wounded cell swells and bursts, releasing its contents and likely causing an inflammatory response. 

Each hematopoiesis-produced leukocyte has a characteristic lifetime and then dies by programmed cell death. For example, there are around 5 ×1010 neutrophils in the circulation in adults. These cells only last a few days before programmed cell death is triggered. Together with constant neutrophil development, this death maintains a stable number of these cells. If programmed cell death fails, leukemia can develop. Also, programmed cell death plays a part in holding decent numbers of hematopoietic progenitor cells. For example, in removing colony-stimulating factors, progenitor cells undergo apoptosis. Beyond hematopoiesis, apoptosis is critical in tolerance and killing target cells by cytotoxic T cells or natural killer cells.

Regulation of Activated B-cell numbers by Apoptosis :

1. Bcl-2 levels were found to play an essential role in controlling the expected lifespan of different hematopoietic cell lines, including lymphocytes.

2. An average adult has around 5 L of blood with about 2000 lymphocytes / mm3 for around 1010 lymphocytes.

3. During acute infection, the lymphocyte count increases 4- to 15-fold, resulting in a total lymphocyte count of 40 ×50 ×109.

4. Since the immune system cannot withstand such a massive increase in cell numbers for a prolonged time, the system needs to remove excess activated lymphocytes after the antigenic threat has passed.

5. Activated lymphocytes express lower levels of Bcl-2 and are thus more vulnerable to apoptotic death induction than naive lymphocytes or memory cells.

6. However, if antigen activates the lymphocytes, then the signals obtained during activation block the apoptotic signal. As antigen levels subside, block activation and lymphocytes begin to die from apoptosis.

Several gene expressions accompany leukocyte apoptosis and other cell types. Some proteins specified by these genes are apoptosis induced; others are essential during apoptosis, while others inhibit apoptosis. For example, radiation can cause apoptosis in thymocytes, but only if the protein p53 is present; Fas signals cause many cell deaths, a molecule found on the surface of several cells, and proteases known as caspases are involved in a cascade of reactions that lead to apoptosis. By contrast, the family members of the bcl-2 (B-cell lymphoma 2) gene, bcl-2, and bcl-XL encode protein products that inhibit apoptosis. Interestingly, in studies involving non-cell death but an uncontrolled proliferation of B cells in the form of cancer called B-lymphoma. bcl-2 was recognized as the first member of this gene family. The bcl-2 gene was at the break-point of chromosomal translocation in human B-cell lymphoma. The translocation transferred the bcl-2 gene into the immunoglobulin heavy-chain locus, resulting in transcriptional activation of the bcl-2 gene and lymphoma cells overproduction of the encoded Bcl-2 protein. The resulting high Bcl-2 levels are thought to help transform lymphoid cells into cancer cells by inhibiting signals that would typically induce apoptotic cell death. 

Functions of genes and their role in apoptosis :

GenesFunctionRole in Apoptosis
bcl-2Prevents apoptosisInhibits
baxOpposes bcl-2Promotes
bcl-XL (bcl-Long)Prevents apoptosisInhibits
bcl-XS (bcl-Short)Opposes bcl-XLPromotes
CaspaseProteasePromotes
fasInduces apoptosisInitiates

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