Podcast
Questions and Answers
In T lymphocytes subjected to strong negative selection, the resulting apoptosis is most directly mediated by which of the following?
In T lymphocytes subjected to strong negative selection, the resulting apoptosis is most directly mediated by which of the following?
- Direct activation of caspase-8, independent of mitochondrial involvement.
- Increased expression of Fas ligand (FasL) on the T lymphocyte surface.
- Leakage of cytochrome c from the mitochondria, leading to caspase-9 activation. (correct)
- Activation of the Fas-FasL (CD95/APO-1) pathway and DISC formation.
The Fas-FasL pathway mediates apoptosis in T cells through the activation of a death-inducing signaling complex (DISC). Which component is critical for DISC formation and direct activation of caspase-8?
The Fas-FasL pathway mediates apoptosis in T cells through the activation of a death-inducing signaling complex (DISC). Which component is critical for DISC formation and direct activation of caspase-8?
- Cytochrome c released from the mitochondria.
- Bcl-2 family proteins regulating mitochondrial membrane permeability.
- Apoptotic protease activating factor 1 (Apaf-1).
- Fas-associated protein with death domain (FADD). (correct)
A researcher is investigating the time course of apoptosis in T cells. Which of the following observations would best distinguish between Fas-mediated and mitochondrial-dependent apoptosis?
A researcher is investigating the time course of apoptosis in T cells. Which of the following observations would best distinguish between Fas-mediated and mitochondrial-dependent apoptosis?
- The presence or absence of caspase-3 activation.
- The time required for cell removal, with Fas-mediated apoptosis being faster. (correct)
- The rate at which DNA fragmentation occurs.
- Whether the process is accompanied by cellular swelling or shrinkage.
In the context of lymphocyte regulation, what is the primary role of FasL expressed on the surface of stromal cells in various tissues?
In the context of lymphocyte regulation, what is the primary role of FasL expressed on the surface of stromal cells in various tissues?
Unlike Fas-mediated apoptosis, mitochondrial-dependent apoptosis involves an intrinsic pathway initiated by intracellular signals. Which cellular event is a critical step unique to this pathway?
Unlike Fas-mediated apoptosis, mitochondrial-dependent apoptosis involves an intrinsic pathway initiated by intracellular signals. Which cellular event is a critical step unique to this pathway?
A researcher discovers a novel compound that inhibits the interaction between cytochrome c and Apaf-1. What direct effect would this compound have on mitochondrial-dependent apoptosis?
A researcher discovers a novel compound that inhibits the interaction between cytochrome c and Apaf-1. What direct effect would this compound have on mitochondrial-dependent apoptosis?
A patient with ALPS is found to have a mutation affecting the intracellular domain of the Fas receptor. How does this mutation most directly contribute to the disease's immunological manifestations?
A patient with ALPS is found to have a mutation affecting the intracellular domain of the Fas receptor. How does this mutation most directly contribute to the disease's immunological manifestations?
A clinician is evaluating a patient suspected of having ALPS. Which laboratory finding would be most indicative of defective Fas-mediated apoptosis in this patient?
A clinician is evaluating a patient suspected of having ALPS. Which laboratory finding would be most indicative of defective Fas-mediated apoptosis in this patient?
Which of the following best describes the rationale for using IVIG to treat autoimmune cytopenias in ALPS patients?
Which of the following best describes the rationale for using IVIG to treat autoimmune cytopenias in ALPS patients?
A researcher aims to develop a targeted therapy for ALPS that specifically enhances Fas-mediated apoptosis in autoreactive lymphocytes. Which approach would be the most promising?
A researcher aims to develop a targeted therapy for ALPS that specifically enhances Fas-mediated apoptosis in autoreactive lymphocytes. Which approach would be the most promising?
Flashcards
Apoptosis
Apoptosis
A programmed cell death mechanism essential for removing unnecessary or potentially harmful cells in multicellular organisms.
Caspases
Caspases
A family of proteases that execute apoptosis by cleaving specific cellular substrates.
Activation-Induced Cell Death (AICD)
Activation-Induced Cell Death (AICD)
TCR mediated apoptosis, caused by self-antigen stimulation, which leads to increased Fas and FasL expression and caspase activation and subsequent apoptosis.
Fas (CD95/APO-1)
Fas (CD95/APO-1)
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Fas Ligand (FasL)
Fas Ligand (FasL)
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Mitochondrial-Dependent Apoptosis
Mitochondrial-Dependent Apoptosis
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Cytochrome c
Cytochrome c
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Fas-Mediated Apoptosis
Fas-Mediated Apoptosis
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Autoimmune Lymphoproliferative Syndrome (ALPS)
Autoimmune Lymphoproliferative Syndrome (ALPS)
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Study Notes
- Cell death is an important part of lymphocyte development and removes potentially harmful cells.
- Apoptosis occurs in multicellular organisms and helps with shaping and forming the body.
- Apoptosis involves the activation of caspases, a specialized set of proteases.
- Every cell produces caspase, suggesting every cell has the potential to initiate apoptosis.
- Most TCR-mediated apoptosis is facilitated by the Fas-FasL pathway outside the thymus.
- Self-antigen stimulation leads to T cell proliferation and production of IL-2.
- Fas and Fas ligand expression increases upon activation.
- When Fas binds to FasL, FADD is recruited, allowing recruitment of pro-caspase-8, then active caspase-8.
- Activation-induced cell death (AICD) leads to the Fas-facilitated death of T cells, resulting in cytochrome c release and caspase-3 activation.
- Active caspase-3 results in apoptosis.
- T cells can be deleted through a pathway that does not activate pro-caspase-8.
- A strong negative selecting signal induces the mitochondrial-dependent apoptotic pathway.
- Cytochrome c leaks from the mitochondria and binds to Apaf-1.
- Caspase-9 is activated, leading to active caspase-3 and apoptosis.
- Cell death induced by Fas-FasL occurs rapidly, leading to cell removal in 2-4 hours.
- Negative selection and mitochondrial-dependent apoptosis take 8-10 hours.
- Repeated interactions with cell antigens and failure to generate a non-self-reactive lymphocyte receptor lead to apoptosis activation.
- FasL is predominantly expressed by activated T cells and NK cells.
- FasL expression by stroll cells leads to the death of Fas-positive cells.
Fas-Mediated (Extrinsic) Apoptosis Pathway
- Triggered by the binding of FasL to the Fas receptor on the cell surface.
- FasL is expressed by cytotoxic T cells and NK cells.
- Fas activation leads to the formation of the DISC on the cell membrane.
- Caspase-8 is activated within the DISC, activating downstream executioner caspases like caspase-3.
- Activated caspases cleave cellular substrates, leading to the morphological changes of apoptosis.
- Crucial for immune homeostasis and eliminating activated or potentially harmful immune cells.
- Plays a role in immune cell regulation and eliminating target cells recognized by the immune system.
- Activation occurs at the cell surface.
- Can be rapidly induced upon immune recognition or activation
Mitochondrial-Dependent (Intrinsic) Apoptosis Pathway
- Cellular stresses trigger the release of pro-apoptotic proteins from the mitochondria.
- Mitochondrial outer membrane permeabilization (MOMP) leads to the release of cytochrome c.
- Cytochrome c activates caspase-9 within the apoptosome complex.
- Caspase-9 activates downstream caspases, including caspase-3.
- Involved in eliminating damaged or stressed cells, preventing their transformation into cancer cells.
- Plays a role in tissue homeostasis and immune cell development.
- Key events occur within mitochondria, including the release of pro-apoptotic proteins.
- Bcl-2 family proteins regulate the permeability of the mitochondrial outer membrane.
ALPS (Autoimmune Lymphoproliferative Syndrome)
- Often associated with mutations in the FAS gene, impairing Fas receptor function.
- Fas is crucial for inducing apoptosis in activated or autoreactive lymphocytes.
- Lymphocytes fail to undergo apoptosis properly.
- Autoreactive lymphocytes accumulate, leading to autoimmune manifestations.
- Defective Fas signaling contributes to uncontrolled lymphocyte proliferation.
- Lymphoproliferation, is a hallmark of ALPS, involves lymph nodes, spleen, and other lymphoid tissues.
- Patients may experience immunodeficiency due to the impaired elimination of infected or dysfunctional lymphocytes.
- Recurrent infections may be observed.
- Autoimmune cytopenias (e.g., autoimmune hemolytic anemia, immune thrombocytopenia) occur due to the destruction of blood cells by autoreactive lymphocytes.
- Autoimmune manifestations may affect other organs, leading to arthritis, nephritis, or skin disorders.
Clinical Signs and Symptoms of ALPS
- Enlarged lymph nodes and spleen (lymphadenopathy and splenomegaly) are common clinical findings.
- Patients may present with anemia, thrombocytopenia, or neutropenia.
- Immunodeficiency may result in recurrent bacterial or viral infections.
- Skin disorders, such as rash or eczema, may occur.
- Autoimmune arthritis or nephritis may manifest.
- Elevated lymphocyte counts, particularly of double-negative T cells (CD3+CD4-CD8-), may be observed (lymphocytosis).
- Increased risk of developing lymphomas, reflecting the dysregulation of lymphocyte survival.
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