Three types of apoptosis disorders
Tissue homeostasis critically depends on the balance between mitosis and cell death. There are three main scenarios of pathological changes:
- Excessive apoptosis. Cell death predominates over proliferation, leading to the loss of functional tissue and atrophy. This mechanism is prominently manifested in HIV infection, fulminant forms of viral hepatitis B and C, chronic myocardial ischemia, as well as neurodegenerative diseases.
- Insufficient apoptosis. Cells survive where they should normally die. This is the fundamental basis of hyperplastic processes and oncology (especially with mutations in the p53 gene and in hormone-dependent carcinomas of the ovary, breast, and prostate). Also, a lack of apoptosis leads to autoimmune diseases, as "forbidden" clones of B lymphocytes producing autoantibodies persist in the body.
- Unfinished apoptosis. A specific state characteristic of tumor growth. Due to the lack of adequate phagocytosis, apoptotic bodies undergo autolysis. Cellular oncogenes, cytokines, and growth factors are released into the environment. They act as potent mitogens, driving the division of neighboring living tumor cells.
Physiological triggers and their failures
Cells die under the action of strictly defined stimuli. If these mechanisms break down or become distorted, pathology arises:
- Growth factor deprivation. Without specific survival signals, the mitochondrial pathway of death is triggered. Pro-apoptotic proteins of the Bcl-2 family are activated, while the synthesis of protective factors (Bcl-2, Bcl-XL) drops. This is how hormone-dependent cells die without hormones, neurons upon the loss of nerve growth factor, and lymphocytes without antigenic stimulation.
- DNA damage. Normally, the p53 protein halts the cell cycle in the G1 phase, allowing time for repair. If DNA cannot be repaired, p53 activates the sensors Bax and Bak, triggering death. Upon mutation or absence of p53, the cell survives, accumulates genetic defects, and undergoes malignant transformation.
- Accumulation of misfolded proteins. Mutations, aging, thermal stress, or a deficiency of oxygen and glucose lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER). ER stress develops along with the Unfolded Protein Response, the outcome of which is the activation of caspases. This is a key mechanism of Alzheimer's, Parkinson's, Huntington's diseases, and likely type 2 diabetes mellitus.
Role in immunity and clinical significance
Apoptosis is critically important for the functioning of the immune system and tissue adaptation to damage:
- Elimination of autoreactive lymphocytes. Normally, lymphocytes capable of attacking self-antigens are destroyed. Failure of this safeguard is a direct pathway to autoimmune aggression.
- Function of cytotoxic T-lymphocytes (CTLs). They destroy infected and tumor targets, bypassing classical pathways. CTLs release granzymes (proteases that directly cleave proteins and activate caspases) or bind to death receptors via FasL.
- Atrophy upon obstruction. Obstruction of excretory ducts causes parenchymal apoptosis. Classic examples: atrophy of the pancreas and parotid salivary glands, as well as hydronephrosis upon ureteral obstruction.
- Inflammation and immune responses. Infiltrate cells die via apoptosis (lymphocytes in immune inflammation, polymorphonuclear leukocytes in purulent inflammation). Apoptosis also underlies transplant rejection and the death of cortical thymocytes (under the action of corticosteroids or the formation of tolerance).
Briefly: answers to topical questions
What morphological changes occur in the cell at different stages of apoptosis?
Morphological changes in apoptosis include cell shrinkage, chromatin condensation, and nuclear fragmentation followed by the formation of apoptotic bodies.
- Formation of apoptotic bodies — the breakup of the cell into rounded eosinophilic formations. Each body contains a nuclear fragment and a set of organelles surrounded by a double-contoured membrane.
- Phagocytosis — rapid engulfment of the formed bodies by neighboring cells and macrophages.
Which caspases are initiator and which are effector?
Caspases are divided into initiator caspases, which trigger the apoptotic process, and effector caspases, which directly destroy cellular structures.
- Initiator caspases — these include caspase 8 (activated in the receptor pathway) and caspase 9 (activated in the mitochondrial pathway).
- Effector caspases — these include caspase 3, which is activated by initiator caspases and cleaves various intracellular proteins, ensuring the degradation of cellular components.
How are Bcl-2 family proteins classified according to their effect on apoptosis?
Proteins of the Bcl-2 family are classified into two main groups depending on their effect on apoptosis: pro-apoptotic and anti-apoptotic.
- Pro-apoptotic proteins (Bid, Bax, Bak, Bcl-X_S) promote the initiation of apoptosis.
- Anti-apoptotic proteins (Bcl-2, Bcl-X_L, Mcl-1) inhibit apoptosis.
The balance between these homo- and heterodimers determines the fate of the cell.
Which death receptors participate in the extrinsic pathway of apoptosis, besides the Fas receptor?
In the extrinsic pathway of apoptosis, besides the Fas receptor, other membrane molecules of the TNFα receptor family containing an intracellular death domain participate. These include:
- TNF-R1 receptor (p55, CD120a, DR1) — interacts with the TNFα ligand.
- DR4 and DR5 receptors — bind to the specific TRAIL ligand.
- DR3 and DR6 receptors — are activated upon interaction with the TL1A ligand.
The interaction of these receptors with their trimeric ligands leads to the assembly of the DISC complex and the activation of the caspase cascade.
The acronym EIN for types of dysregulation: Excessive (leads to atrophy), Insufficient (leads to tumors and autoimmunity), Unfinished (breakdown of bodies stimulates cancer growth).
Class and exam questions
What is the role of the p53 protein in the regulation of apoptosis?
It assesses DNA integrity. Upon critical damage, p53 blocks the cell cycle and initiates apoptosis through the activation of Bax and Bak proteins, preventing the development of malignant tumors.
How do cytotoxic T-lymphocytes kill target cells?
They use granzymes, which penetrate the cell and directly activate effector caspases. An alternative option is the destruction of the target through the binding of Fas ligand (FasL) to Fas receptors.
What happens during unfinished apoptosis?
Apoptotic bodies are not engulfed by macrophages, but undergo autolysis. Growth factors, cytokines, and oncogenes are released from them, stimulating the division of neighboring tumor cells.
Why does ER stress occur?
It develops due to the accumulation of proteins with incorrect spatial structure in the endoplasmic reticulum against the background of hypoxia, aging, thermal stress, or genetic mutations.
What else to study on this topic
- Mitochondrial pathway of apoptosis and functions of the Bcl-2 protein family
- Molecular mechanisms of the Unfolded Protein Response
- Morphology of Councilman bodies in viral liver lesions
- The role of apoptosis in establishing immunological tolerance in the thymus
- Receptor pathway of apoptosis: Fas and FasL interaction
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