Apoptosis: what is it, mechanism, anatomical pathology, clinical significance

What is apoptosis?

Apoptosis Is an ATP-dependent, enzyme-mediated, genetically programmed death of cells that are no longer needed or pose a threat to the body. Apoptosis occurs when the cytoskeleton (by proteases) and DNA (by endonucleases) is destroyed. Both are mediated by caspases.

Anatomical pathology

Dying cells undergo shrinkage due to disruption of the cell's cytoskeleton, mainly caused by caspases. The cells become deeply eosinophilic. A cell moves away from its neighbors with loss of contact between cells. The nucleus of a dying cell becomes deeply basophilic.

A hallmark of apoptosis is pycnosis, in which nuclear chromatin condenses to form one or more dark masses against the background of the nuclear envelope. Dissolution of the nuclear membrane occurs, and the endonuclease cuts the DNA into short fragments, evenly distributed in size (karyorrhexis). This condensed cytoplasm and nucleus then breaks down into fragments called apoptotic bodies, which are detached from the cell like leaves falling from trees. The macrophages then remove these apoptotic bodies in a process called eferocytosis. The cell membrane remains intact without inflammation, in contrast to necrosis, in which cell swelling and inflammation are common. Apoptotic cells are quickly removed by macrophages, while in the surrounding tissues there is practically no inflammation.

Biochemical and genetic pathology

As described above, when a cell receives stress signals from other cells, an external pathway comes into play.

- WAY TNF.

TNF-alpha is a cytokine produced by macrophages and is a major external mediator of apoptosis. Tumor necrosis factor (TNF-alpha) binds to its receptor TNFR1, which leads to the activation of caspases.

- Fas PATH.

The Fas receptor is a TNF family transmembrane protein that binds the Fas ligand (FasL). This interaction between the Fas receptor and Fas L results in the activation of the caspase.

For example, apoptosis removes activated T lymphocytes after the infection has cleared. T cells produce the surface FAS receptor. FAS production is increased during infection, and after a few days, activated T lymphocytes begin to produce the FAS ligand. The binding of FAS to the FAS ligand on the same or different cells triggers apoptosis through the activation of caspases.

- Genetic regulation of mitochondrial apoptosis and the role of cytochrome C.

When a cell is stressed from the inside out, the role of Bcl-2 family proteins comes into play, which regulate mitochondrial permeability in response to apoptotic signals.

- Bcl-2 gene family.

Located on chromosome 18, these genes are anti-apoptotic because they produce the Bcl-2 protein. Bcl-2 binds to and inhibits APAF-1, thereby preventing the release of cytochrome c from mitochondria. Cytochrome c is present between the inner and outer membranes of mitochondria. Once released, it binds to APAF-1 and activates procaspase 9.

- Suppressor gene TP53.

This gene encodes a protein that regulates the cell cycle and causes tumor suppression. If DNA is damaged, for example, by ionizing radiation, chemotherapeutic agents, or hypoxia, TP53 stops the cell in the G1 phase of the cell cycle and prevents the proliferation of cells with damaged DNA and DNA recovery. But if the DNA damage is too great, it will promote apoptosis by activating the BAX apoptosis genes. BAX gene products inactivate the BCL 2 antiapoptotic gene.

Mechanisms

In all normal tissues of multicellular organisms, cell proliferation and cell death are balanced. This normal cell death, vital for normal cell development and health, is called apoptosis and involves the following pathways. All pathways involve the activation of caspases as a final tool.

- Internal pathway (mitochondrial pathway).

It is activated when a cell is stressed from the inside out by a variety of factors, such as damage to DNA from x-rays or UV radiation; chemotherapeutic agents; hypoxia; accumulation of misfolded proteins inside the cell, as, for example, in Alzheimer's disease, Parkinson's disease or Huntington's disease; and much more. When a cell is exposed to stress, cytochrome c leaks from the intermembrane space of mitochondria into the cytosol, which leads to the activation of caspases 9. The genes of the Bcl-2 and TP53 family regulate this pathway.

- External path.

This pathway is triggered when a cell receives death signals from another cell (s). The extrinsic pathway is associated with a receptor, and ligands from other cells bind to these death receptors on the cell surface, resulting in the activation of apoptosis. This includes the following cell surface receptors and corresponding ligands, which ultimately lead to the activation of caspase 8:

• Fas receptor (CD95) activated by FasL (Fas ligand);
• TNFR activated by the cytokine TNF.

- Cytotoxic CD8 + T-cell mediated pathway.

CD8 + T cells secrete perforins, which create holes in target cells. CD8 + T cells then secrete granzymes, which enter target cells through these holes and activate caspases.

- Caspas.

Caspases are a group of protease enzymes. They are the primary effectors of the apoptotic response. They are divided into the following 2 types:

Caspase initiator.

Initiator caspases are 2,8.9.10,11,12, and effector caspases are — these are caspases 3,6,7. Caspases exist in the cell in an inactive form and require proteolytic cleavage to an active form.

Effector caspases.

Activated initiator caspases cause the activation of effector caspases. These active effector caspases cause the cleavage of several proteins in the cell, resulting in cell death and, ultimately, phagocytosis and removal of cellular debris.

Of all caspases, caspase 3 is most frequently activated, which catalyzes the cleavage of basic cellular proteins and chromatin condensation. Caspase also activates DNase enzymes that cause DNA fragmentation followed by internucleosomal fragmentation.

Clinical and pathological correlations

- During embryogenesis (for normal development).

The formation of fingers during embryogenesis in the fetus occurs by apoptosis of interdigital tissues.

Loss of Müllerian structures in a male fetus under the influence of Müller's inhibitory factor synthesized by Sertoli cells.

- During the menstrual cycle.

Detachment of the inner lining of the uterus (endometrium) after estrogen and progesterone withdrawal menstrual cycle.

— Apoptosis needed to destroy dangerous cells (for the well-being of the body).

• Cells infected with the virus: cytotoxic T cells kill virus-infected cells by apoptosis.
• Cells with DNA damage: cells whose DNA is damaged by radiation exposure or chemotherapeutic agents are delayed in the G1 phase of the cell cycle to recover by p53 activation. P53 is a tumor suppressor gene. The P53 mutation suppresses apoptosis, which leads to the survival of abnormal cells and the development of carcinomas.
• Autoreactive T cells: Autoreactive T cells in the thymus are killed by apoptosis.

- Apoptosis is essential for a healthy immune system.

Apoptosis is essential for the development and maintenance of a healthy immune system. When B and T lymphocytes are first formed, they are tested to see if they are responding to any of the body's own components. The cells that respond die as a result of apoptosis. If these cells are not removed, self-reactive cells can enter the body, which can attack tissues and cause autoimmune conditions.

Apoptosis is necessary to shut down the immune system after the causative agent of the disease is eliminated from the body; for example, removing acute inflammatory cells such as neutrophils from healing sites.

In addition, the destruction of B and T lymphocytes corticosteroids occurs by apoptosis.

- Removal of misfolded proteins.

This occurs through apoptosis; for example, amyloid, proteins in prion-related diseases.

Clinical significance

Too little or too much apoptosis can have serious clinical consequences, such as the following:

- Tumor formation.

A decrease in apoptosis leads to an increase in cell survival, which leads to the development of cancer.

1. At follicular lymphoma gene translocation occurs BCL 2 from chromosome 18 to chromosome 14. This leads to over-transcription of elevated levels BCL 2, which causes excessive inhibition of APAF-1 and thus inactivation of caspases and apoptosis, leading to follicular lymphoma.
2. A mutation or deletion of the p53 genes dramatically increases the chances of developing a tumor as cells with damaged DNA continue to divide uncontrollably. Chemicals, radiation and viruses can damage P53. Patients with Li-Fraumeni syndrome have only one functional copy of p53, so they are more likely to develop a tumor in early adulthood.

— Autoimmune diseases.

Decreased apoptosis of autoreactive immune cells can lead to the development of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE), autoimmune lymphoproliferative syndrome and others.

- Neurodegenerative diseases.

Cell death is also implicated in many neurodegenerative disorders. Both necrosis and apoptosis occur in acute neurological disease such as acute ischemic syndrome. In chronic neurodegenerative disorders, neuronal cell death mainly due to apoptosis is associated with diseases such as Parkinson's disease, Alzheimer's disease and Huntington's disease.

- Myocardial infarction.

Necrosis has long been considered the only cause myocardial infarctionbut recent studies have shown that apoptosis also occurs mainly during the reperfusion phase after acute infarction, leading to further myocardial damage.