Three Variants of Apoptotic Dysfunction
Tissue homeostasis critically depends on the balance between mitosis and cell death. There are three main scenarios of pathological alterations:
- Excessive apoptosis. Cell death outpaces proliferation, leading to the loss of functional tissue and atrophy. This mechanism is prominent in HIV infection, fulminant forms of viral hepatitis B and C, chronic myocardial ischemia, and 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). Insufficient apoptosis also leads to autoimmune diseases because "forbidden" clones of B lymphocytes producing autoantibodies persist in the body.
- Incomplete apoptosis. A specific condition 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 extracellular environment. They act as potent mitogens, stimulating the division of neighboring viable tumor cells.
Physiological Triggers and Their Failures
Cells die in response to strictly defined stimuli. If these mechanisms break down or become aberrant, pathology ensues:
- Growth factor deprivation. Without specific survival signals, the mitochondrial pathway of death is initiated. 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 in the absence of hormones, neurons upon loss of nerve growth factor, and lymphocytes without antigenic stimulation.
- DNA damage. Normally, the p53 protein arrests the cell cycle at the G1 phase, providing time for repair. If the DNA cannot be repaired, p53 activates the sensors Bax and Bak, triggering death. When p53 is mutated or absent, the cell survives, accumulates genetic defects, and undergoes malignant transformation.
- Accumulation of misfolded proteins. Mutations, aging, thermal stress, or a deficit of oxygen and glucose lead to the accumulation of improperly folded proteins in the endoplasmic reticulum (ER). ER stress and the Unfolded Protein Response (UPR) develop, culminating in the activation of caspases. This is a key mechanism in Alzheimer's, Parkinson's, and Huntington's diseases, and likely type 2 diabetes mellitus.
Role in Immunity and Clinical Significance
Apoptosis is critical for immune system function and tissue adaptation to injury:
- 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 due to obstruction. Blockage of excretory ducts causes parenchymal apoptosis. Classic examples include atrophy of the pancreas and parotid salivary glands, as well as hydronephrosis due to ureteral obstruction.
- Inflammation and immune reactions. 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 (induced by corticosteroids or during the induction of tolerance).