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What is immunological tolerance?
What is immunological tolerance?
Immunological tolerance is the state where the immune system does not react against an individual's own (self) antigens. This unresponsiveness to self-antigens is crucial for preventing autoimmune diseases.
Which of the following processes are involved in central tolerance?
Which of the following processes are involved in central tolerance?
What is the difference between central and peripheral tolerance?
What is the difference between central and peripheral tolerance?
What is the mechanism of negative selection in the thymus?
What is the mechanism of negative selection in the thymus?
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How do regulatory T cells contribute to peripheral tolerance?
How do regulatory T cells contribute to peripheral tolerance?
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Anergy is a state of functional inactivation of T cells, where they are unable to respond to antigen due to the lack of a costimulatory signal.
Anergy is a state of functional inactivation of T cells, where they are unable to respond to antigen due to the lack of a costimulatory signal.
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What is activation-induced cell death?
What is activation-induced cell death?
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Which of the following conditions is associated with a mutation in the FOXP3 gene?
Which of the following conditions is associated with a mutation in the FOXP3 gene?
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What is molecular mimicry in the context of autoimmune disease?
What is molecular mimicry in the context of autoimmune disease?
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How do infections contribute to the development of autoimmune diseases?
How do infections contribute to the development of autoimmune diseases?
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Study Notes
Immunology Tolerance
- Immunological tolerance describes the immune system's inability to react against its own (self) antigens. This lack of response is also known as unresponsiveness to self-antigens.
- Tolerance occurs when an immunocompetent host fails to respond to an immunogenic challenge with a specific antigen.
- Autoimmunity occurs when the immune system mistakenly attacks the body's own cells and tissues. The resulting diseases are called autoimmune diseases.
- The mechanisms preventing immune responses to self-antigens can fail, leading to the immune system attacking the body's own cells and tissues. This is autoimmunity.
Learning Outcomes
- Students should be able to define immunological tolerance.
- Students should be able to explain the mechanisms of both central and peripheral tolerance in T and B cells.
- Students should be able to discuss anergy, deletion, immune suppression, and privileged sites.
Outline
- Definition of tolerance, autoimmunity, and autoimmune diseases
- Central tolerance of T lymphocytes
- Peripheral tolerance of T lymphocytes
- Central tolerance of B lymphocytes
- Peripheral tolerance of B lymphocytes
- Pathogenesis of autoimmune diseases
Definition
- The immune system does not react against an individual's own (self) antigens. This is also known as immunological tolerance.
- Immunological tolerance occurs when an immunocompetent host fails to respond to an immunogenic challenge presented by a specific antigen.
Autoimmunity and Autoimmune Diseases
- Mechanisms exist to prevent the immune system from responding to self-antigens.
- If these mechanisms fail, the immune system may attack an individual's own cells and tissues. These reactions are called autoimmunity, and the related diseases are autoimmune diseases.
Tolerance
- Central Tolerance: Inactivation or destruction of lymphocytes during early development in bone marrow or thymus.
- Peripheral Tolerance: Inactivation or destruction of mature lymphocytes encountering self-antigens in peripheral tissues.
Central Tolerance (T and B Cells)
- Central tolerance occurs during early B cell differentiation in bone marrow and T cell differentiation in the thymus.
- B and T cells with high affinity for self-antigens undergo apoptosis (programmed cell death) during early development—a process called negative selection.
- Some self-reactive T cells develop into regulatory T cells in the thymus, while immature B cells in the bone marrow can alter their receptors.
Central T Lymphocyte Tolerance
- Immature lymphocytes strongly interacting with self-antigens displayed on MHC molecules trigger apoptosis. The cell dies before it can mature.
- Some immature CD4+ T cells recognizing self-antigens in the thymus become regulatory T cells and enter peripheral tissues rather than dying.
Peripheral T Lymphocyte Tolerance
- Mature T lymphocytes within peripheral lymphoid tissues (e.g., spleen, lymph nodes)
- This tolerance involves:
- Clonal anergy (functional inactivation)
- Clonal deletion (activation-induced cell death)
- Immune suppression, including regulatory T cells
T Cell Activation
- T cell activation requires two signals.
- Signal 1: Antigen recognition
- Signal 2: Costimulation from antigen-presenting cells (APC).
Anergy
- Functional inactivation of T lymphocytes due to antigen recognition without adequate levels of the second (co-stimulation) signal.
- Involves TCR-interaction with Ag/MHC, lack of co-stimulatory molecules (B7 reacting with CD28), and expression of inhibitory molecules (CTLA4).
Activation-Induced Cell Death
- Repeated activation of mature T lymphocytes by self-antigens leads to cell death.
- This involves co-expression of death receptors (like Fas and FasL) and production of apoptotic proteins within T cells.
Regulatory T Cells
- Regulatory T cells (CD4+/CD25+), which require a transcription factor called Foxp3 for generation and function.
- These cells mediate their function through soluble factors (IL-10, TGFβ), expressing CTLA-4, and high levels of IL-2 receptor expression.
Central B Cell Tolerance
- Elimination of B lymphocytes with high-affinity receptors for abundant self-antigens during development in bone marrow involves apoptosis and receptor editing (expressing new antigen receptors).
Peripheral B Cell Tolerance
- Mature B cells encountering self-antigens in peripheral tissues without specific T helper cells become unresponsive or undergo apoptosis.
Organ-Specific and Systemic Autoimmune Diseases
- Autoimmune diseases affecting specific organs include Graves' disease, type 1 diabetes, myasthenia gravis, autoimmune hemolytic anemia, Sjogren's syndrome, and rheumatoid arthritis.
- Systemic autoimmune diseases encompass systemic lupus erythematosus.
Pathogenesis of Autoimmune Disease
- Autoimmune diseases arise from a combination of genetic predisposition, environmental triggers, and immune dysregulation.
- Genetic factors, such as HLA genes and other non-HLA genes, play a role.
- Environmental factors, including infections, drugs, smoking, hormones, and nutrition, can be involved.
Role of Infections
- Infections may lead to immune system activation that can lead to self-reactive lymphocytes, especially:
- Molecular mimicry where microbial antigens resemble self-antigens and trigger autoimmunity.
- Damage to tissue releasing sequestered antigens.
Case Scenario
- A 9-month-old boy presents with symptoms like watery diarrhea, eczema, and below-average growth.
- Genetic analysis shows a mutation in FOXP3 (a regulatory T cell factor).
- The patient is at increased risk for autoimmune endocrinopathies (e.g., hypothyroidism by autoimmune disease of the thyroid). and a defect in T regulatory cells suggests increased risk of these problems
Conclusion
- Autoimmune diseases are associated with a breakdown of immunological self-tolerance.
- Central and peripheral tolerance mechanisms are crucial for regulating immune responses.
- Factors like genetics and environment contribute to the pathogenesis of autoimmune diseases.
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Description
Test your knowledge on immunological tolerance and its mechanisms. This quiz covers definitions, autoimmunity, and the functions of T and B cells. Understand key concepts like anergy, deletion, and immune suppression.
