Model Answer
0 min readIntroduction
Immunological tolerance is the deliberate inactivation of immune responses to self-antigens, preventing the immune system from attacking the body’s own tissues. This is a crucial mechanism for maintaining homeostasis and preventing autoimmune diseases. The development of tolerance isn’t a single event but a complex process involving both central and peripheral mechanisms. Failure of these mechanisms leads to a loss of self-tolerance, resulting in the activation of self-reactive lymphocytes and subsequent autoimmune pathology. Understanding the intricacies of immunological tolerance is paramount in comprehending the pathogenesis of autoimmune disorders, which are increasingly prevalent globally.
Defining Immunological Tolerance
Immunological tolerance can be defined as the unresponsiveness of the immune system to specific antigens. This unresponsiveness can be induced in various ways, and is essential for preventing reactions against self-antigens, harmless environmental antigens, and even the commensal microbiota.
Types of Immunological Tolerance
Central Tolerance
Central tolerance occurs during lymphocyte development in the primary lymphoid organs – the thymus for T cells and the bone marrow for B cells. It involves the deletion or inactivation of self-reactive lymphocytes.
- T Cell Central Tolerance: Immature T cells (thymocytes) undergo positive and negative selection in the thymus. Positive selection ensures T cells recognize MHC molecules, while negative selection eliminates T cells that strongly bind to self-antigens presented on MHC.
- B Cell Central Tolerance: B cells that strongly bind to self-antigens in the bone marrow undergo receptor editing (changing their antigen receptor), clonal deletion (apoptosis), or become anergic (unresponsive).
Peripheral Tolerance
Peripheral tolerance operates in the secondary lymphoid organs and peripheral tissues, controlling self-reactive lymphocytes that escaped central tolerance. Several mechanisms contribute to peripheral tolerance:
- Anergy: Lymphocytes become unresponsive to antigen stimulation due to a lack of co-stimulatory signals.
- Suppression by Regulatory T cells (Tregs): Tregs (CD4+CD25+FoxP3+) actively suppress the activation and function of other lymphocytes, including self-reactive ones.
- Activation-Induced Cell Death (AICD): Repeated stimulation of lymphocytes can lead to apoptosis.
- Ignorance: Some self-antigens are sequestered in immunologically privileged sites (e.g., brain, eye) and are not readily accessible to the immune system.
Autoimmunity: Breakdown of Tolerance
Autoimmunity arises when immunological tolerance fails, leading to the immune system attacking the body’s own tissues. This can occur due to defects in central or peripheral tolerance mechanisms.
- Genetic Predisposition: Certain genes, particularly those involved in MHC and immune regulation (e.g., PTPN22, IL2RA), increase susceptibility to autoimmunity.
- Environmental Triggers: Infections, exposure to certain chemicals, and even stress can trigger autoimmunity in genetically predisposed individuals. Molecular mimicry, where microbial antigens resemble self-antigens, can initiate an autoimmune response.
- Defects in Regulatory T Cells: Dysfunction or reduced numbers of Tregs can impair peripheral tolerance, allowing self-reactive lymphocytes to become activated.
Example: Type 1 Diabetes
Type 1 Diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing beta cells in the pancreatic islets of Langerhans.
In T1D, a combination of genetic susceptibility (particularly HLA-DR3 and HLA-DR4) and environmental triggers (likely viral infections) leads to the activation of self-reactive T cells that target beta cell antigens (e.g., glutamic acid decarboxylase - GAD65). These T cells infiltrate the pancreas, causing inflammation (insulitis) and ultimately beta cell destruction. The loss of beta cells results in insulin deficiency and hyperglycemia. Peripheral tolerance mechanisms, specifically Treg function, are often impaired in individuals with T1D, contributing to the unchecked autoimmune response.
| Mechanism of Tolerance | Breakdown in Type 1 Diabetes |
|---|---|
| Central Tolerance | May be incomplete, allowing some self-reactive T cells to escape the thymus. |
| Peripheral Tolerance (Tregs) | Reduced Treg numbers or impaired function, leading to insufficient suppression of self-reactive T cells. |
| Antigen Presentation | Beta cell antigens are presented by antigen-presenting cells, activating self-reactive T cells. |
Conclusion
Immunological tolerance is a fundamental process for maintaining immune homeostasis and preventing autoimmunity. Its breakdown, whether due to genetic predisposition, environmental factors, or defects in regulatory mechanisms, can lead to the development of debilitating autoimmune diseases like Type 1 Diabetes. Further research into the mechanisms of tolerance and its regulation is crucial for developing effective therapies to prevent and treat autoimmune disorders, potentially restoring self-tolerance and halting disease progression.
Answer Length
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