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Questions and Answers
What type of T cell develops from a slightly weaker signal during T cell development in the thymus?
What type of T cell develops from a slightly weaker signal during T cell development in the thymus?
Which process involves programmed cell death through mitochondrial regulation?
Which process involves programmed cell death through mitochondrial regulation?
What occurs during negative selection of T cells in the thymus?
What occurs during negative selection of T cells in the thymus?
Which interaction is crucial for T cell activation according to the two signals hypothesis?
Which interaction is crucial for T cell activation according to the two signals hypothesis?
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What initiates apoptosis in the extrinsic pathway?
What initiates apoptosis in the extrinsic pathway?
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What results in anergy of mature CD4+ T cells?
What results in anergy of mature CD4+ T cells?
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Which mechanism is associated with the blockage of TCR-induced signal transduction in anergy?
Which mechanism is associated with the blockage of TCR-induced signal transduction in anergy?
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Where does clonal deletion most likely occur for double-positive T cells?
Where does clonal deletion most likely occur for double-positive T cells?
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What is the primary function of Treg cells?
What is the primary function of Treg cells?
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Which factor is NOT known to enhance Treg cell formation?
Which factor is NOT known to enhance Treg cell formation?
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What characterizes thymic Treg (tTreg) cells?
What characterizes thymic Treg (tTreg) cells?
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What is the mechanism by which CTLA-4 inhibits T cell activation?
What is the mechanism by which CTLA-4 inhibits T cell activation?
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What effect does IL-10 have in the immune response?
What effect does IL-10 have in the immune response?
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Which statement about peripheral tolerance is incorrect?
Which statement about peripheral tolerance is incorrect?
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What is the significance of the IL-2 receptor alpha chain (CD25) in Treg cells?
What is the significance of the IL-2 receptor alpha chain (CD25) in Treg cells?
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How does PD-1 receptor inhibit T cell activity?
How does PD-1 receptor inhibit T cell activity?
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What occurs when a highly self-reactive immature B cell encounters a strong signal in the bone marrow?
What occurs when a highly self-reactive immature B cell encounters a strong signal in the bone marrow?
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What is the primary cause of autoimmune diseases?
What is the primary cause of autoimmune diseases?
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How do peripheral events contribute to B cell tolerance?
How do peripheral events contribute to B cell tolerance?
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In what circumstance does receptor editing occur in B cells?
In what circumstance does receptor editing occur in B cells?
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What are chronic autoimmune diseases characterized by?
What are chronic autoimmune diseases characterized by?
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Which of the following statements about autoimmune diseases is correct?
Which of the following statements about autoimmune diseases is correct?
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Which is an example of a systemic autoimmune disease?
Which is an example of a systemic autoimmune disease?
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What role do genetic polymorphisms play in autoimmunity?
What role do genetic polymorphisms play in autoimmunity?
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Which MHC gene is associated with ankylosing spondylitis?
Which MHC gene is associated with ankylosing spondylitis?
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Which deficiency is most likely to lead to lupus-like diseases?
Which deficiency is most likely to lead to lupus-like diseases?
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What is the consequence of defects in the AIRE protein?
What is the consequence of defects in the AIRE protein?
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Which of the following variants is known to enhance TH17 function, potentially causing psoriasis?
Which of the following variants is known to enhance TH17 function, potentially causing psoriasis?
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Which gene's defect is associated with the IPEX syndrome?
Which gene's defect is associated with the IPEX syndrome?
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What role does the complement system play in autoimmunity?
What role does the complement system play in autoimmunity?
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Which condition is linked to polymorphisms in insulin that impair central tolerance?
Which condition is linked to polymorphisms in insulin that impair central tolerance?
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Which of the following is an environmental trigger for autoimmunity?
Which of the following is an environmental trigger for autoimmunity?
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What is the main function of immunological tolerance?
What is the main function of immunological tolerance?
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Which statement accurately describes central tolerance?
Which statement accurately describes central tolerance?
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What mechanism is NOT associated with central tolerance?
What mechanism is NOT associated with central tolerance?
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Which mechanism is involved in peripheral tolerance?
Which mechanism is involved in peripheral tolerance?
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What is the outcome of negative selection in central tolerance?
What is the outcome of negative selection in central tolerance?
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Which of the following is a characteristic of regulatory T (Treg) cells?
Which of the following is a characteristic of regulatory T (Treg) cells?
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How does receptor editing help maintain tolerance in B cells?
How does receptor editing help maintain tolerance in B cells?
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What role does sequestration of self-antigens play in immunological tolerance?
What role does sequestration of self-antigens play in immunological tolerance?
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Study Notes
Immunological Tolerance
- Immunological tolerance refers to the immune system's unresponsiveness to previously encountered antigens, especially self-antigens, protecting against autoimmunity.
- Tolerogens, substances that induce tolerance, play a critical role in preventing inappropriate immune responses.
Types of Tolerance
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Central Tolerance: Occurs in primary lymphoid organs (bone marrow and thymus); eliminates self-reactive immature lymphocytes.
- Mechanisms include negative selection (clonal deletion), receptor editing (in B cells only), and development of regulatory T cells (Treg).
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Peripheral Tolerance: Involves inactivation of mature lymphocytes outside of primary lymphoid organs.
- Employs apoptosis, anergy (functional inactivation), and active suppression via Treg cells.
- Sequestration of self-antigens in immune-privileged areas minimizes the risk of an immune response.
T Cell Development and Tolerance
- T cells undergo development processes in the thymus, where strong recognition of self-antigens leads to negative selection and clonal deletion.
- Treg cells develop from slightly weaker signals and play a major role in maintaining peripheral tolerance and inhibiting immune responses.
Mechanisms of Apoptosis
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Intrinsic Pathway: Involves mitochondrial regulation by proteins like Bim; leakage of cytochrome c leads to activation of caspase 9 and subsequent cell death.
- Related to central T cell tolerance where the absence of co-stimulation leads to apoptosis.
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Extrinsic Pathway: Triggered by Fas ligand binding to Fas receptor (CD95), activating caspase 8 and resulting in apoptosis.
- Linked to repeated T cell activation in the periphery.
Anergy in T Cells
- Anergy occurs when TCR recognizes an antigen without the necessary co-stimulation from innate immunity, leading to functional unresponsiveness.
- Mechanisms involves blockage of TCR signaling and attenuation of immune receptor signaling (e.g., ubiquitination via Cbl-b and activation of inhibitory receptors like CTLA-4).
Regulatory T Cells (Treg)
- Treg cells suppress immune responses and express IL-2 receptor alpha chain (CD25) and FoxP3 transcription factor, crucial for their function.
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Types of Treg:
- Thymic Treg (tTreg): Natural formation in thymus upon exposure to self-antigens.
- Peripheral Treg (pTreg): Induced in peripheral tissues upon exposure to antigens without strong innate responses.
- Factors enhancing Treg formation include IL-2, TGF-β, and retinoic acid.
Effects of Treg Cells
- Treg cells exert effects through CTLA-4, reducing B7 availability on APCs, dampening T cell responses.
- Treg cells also consume IL-2, depriving other immune cells of this growth factor.
Immunosuppressive Cytokines
- TGF-β: Inhibits macrophage activation and promotes Treg and tissue repair.
- IL-10: Targets dendritic cells and macrophages to inhibit pro-inflammatory cytokines and co-stimulatory molecules.
Summary of T Cell Tolerance
- Central tolerance involves clonal deletion of self-reactive T cells in the thymus.
- Peripheral tolerance includes Treg cell suppression, anergy, and cytokine action.
- CTLA-4 modulates co-stimulation and contributes to T cell anergy through competing with CD28.
B Cell Tolerance
- B cells achieve tolerance through events in both bone marrow and peripheral tissues.
- Strong self-reactivity leads to receptor editing or apoptosis; weak signals may result in anergy.
- Peripheral B cells need additional stimuli from TH cells or innate receptors for activation.
Autoimmunity
- Autoimmunity occurs when the immune system mistakenly targets its cells and tissues; attributed largely to breakdowns in self-tolerance.
- Autoimmune diseases can be systemic (e.g., systemic lupus erythematosus) or organ-specific (e.g., myasthenia gravis, type 1 diabetes, multiple sclerosis).
Genetic Factors in Autoimmunity
- Multiple genetic polymorphisms contribute to the susceptibility of autoimmune diseases.
- MHC Genes: Certain alleles can present self-antigens to T cells (e.g., HLA-B27 links to ankylosing spondylitis).
- Other genes like complement proteins, CD25, IL-23R, and insulin variants link to various autoimmune conditions.
Environmental Triggers
- Autoimmunity can be triggered by microbial agents influencing the immune system in genetically predisposed individuals.
- Environmental effects synergize with genetic predisposition to precipitate autoimmune diseases.
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