What Is Apoptosis?
Apoptosis is a physiological process where the cells that are harmful to the body are eliminated.
Apoptosis refers to programmed cell death and plays a pivotal role in autoimmune diseases. Modifications of the apoptosis mechanism may lead to the development of autoantibodies leading to autoimmune diseases. If the mechanism of apoptosis is suppressed, there is an increased susceptibility of a person to develop malignancy whereas apoptosis that is uncontrolled is associated with the occurrence of degenerative disorders. Apoptosis might be associated with the pathogenesis of autoimmunity, whereas the mechanisms might be distinct in each autoimmune disease.
What Are Autoimmune Diseases?
Autoimmune diseases occur when the body’s own defense mechanism fails to differentiate between its own cells and the foreign antigen (foreign body) and mistakenly starts attacking the normal cells.
They fall under the fatal group of chronic diseases that are related to malfunctioning of the organs progressing to end-organ failure. These diseases include type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and multiple sclerosis to name a few. These diseases are characterized by T-cell-mediated autoimmune response mechanism, multifactorial etiology, and long-term therapeutic treatment. They significantly contribute to the worldwide morbidity and mortality rate.
How Does Apoptosis Cause Autoimmunity?
Apoptosis is a process of programmed cell death where too much cellular death or too little can lead to the pathology of autoimmunity. The uncontrolled self-renewal capacity of the cell is a dangerous trait to acquire, and many cases of autoimmune diseases occur through genetic mutations in the apoptosis process. The failure to achieve the process of apoptosis and the inability to clear the apoptotic cell fragments appropriately is considered the main pathogenetic factor causing autoimmunity.
The most crucial regulatory mechanisms in humans include the death receptors Fas (CD95), CD120a, caspases, mitochondria, and the Bcl-2 (B-cell lymphoma 2) family of proto-oncogenes, and tumor-suppressor gene p53. The death receptors that initiate the process of apoptosis are responsive to the cytokine family of tumor necrosis factors.
Naive T cells are activated by an antigen that results in clonal expansion of antigen-specific T cells (these cells attack the foreign particles). Most of the T cells undergo the process of apoptosis while the remaining ones differentiate into memory cells and survive. This fate of the T-cells is important since this cell destiny helps to evade the development of autoimmunity in individuals. However, few of the autoreactive T cells escape the natural phenomenon of apoptosis and act as a constant threat with the potential of developing an autoimmune response.
Massive, uncontrolled apoptosis may present multiple nucleosomes (basic structural units of DNA) to the host’s immune system thereby triggering an autoimmune reaction.
Apoptotic cells can exhibit an autoreactive antigen on their surface in turn activating the dendritic cells (a type of innate immune cells that capture, identify, process, and present antigen to the adaptive immune cells and modify them into effector cells). These dendritic cells can thereby stimulate the formation of autoantibodies.
How Is Apoptosis Linked to Systemic Lupus Erythematosus?
In systemic lupus erythematosus, autoantibodies are directed against the intracellular antigens. The nucleosomes act as potential autoantigens. Apoptosis is induced in the epithelial keratinocytes after ultraviolet rays exposure. The communication established between the uncleared apoptotic cells and dendritic cells plays a crucial role in disease pathogenesis. Defects in the mechanism of phagocytosis suggest a strong correlation between the apoptotic process and systemic lupus erythematosus.
How Is Apoptosis Linked to Rheumatoid Arthritis?
Rheumatoid arthritis is another autoimmune disorder that is characterized by defects in apoptosis. The inflammatory cell infiltration might cause destruction of the synovial lining (membrane lining the joints), resulting in an increased number of synoviocytes along with the increased secretion of inflammatory cytokines such as interleukins and tumor necrosis factor. There is increased accumulation of the T-cells which can serve as autoantigens for the autoantibodies to attack.
How Is Apoptosis Linked to Diabetes Mellitus 1?
Diabetes mellitus type 1 occurs when the person’s own immune system destroys the insulin-making cells in the pancreas. It is caused due to organ-specific autoimmune response leading to a marked loss of insulin-secreting β cells. It is a chronic destructive process. Medical literature has suggested that the insulin-secreting β-cell apoptosis might provide autoantigens that can trigger specific β-cell-directed autoimmunity.
How Is Apoptosis Linked to Sjogren’s Syndrome?
Sjogren’s syndrome is a disorder of the immune system characterized by autoimmune-mediated destruction and damage of the salivary and lacrimal glands resulting in dry mouth and dry eyes. It is suggested that defects in apoptosis usually lead to mononuclear inflammatory cell infiltration in the target tissues causing the destruction of lacrimal and salivary glands.
How Is Apoptosis Linked to Autoimmune Thyroid Disorder?
Hashimoto’s thyroiditis is an autoimmune thyroid disorder. It is characterized by progressive degeneration and destruction of the epithelial cells of the thyroid gland leading to decreased thyroid hormone production. An exceptionally low rate of apoptosis is found in a normal thyroid gland resulting in a slower biological turnover of thyrocytes. The percentage of apoptotic thyrocytes increases in Hashimoto’s thyroiditis disease. However, the percentage decreases in Graves’ disease. Graves’ disease is an autoimmune thyroid disorder characterized by excessive production of thyroid hormones.
How Is Apoptosis Linked to Multiple Sclerosis?
Multiple sclerosis is a chronic progressive demyelinating disease of the brain and spinal cord. The immune system attacks the myelin (protective membrane) that covers nerve fibers. This creates communication problems between the central nervous system and the rest of the body. Gradually the disease leads to permanent damage to the nerves. It has been suggested that the destruction of oligodendrocytes (myelinating cells of the nervous system) by the initiation of apoptosis at the inflammation site might play a role in the pathogenesis of the disease.
How to Modulate Apoptosis as a Therapeutic Approach for Autoimmune Diseases?
With recent advances in the medical field, there is an upsurge of innovative therapeutic strategies to find solutions to the management of autoimmune diseases. One such exciting project is the modulation of the apoptotic process to serve as a novel therapy for autoimmunity.
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One way is to target the molecules involved in the process of apoptosis to either prevent or induce cell death.
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Modifying the genetic signaling proteins of the apoptotic pathway can be another potential therapeutic method to regulate the mechanism of apoptosis.
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Preparing innovative drug molecules to target the apoptosis process for autoimmune disease treatment. Inhibitors of caspases are currently being tested as novel therapeutic drug molecules in rheumatoid arthritis and multiple sclerosis to prevent damage of synovial or neural cells.
Conclusion
Apoptosis is the process of programmed cell death that eliminates the unwanted cells of the body. It has been proved that apoptosis is involved in the pathogenesis of autoimmune diseases. Defects at different stages along with failure to clear the apoptotic cells are mainly responsible for the autoimmune response. But it is crucial to understand the association between apoptosis and autoimmune diseases to invent newer novel therapies that can help doctors to manage autoimmune diseases more efficiently. More research is required in this field.
