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Chronic Granulomatous Disease and MPO Deficiency
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Chronic Granulomatous Disease and MPO Deficiency

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Questions and Answers

What is the primary mechanism through which cytotoxic T cells induce apoptosis in target cells?

  • Secretion of perforin and granzyme (correct)
  • Activation of complement proteins
  • Binding of cytokines to surface receptors
  • Secretion of interleukin 2 and interferon gamma

    • Which of the following statements about B cell activation is NOT true?

  • B cells require antigen binding to surface immunoglobulins for activation.
  • Helper T cells provide essential second signals for B-cell activation.
  • B-cell activation leads directly to the secretion of IgG without intermediate steps. (correct)
  • Immunoglobulin rearrangements occur during B-cell maturation in the bone marrow.

    • What characterizes caseating granulomas compared to noncaseating granulomas?

  • Associated only with foreign material reactions
  • A collection of lymphocytes without histiocytes
  • Presence of necrosis in the center of the granuloma (correct)
  • Lack of epithelioid histiocytes

    • Which cytokines are secreted by helper T cells to mediate B-cell isotype switching and maturation?

    <p>IL-4 and IL-5</p> Signup and view all the answers

    What is a common etiology of noncaseating granulomas?

    <p>Sarcoidosis</p> Signup and view all the answers

    What type of cells are primarily involved in promoting chronic inflammation?

    <p>Macrophages</p> Signup and view all the answers

    Which of the following stimuli is NOT commonly associated with chronic inflammation?

    <p>Acute bacterial infection</p> Signup and view all the answers

    What is required for T cell activation besides the binding of the antigen/MHC complex?

    <p>An additional second signal from another source</p> Signup and view all the answers

    Which subset of CD4+ helper T cells is responsible for secreting cytokines that promote eosinophil activation?

    <p>TH2 subset</p> Signup and view all the answers

    The TCR complex of T cells primarily recognizes antigens presented by which molecules?

    <p>MHC molecules</p> Signup and view all the answers

    In chronic inflammation, what role do cytokines from activated CD4+ helper T cells play?

    <p>Enhancement of inflammation</p> Signup and view all the answers

    Which of the following best describes the activation process of CD8+ cytotoxic T cells?

    <p>Requires IL-2 from CD4+ TH1 cells for second activation signal</p> Signup and view all the answers

    Which cytokine secreted by the TH1 subset is crucial for activating macrophages?

    <p>IFN-γ</p> Signup and view all the answers

    What defect characterizes chronic granulomatous disease (CGD)?

    <p>NADPH oxidase defect</p> Signup and view all the answers

    What is the critical test for screening chronic granulomatous disease?

    <p>Nitroblue tetrazolium test</p> Signup and view all the answers

    Which organism is particularly associated with recurrent infections in chronic granulomatous disease?

    <p>Aspergillus</p> Signup and view all the answers

    What occurs to neutrophils after the resolution of the inflammatory stimulus?

    <p>They undergo apoptosis and disappear within 24 hours</p> Signup and view all the answers

    What is the primary function of macrophages after inflammation begins?

    <p>Predominate and manage the next step of the inflammatory process</p> Signup and view all the answers

    What distinguishes MPO deficiency in terms of infection risk?

    <p>Increased risk for Candida infections</p> Signup and view all the answers

    Which mechanism allows O2-independent killing in leukocytes?

    <p>Enzymatic activity using secondary granules</p> Signup and view all the answers

    Which of the following outcomes is NOT a result of macrophage activity during inflammation?

    <p>Immediate apoptosis after recognition of pathogens</p> Signup and view all the answers

    Cytotoxic T cells activate apoptosis through both the secretion of perforin and the expression of FasL.

    <p>True</p> Signup and view all the answers

    Immature B cells are exclusively produced in the spleen before they mature into naïve B cells.

    <p>False</p> Signup and view all the answers

    Caseating granulomas are characterized by the absence of central necrosis.

    <p>False</p> Signup and view all the answers

    The activation of B cells requires antigen binding to surface IgM or IgD along with a second signal from helper T cells.

    <p>True</p> Signup and view all the answers

    Noncaseating granulomas are solely caused by infectious agents.

    <p>False</p> Signup and view all the answers

    Chronic granulomatous disease results from a defect in NADPH oxidase, leading to poor O2-dependent killing.

    <p>True</p> Signup and view all the answers

    The nitroblue tetrazolium test turns blue if NADPH oxidase is active and can convert O2 to superoxide.

    <p>True</p> Signup and view all the answers

    MPO deficiency significantly increases the risk for infections caused by catalase-positive organisms.

    <p>False</p> Signup and view all the answers

    O2-independent killing mechanisms are generally considered more effective than O2-dependent killing mechanisms.

    <p>False</p> Signup and view all the answers

    Macrophages peak in the inflammatory response approximately 2-3 days after the onset of inflammation.

    <p>True</p> Signup and view all the answers

    Resolution of neutrophils occurs immediately after the inflammatory stimulus is resolved.

    <p>False</p> Signup and view all the answers

    IL-10 is an anti-inflammatory cytokine produced by macrophages that aids in resolution and healing.

    <p>True</p> Signup and view all the answers

    Granuloma formation in chronic granulomatous disease is mainly associated with catalase-negative organisms.

    <p>False</p> Signup and view all the answers

    CD4+ helper T cells secrete cytokines that promote chronic inflammation primarily in response to intracellular antigens.

    <p>False</p> Signup and view all the answers

    The primary role of B7 on antigen presenting cells is to bind to CD28 on CD8+ cytotoxic T cells.

    <p>False</p> Signup and view all the answers

    Chronic inflammation typically involves a delayed immune response that is more specific than acute inflammation.

    <p>True</p> Signup and view all the answers

    In chronic inflammation, the TH2 subset of CD4+ helper T cells secretes cytokines that promote the activation of macrophages.

    <p>False</p> Signup and view all the answers

    T cell activation requires the binding of the antigen/MHC complex and an additional second signal.

    <p>True</p> Signup and view all the answers

    The primary source of IL-2 during the activation of CD8+ T cells is the CD8+ cytotoxic T cell itself.

    <p>False</p> Signup and view all the answers

    MHC class II molecules present intracellular antigens processed from the cytoplasm.

    <p>False</p> Signup and view all the answers

    The presence of plasma cells is characteristic of acute inflammation, rather than chronic inflammation.

    <p>False</p> Signup and view all the answers

    Describe the role of perforin and granzyme in the mechanism of killing by cytotoxic T cells.

    <p>Perforin creates pores in the target cell membrane, allowing granzyme to enter and activate apoptosis.</p> Signup and view all the answers

    What is the significance of CD40 receptor interaction in B-cell activation?

    <p>The CD40 receptor binds to CD40L on helper T cells, providing a necessary second activation signal for B cells.</p> Signup and view all the answers

    Differentiate between caseating and noncaseating granulomas regarding their characteristics and common causes.

    <p>Caseating granulomas exhibit central necrosis and are typically seen in infections like tuberculosis, while noncaseating granulomas lack necrosis and can arise from conditions like sarcoidosis.</p> Signup and view all the answers

    Explain the role of helper T cells in B-cell maturation and isotype switching.

    <p>Helper T cells secrete IL-4 and IL-5, which mediate B-cell isotype switching and maturation to plasma cells.</p> Signup and view all the answers

    What are the hallmarks of granuloma formation, and what types of cells are primarily involved?

    <p>Granulomas are characterized by a collection of epithelioid macrophages often surrounded by giant cells and lymphocytes, indicating chronic inflammation.</p> Signup and view all the answers

    What is the impact of a NADPH oxidase defect in Chronic Granulomatous Disease (CGD)?

    <p>It leads to poor O2-dependent killing, resulting in recurrent infections and granuloma formation by catalase-positive organisms.</p> Signup and view all the answers

    How does the Nitroblue Tetrazolium (NBT) test indicate NADPH oxidase activity?

    <p>The test turns blue if NADPH oxidase can convert O2 to superoxide; if defective, it remains colorless.</p> Signup and view all the answers

    What role do macrophages play in the resolution of inflammation?

    <p>They produce anti-inflammatory cytokines like IL-10 and TGF-β, promoting healing and resolution.</p> Signup and view all the answers

    What distinguishes the infection risk associated with MPO deficiency?

    <p>It increases the risk for Candida infections, but most patients remain asymptomatic.</p> Signup and view all the answers

    Why is O2-independent killing considered less effective than O2-dependent killing?

    <p>O2-independent killing relies on enzymes in leukocyte granules, which are generally less potent than reactive oxygen species.</p> Signup and view all the answers

    What are the key steps for macrophages to infiltrate tissues during inflammation?

    <p>They undergo margination, rolling, adhesion, and transmigration to reach the inflamed site.</p> Signup and view all the answers

    In which ways can macrophages influence the outcome of inflammation?

    <p>They can promote resolution and healing, cause continued inflammation, or contribute to abscess formation.</p> Signup and view all the answers

    What characterizes the types of organisms that are notably associated with CGD?

    <p>CGD is primarily associated with recurrent infections from catalase-positive organisms such as Staphylococcus aureus and Aspergillus.</p> Signup and view all the answers

    What role do CD4+ helper T cells play in promoting chronic inflammation?

    <p>CD4+ helper T cells secrete cytokines that help sustain and amplify the inflammatory response.</p> Signup and view all the answers

    How do CD4+ T cells distinguish between different types of antigens?

    <p>CD4+ T cells use T cell receptors (TCRs) that specifically recognize antigens presented on MHC class II molecules.</p> Signup and view all the answers

    What primary signal is necessary for the activation of CD8+ cytotoxic T cells?

    <p>The primary signal required is the binding of the antigen/MHC class I complex provided by infected cells.</p> Signup and view all the answers

    What is the significance of the TH1 and TH2 subsets of CD4+ helper T cells in chronic inflammation?

    <p>TH1 cells primarily activate macrophages and promote IgG production, while TH2 cells facilitate B-cell class switching to IgE.</p> Signup and view all the answers

    Describe the importance of B7 in T cell activation.

    <p>B7 on antigen presenting cells provides a necessary second signal by binding to CD28 on CD4+ helper T cells.</p> Signup and view all the answers

    What cell type is crucial for presenting antigens to CD4+ T cells during chronic inflammation?

    <p>Antigen presenting cells (APCs), such as dendritic cells and macrophages, are crucial for this process.</p> Signup and view all the answers

    What is the connection between chronic inflammation and autoimmune diseases?

    <p>Chronic inflammation can arise from autoimmune diseases, where the immune system mistakenly attacks healthy tissue.</p> Signup and view all the answers

    Explain the role of cytokines in the activation of eosinophils during chronic inflammation.

    <p>Cytokines such as IL-5 secreted by TH2 cells promote eosinophil activation and recruitment to sites of inflammation.</p> Signup and view all the answers

    Cytotoxic T cells induce apoptosis via the secretion of ______ and granzyme.

    <p>perforin</p> Signup and view all the answers

    Immature B cells undergo immunoglobulin rearrangements to become naïve B cells that express surface ______ and IgD.

    <p>IgM</p> Signup and view all the answers

    Granulomas can be divided into ______ and caseating subtypes.

    <p>noncaseating</p> Signup and view all the answers

    B-cell activation occurs when an antigen binds to surface IgM or IgD along with a second signal from ______ T cells.

    <p>helper</p> Signup and view all the answers

    Caseating granulomas exhibit central ______ and are characteristic of infections such as tuberculosis.

    <p>necrosis</p> Signup and view all the answers

    Chronic granulomatous disease (CGD) is characterized by poor O2-dependent killing due to a defect in ______.

    <p>NADPH oxidase</p> Signup and view all the answers

    The ______ test is used to screen for chronic granulomatous disease.

    <p>nitroblue tetrazolium</p> Signup and view all the answers

    MPO deficiency results in defective conversion of H2O2 to ______.

    <p>HOCl</p> Signup and view all the answers

    Macrophages predominate after neutrophils and peak ______ days after inflammation begins.

    <p>2-3</p> Signup and view all the answers

    Chronic inflammation is characterized by the presence of ______ and plasma cells in tissue.

    <p>lymphocytes</p> Signup and view all the answers

    Neutrophils undergo apoptosis and disappear within ______ hours after resolution of the inflammatory stimulus.

    <p>24</p> Signup and view all the answers

    CD4+ helper T cells secrete ______ that promote chronic inflammation.

    <p>cytokines</p> Signup and view all the answers

    T cells use a complex known as ______ for antigen surveillance.

    <p>TCR</p> Signup and view all the answers

    O2-independent killing in leukocytes occurs via enzymes found in leukocyte secondary ______.

    <p>granules</p> Signup and view all the answers

    CD4+ T cells recognize antigens presented on ______ class II molecules.

    <p>MHC</p> Signup and view all the answers

    Macrophages manage the next step of the inflammatory process, which includes resolution and ______.

    <p>healing</p> Signup and view all the answers

    The TH1 subset of CD4+ T cells secretes ______, which activates macrophages.

    <p>IFN-γ</p> Signup and view all the answers

    The presence of ______ is characteristic of continued acute inflammation, marked by persistent pus formation.

    <p>IL-8</p> Signup and view all the answers

    The main source of ______ during the activation of CD8+ T cells is the CD4+ TH1 cell.

    <p>IL-2</p> Signup and view all the answers

    CD8+ T cells are activated by intracellular antigens presented on ______ class I molecules.

    <p>MHC</p> Signup and view all the answers

    B7 on antigen presenting cells provides a second activation signal to ______ on CD4+ helper T cells.

    <p>CD28</p> Signup and view all the answers

    Match the following components of B-cell activation with their respective processes:

    <p>Antigen binding = Triggers maturation to plasma cells CD40 receptor binding = Provides second activation signal IL-4 secretion = Mediates isotype switching MHC class II presentation = Facilitates T-cell help for B cells</p> Signup and view all the answers

    Match the following characteristics with the respective types of granulomas:

    <p>Noncaseating granulomas = Lack central necrosis and involve foreign material Caseating granulomas = Characterized by tuberculosis and fungal infections Epithelioid histiocytes = Abundant pink cytoplasm in granuloma Giant cells = Formed by fusion of macrophages in granulomas</p> Signup and view all the answers

    Match the following mechanisms used by cytotoxic T cells with their functions:

    <p>Perforin = Creates pores in target cell membrane Granzyme = Initiates apoptosis in target cells FasL expression = Bind Fas on target cells to induce apoptosis Cytokine secretion = Enhances immune response and activation</p> Signup and view all the answers

    Match the following cytokines with their roles in B-cell maturation:

    <p>IL-4 = Promotes isotype switching IL-5 = Enhances B-cell proliferation and survival CD40L = Interacts with CD40 receptor for B-cell activation IL-2 = Supports T-cell growth and activation</p> Signup and view all the answers

    Match the following types of T cells with their activating signals:

    <p>CD8+ T cells = Require antigen/MHC and costimulatory signals CD4+ T helper cells = Activated by Antigen presenting cells via MHC class II Naïve T cells = Need IL-2 for full activation and proliferation Memory T cells = Respond quickly to previously encountered antigens</p> Signup and view all the answers

    Match the following conditions with their specific characteristics:

    <p>Chronic Granulomatous Disease (CGD) = Defect in NADPH oxidase leading to poor O2-dependent killing MPO Deficiency = Defective conversion of H2O2 to HOCl, increased risk for Candida infections O2-independent Killing = Mechanism utilizing enzymes in leukocyte secondary granules Resolution of Neutrophils = Occurs within 24 hours after resolution of inflammation</p> Signup and view all the answers

    Match the following organisms with their association to chronic granulomatous disease:

    <p>Staphylococcus aureus = Catalase-positive organism leading to recurrent infections in CGD Pseudomonas cepacia = Associated with recurrent infections in CGD patients Aspergillus = Fungal organism significant in CGD infections Serratia marcescens = Catalase-positive bacterium involved in CGD-related infections</p> Signup and view all the answers

    Match the following tests with their purpose:

    <p>Nitroblue Tetrazolium (NBT) Test = Screens for NADPH oxidase activity MPO Test = Evaluates the conversion of H2O2 to HOCl Respiratory Burst Test = Measures the ability of leukocytes to produce reactive oxygen species Phagocytosis Test = Assesses the organism ingestion capabilities of leukocytes</p> Signup and view all the answers

    Match the phases of inflammation with their descriptions:

    <p>Acute Inflammation = Predominantly characterized by neutrophils at the site Chronic Inflammation = Involves macrophages and persistent cytokine production Resolution phase = Release of anti-inflammatory cytokines leading to healing Abscess Formation = Resulting from continued acute inflammation and fibrosis</p> Signup and view all the answers

    Match the following cytokines with their roles:

    <p>IL-10 = Anti-inflammatory cytokine promoting healing TGF-β = Facilitates resolution of inflammation and healing processes IL-8 = Recruits neutrophils in continued acute inflammation Fibrogenic Growth Factors = Mediates fibrosis in abscess formation</p> Signup and view all the answers

    Match the following immune cells with their primary functions:

    <p>Neutrophils = The first responders to infection Macrophages = Predominate after neutrophils and manage resolution Eosinophils = Involved in O2-independent killing of parasites Monocytes = Differentiates into macrophages and dendritic cells</p> Signup and view all the answers

    Match the following definitions with their associated processes:

    <p>Phagocytosis = Ingests and destroys pathogens by immune cells Granuloma Formation = Localized inflammatory response to persistent stimuli Opsonization = Enhances phagocytosis through antibody binding Transmigration = Movement of leukocytes from blood to tissue</p> Signup and view all the answers

    Match the following statements about macrophage activity during inflammation:

    <p>Resolution and Healing = Macrophages produce anti-inflammatory cytokines like IL-10 Continued Inflammation = IL-8 secretion leads to more neutrophil recruitment Fibrosis = Macrophages mediate the formation of fibrous tissue during healing Phagocytosis = Macrophages ingest pathogens augmented by opsonins</p> Signup and view all the answers

    Match the following types of T cells with their primary functions:

    <p>CD4+ helper T cells = Secrete cytokines that promote chronic inflammation CD8+ cytotoxic T cells = Directly kill infected or cancerous cells TH1 subset = Activates macrophages and promotes TH1 phenotype TH2 subset = Facilitates B-cell class switching to IgE</p> Signup and view all the answers

    Match the following immune responses with their characteristics:

    <p>Acute inflammation = Immediate and non-specific immune response Chronic inflammation = Delayed but more specific immune response TCR complex = Recognizes antigens presented on MHC molecules Cytokines = Mediators that influence the immune response</p> Signup and view all the answers

    Match the following cytokines with their associated functions:

    <p>IFN-γ = Activates macrophages and promotes B-cell switching to IgG IL-4 = Facilitates B-cell class switching to IgE IL-5 = Eosinophil chemotaxis and activation IL-13 = Function similar to IL-4</p> Signup and view all the answers

    Match the following antigen presentation pathways with the T cell subsets they activate:

    <p>MHC class I = Activates CD8+ cytotoxic T cells MHC class II = Activates CD4+ helper T cells Extracellular antigens = Presented on MHC class II Intracellular antigens = Presented on MHC class I</p> Signup and view all the answers

    Match the following signals in T cell activation with their sources:

    <p>Binding of antigen/MHC complex = Necessary for initial T cell activation B7 binding to CD28 = Provides the second activation signal for CD4+ T cells IL-2 from CD4+ TH1 = Provides a second activation signal for CD8+ T cells CD3 complex = Works with TCR for antigen surveillance</p> Signup and view all the answers

    Match the following stimuli of chronic inflammation with their examples:

    <p>Persistent infection = Most common cause of chronic inflammation Autoimmune disease = Self-reactive immune response leading to inflammation Foreign material = Can induce chronic inflammatory response Cancer = Some tumors provoke chronic inflammatory changes</p> Signup and view all the answers

    Match the following CD4+ T cell subset functions with their effects:

    <p>TH1 subset = Promotes TH1 phenotype and inhibits TH2 phenotype TH2 subset = Helps in B-cell class switching to IgE Cytokine secretion = Influences inflammation and immune responses Extracellular antigen processing = Leads to TH2 activation</p> Signup and view all the answers

    Match the following immune components with their roles in inflammation:

    <p>Macrophages = Present antigens and activate T cells Lymphocytes = Key players in adaptive immunity during chronic inflammation Plasma cells = Produce antibodies during the immune response CD28 = Co-stimulatory receptor on T cells for activation</p> Signup and view all the answers

    Study Notes

    Chronic Granulomatous Disease (CGD)

    • Characterized by defective O2-dependent killing.
    • Caused by a NADPH oxidase defect, which can be X-linked or autosomal recessive.
    • Results in recurrent infections and granuloma formation with catalase-positive organisms.
    • Common organisms include Staphylococcus aureus, Pseudomonas cepacia, Serratia marcescens, Nocardia, and Aspergillus.
    • Nitroblue tetrazolium (NBT) test is used for screening. Leukocytes turn blue when NADPH oxidase converts O2 to O2-, but remain colorless if NADPH oxidase is defective.

    Myeloperoxidase (MPO) Deficiency

    • Defective conversion of H2O2 to HOCl.
    • Increased risk of Candida infections, but most patients are asymptomatic.
    • NBT test is normal, indicating that the respiratory burst (O2 to H2O2) is intact.

    O2-Independent Killing

    • Less effective than O2-dependent killing.
    • Occurs via enzymes in leukocyte secondary granules, such as lysozyme in macrophages and major basic protein in eosinophils.

    Resolution of Inflammation

    • Neutrophils undergo apoptosis and disappear within 24 hours after the inflammatory stimulus resolves.

    Macrophages

    • Predominate after neutrophils, peaking 2-3 days after inflammation begins.
    • Derived from monocytes in the blood.
    • Arrive in tissue via margination, rolling, adhesion, and transmigration.
    • Ingest organisms via phagocytosis (enhanced by opsonins) and destroy phagocytosed material using enzymes in secondary granules (O2-independent killing).
    • Manage the next stage of the inflammatory process with the following outcomes:
      • Resolution and healing: Anti-inflammatory cytokines (IL-10 and TGF-β) are produced by macrophages.
      • Continued acute inflammation: Marked by persistent pus formation; IL-8 from macrophages recruits additional neutrophils.
      • Abscess: Acute inflammation surrounded by fibrosis; macrophages mediate fibrosis via fibrogenic growth factors and cytokines.
      • Chronic inflammation: Macrophages present antigen to activate CD4+ helper T cells, which secrete cytokines that promote chronic inflammation.

    Chronic Inflammation

    • Characterized by the presence of lymphocytes and plasma cells in the tissue.
    • Delayed response, but more specific (adaptive immunity) than acute inflammation.
    • Stimuli include:
      • Persistent infection (most common)
      • Viral, mycobacterial, parasitic, and fungal infections
      • Autoimmune disease
      • Foreign material
      • Some cancers

    T Lymphocytes

    • Originate in bone marrow as progenitor T cells.
    • Develop in the thymus, where the T cell receptor (TCR) undergoes rearrangement and progenitor cells become CD4+ helper T cells or CD8+ cytotoxic T cells.
    • T cells use TCR complex (TCR and CD3) for antigen surveillance.
    • TCR complex recognizes antigen presented on MHC molecules:
      • CD4+ T cells recognize MHC Class II
      • CD8+ T cells recognize MHC Class I
    • T cell activation requires:
      • Binding of antigen/MHC complex
      • A second signal

    CD4+ Helper T Cell Activation

    • Extracellular antigen is phagocytosed, processed, and presented on MHC Class II, which is expressed by antigen-presenting cells (APCs).
    • B7 on APC binds CD28 on CD4+ helper T cells, providing the second activation signal.
    • Activated CD4+ helper T cells secrete cytokines that "help" inflammation and are divided into two subsets:
      • TH1 subset: Secretes IFN-γ, which activates macrophages, promotes B-cell class switching from IgM to IgG, promotes TH1 phenotype, and inhibits TH2 phenotype.
      • T H 2 subset: Secretes IL-4, which facilitates B-cell class switching to IgE; IL-5, which promotes eosinophil chemotaxis and activation and class switching to IgA; and IL-13, which functions similar to IL-4.

    CD8+ Cytotoxic T Cell Activation

    • Intracellular antigen (derived from proteins in the cytoplasm) is processed and presented on MHC Class I, which is expressed by all nucleated cells and platelets.
    • IL-2 from CD4+ TH1 cell provides the second activation signal.
    • Cytotoxic T cells are activated for killing.
    • Killing occurs via:
      • Secretion of perforin and granzyme: Perforin creates pores that allow granzyme to enter the target cell, activating apoptosis.
      • Expression of FasL, which binds Fas on target cells, activating apoptosis.

    B Lymphocytes

    • Immature B cells are produced in bone marrow and undergo immunoglobulin rearrangements to become naive B cells, which express surface IgM and IgD.
    • B-cell activation occurs via:
      • Antigen binding by surface IgM or IgD, resulting in maturation to IgM- or IgD-secreting plasma cells.
      • B-cell antigen presentation to CD4+ helper T cells via MHC Class II:
        • CD40 receptor on B cell binds CD40L on helper T cell, providing the second activation signal.
        • Helper T cell then secretes IL-4 and IL-5, mediating B-cell isotype switching, hypermutation, and maturation to plasma cells.

    Granulomatous Inflammation

    • A subtype of chronic inflammation.
    • Characterized by a granuloma, which is a collection of epithelioid histiocytes (macrophages with abundant pink cytoplasm) usually surrounded by giant cells and a rim of lymphocytes.
    • Divided into noncaseating and caseating subtypes:
      • Noncaseating granulomas: Lack central necrosis. Common etiologies include reaction to foreign material, sarcoidosis, beryllium exposure, Crohn disease, and cat scratch disease.
      • Caseating granulomas: Exhibit central necrosis and are characteristic of tuberculosis and fungal infections.
    • Steps involved in granuloma formation:
      • Macrophages ingest the offending agent.
      • Macrophages activate and differentiate into epithelioid histiocytes.
      • T cells (particularly CD4+ TH1 cells) are recruited and release cytokines (e.g., IFN-γ) that further activate macrophages and contribute to granuloma formation.
      • Giant cells, multinucleated cells formed by fusion of macrophages, may form at the center of the granuloma.

    Chronic Granulomatous Disease (CGD)

    • A deficiency in NADPH oxidase, causing impaired oxygen-dependent killing of pathogens
    • Inherited in an X-linked or autosomal recessive pattern
    • Leads to recurrent infections primarily with catalase-positive organisms like Staphylococcus aureus, Pseudomonas cepacia, Serratia marcescens, Nocardia, and Aspergillus
    • Diagnosis is confirmed using the Nitroblue tetrazolium (NBT) test:
      • Leukocytes incubated with NBT dye turn blue if NADPH oxidase is functional
      • Dye remains colorless if NADPH oxidase is deficient

    Myeloperoxidase Deficiency (MPO Deficiency)

    • Impaired conversion of hydrogen peroxide (H2O2) to hypochlorous acid (HOCl) due to MPO deficiency
    • Increased susceptibility to Candida infections, but many patients remain asymptomatic
    • NBT test is normal as the respiratory burst (O2 to H2O2) remains intact

    Oxygen-Independent Killing

    • Less efficient than oxygen-dependent killing
    • Mediated by enzymes present in leukocyte secondary granules like lysozyme in macrophages and major basic protein in eosinophils

    Neutrophil Apoptosis

    • Neutrophils undergo apoptosis and disappear within 24 hours following the resolution of the inflammatory stimulus

    Macrophage Role in Inflammation

    • Macrophages peak 2-3 days after inflammation begins, replacing neutrophils
    • Derived from blood monocytes
    • Migrate to tissue via margination, rolling, adhesion, and transmigration
    • Phagocytize organisms and destroy phagocytosed material using enzymes in secondary granules (oxygen-independent killing)
    • Determine subsequent inflammatory outcomes:
      • Resolution and healing: Release anti-inflammatory cytokines (IL-10 and TGF-β)
      • Continued acute inflammation: Persistent pus formation, with IL-8 recruitment of neutrophils
      • Abscess: Localized acute inflammation surrounded by fibrosis, mediated by macrophages via fibrogenic growth factors and cytokines
      • Chronic inflammation: Macrophages present antigen to activate CD4+ helper T cells, leading to chronic inflammation

    Chronic Inflammation

    • Characterized by the presence of lymphocytes and plasma cells in the tissue
    • Adaptive (specific) immune response, slower than acute inflammation

    Stimuli for Chronic Inflammation

    • Persistent infections (most common)
    • Viral, mycobacterial, parasitic, and fungal infections
    • Autoimmune disorders
    • Foreign materials
    • Certain cancers

    T Lymphocytes in Immune Response

    • Bone marrow-derived progenitors develop further in the thymus
    • Thymic maturation involves TCR rearrangement, leading to CD4+ helper T cells or CD8+ cytotoxic T cells
    • TCR complex (TCR and CD3) recognizes antigen presented on MHC molecules:
      • CD4+ T cells recognize MHC class II
      • CD8+ T cells recognize MHC class I
    • T cell activation requires antigen/MHC complex binding and a 2nd signal

    CD4+ Helper T Cell Activation

    • Extracellular antigen is presented on MHC class II by antigen-presenting cells (APCs)
    • B7 on APC binds CD28 on CD4+ helper T cells, providing the 2nd activation signal
    • Activated CD4+ helper T cells secrete cytokines and are divided into subsets:
      • TH1 subset: Secretes IFN-γ, activating macrophages, promoting B-cell class switching to IgG, favoring TH1 phenotype and inhibiting TH2 phenotype
      • TH2 subset: Secretes IL-4 (facilitates B-cell class switching to IgE), IL-5 (eosinophil chemotaxis and activation, class switching to IgA), and IL-13 (function similar to IL-4)

    CD8+ Cytotoxic T Cell Activation

    • Intracellular antigen is presented on MHC class I, expressed by all nucleated cells and platelets
    • IL-2 from CD4+ TH1 cells provides the 2nd activation signal
    • Activated cytotoxic T cells kill target cells via:
      • Secretion of perforin and granzyme: Perforin creates pores allowing granzyme to enter the target cell, triggering apoptosis
      • Expression of FasL, which binds Fas on target cells, inducing apoptosis

    B Lymphocytes in Immune Response

    • Immature B cells are produced in the bone marrow and undergo immunoglobulin rearrangements to become naïve B cells expressing surface IgM and IgD
    • B-cell activation involves:
      • Antigen binding by surface IgM or IgD, leading to maturation into IgM- or IgD-secreting plasma cells
      • B-cell antigen presentation to CD4+ helper T cells via MHC class II:
        • CD40 receptor on B cell binds CD40L on helper T cell, serving as the 2nd activation signal
        • Helper T cells secrete IL-4 and IL-5, mediating B-cell isotype switching, hypermutation, and maturation into plasma cells

    Granulomatous Inflammation

    • A subtype of chronic inflammation
    • Characterized by granuloma formation, a collection of epithelioid histiocytes (macrophages with abundant pink cytoplasm) usually surrounded by giant cells and a rim of lymphocytes
    • Classified into noncaseating and caseating types:
      • Noncaseating granulomas lack central necrosis. Common causes: reaction to foreign material, sarcoidosis, beryllium exposure, Crohn disease, and cat scratch disease
      • Caseating granulomas exhibit central necrosis and are characteristic of tuberculosis and fungal infections

    Granuloma Formation

    • Involves a multi-step process:
      • Macrophage activation by various stimuli
      • Aggregation of activated macrophages creating epithelioid histiocytes
      • Formation of giant cells by fusion of macrophages
      • Surrounding lymphocyte rim
      • Potential central necrosis depending on the cause

    Fundamental of Pathology: Acute Inflammation

    • Neutrophils are the first responders to acute inflammation and peak within 6-24 hours
    • Margination refers to the neutrophils adhering to the endothelium of blood vessels
    • Rolling involves neutrophils loosely attaching to the endothelium
    • Adhesion is the firm attachment of neutrophils to the endothelium
    • Transmigration is the process of neutrophils passing through the endothelial wall and into the extra-vascular space
    • Neutrophils are effective at phagocytosis of microorganisms
    • O2-dependent killing involves the creation of reactive oxygen species, such as superoxide, by leukocytes
    • Superoxide is produced by NADPH oxidase
    • Hydrogen peroxide is created from superoxide by superoxide dismutase
    • Hypochlorous acid, a potent oxidant, is created from hydrogen peroxide by myeloperoxidase (MPO)
    • Defective NADPH oxidase causes Chronic granulomatous disease (CGD)
    • People with CGD have recurrent infections and granuloma formation with catalase-positive organisms
    • The nitroblue tetrazolium test is used to screen for CGD
    • Defective MPO causes MPO deficiency
    • People with MPO deficiency have increased risk of Candida infections
    • O2-independent killing relies on enzymes found in leukocyte secondary granules, like lysozyme and major basic protein

    Resolution

    • Neutrophils undergo apoptosis and disappear within 24 hours after the resolution of inflammatory stimulus

    Macrophages

    • Macrophages are the dominant cell type after neutrophils
    • They arrive in tissue via the same steps as neutrophils
    • Macrophages ingest organisms via phagocytosis and destroy them using enzymes found in their secondary granules
    • They manage the next step in the inflammatory process
    • Resolution and healing includes the production of anti-inflammatory cytokines, such as IL-10 and TGF-β
    • Continued Acute Inflammation is marked by persistent pus formation, with IL-8 from macrophages recruiting more neutrophils
    • An abscess is acute inflammation surrounded by fibrosis
    • Chronic inflammation is initiated by macrophages presenting antigen to T-helper cells

    Chronic Inflammation

    • Characterized by the presence of lymphocytes and plasma cells in tissue
    • It is a more specific response than acute inflammation
    • Chronic inflammation is often caused by persistent infections
    • Other causes include infections with viruses, mycobacteria, parasites, fungi, autoimmune disease, foreign material and some cancers

    T Lymphocytes

    • Produced in the bone marrow as progenitor T cells
    • T cells further develop in the thymus, where their T-cell receptors (TCR) undergo rearrangement
    • TCR consists of TCR complex and CD3
    • TCR complex recognizes antigen presented on MHC molecules
    • CD4+ T cells recognize antigens presented on MHC class II
    • CD8+ T cells recognize antigens presented on MHC class I
    • The activation of T cells requires binding of the antigen/ MHC complex and a second signal
    • CD4+ helper T cells are activated by presentation of antigen/MHC class II complex on antigen-presenting cells (APCs)
    • CD4+ Helper T cells can be divided into TH1 and TH2 subsets
    • TH1 subset secretes IFN-γ, which activates macrophages and promotes class switching to IgG
    • TH2 subset secretes IL-4, IL-5 and IL-13
    • IL-4 facilitates class switching to IgE
    • IL-5 promotes eosinophil chemotaxis and activation
    • IL-13 has similar functions to IL-4
    • CD8+ cytotoxic T cells are activated by presentation of antigen/MHC Class I complex by any nucleated cell
    • CD8+ cytotoxic T cells require binding of antigen/MHC complex and a second signal
    • Killing by cytotoxic T cells occurs via secretion of perforin and granzyme, or by expression of FassL
    • Perforin creates pores in target cell, allowing granzyme to enter
    • Granzyme activates apoptosis
    • FasL binds to Fas on target cells, activating apoptosis

    B Lymphocytes

    • Immature B cells are produced in the bone marrow and undergo immunoglobulin rearrangements to become naïve B cells
    • Naïve B cells express surface IgM and IgD
    • B cell activation requires antigen binding by surface IgM or IgD
    • B cells can present antigen to CD4+ helper T cells via MHC class II
    • CD40 receptor on B cells binds to CD40L on helper T cells, providing the second activation signal
    • The helper T cell secretes IL-4 and IL-5, which mediate B-cell hypermutation and maturation to plasma cells

    Granulomatous Inflammation

    • A subtype of chronic inflammation
    • Characterized by granuloma- a collection of epithelioid histiocytes, usually surrounded by giant cells and a rim of lymphocytes
    • Divided into noncaseating and caseating subtypes
    • Noncaseating granulomas lack central necrosis, common causes include reaction to foreign material, sarcoidosis, beryllium exposure, Crohn disease, and cat scratch disease
    • Caseating granulomas exhibit central necrosis, characteristic of tuberculosis and fungal infections
    • Granuloma formation involves an inflammatory response, macrophage activation, and T cell activation.

    Chronic Granulomatous Disease (CGD)

    • Characterized by impaired oxygen-dependent killing of pathogens due to defective NADPH oxidase
    • This defect is inherited either X-linked or autosomal recessive
    • Leads to recurrent infections with catalase-positive organisms, including Staphylococcus aureus, Pseudomonas cepacia, Serratia marcescens, Nocardia, and Aspergillus
    • Nitroblue tetrazolium (NBT) test is used to screen for CGD. Leukocytes turn blue if NADPH oxidase is functional because it converts oxygen to superoxide, but remain colorless when defective.

    Myeloperoxidase Deficiency

    • Results in defective conversion of hydrogen peroxide to hypochlorous acid by myeloperoxidase
    • Increases risk for Candida infections, but most individuals are asymptomatic.
    • NBT test results are normal as respiratory burst is intact (oxygen to hydrogen peroxide).

    Oxygen-Independent Killing

    • Less effective than oxygen-dependent killing
    • Mediated by enzymes present in leukocyte secondary granules. Examples include lysozyme in macrophages and major basic protein in eosinophils.

    Neutrophil Apoptosis

    • Neutrophils undergo apoptosis and disappear within 24 hours after the inflammatory stimulus resolves.

    Macrophages

    • Predominant cell type 2-3 days after inflammation begins
    • Derived from monocytes in the blood
    • Migrate to tissue via a process of margination, rolling, adhesion, and transmigration
    • Phagocytize organisms and destroy them using enzymes in secondary granules (oxygen-independent killing)
    • Manage the next step of inflammatory resolution, leading to:
      • Resolution and healing - Anti-inflammatory cytokines (IL-10 and TGF-β) are produced.
      • Continued acute inflammation - IL-8 attracts more neutrophils.
      • Abscess - Acute inflammation surrounded by fibrous tissue, with macrophages mediating fibrosis.
      • Chronic inflammation - Macrophages present antigens to activate CD4+ helper T cells, leading to chronic inflammation.

    Chronic Inflammation

    • Characterized by lymphocytes and plasma cells in the tissue
    • Slower but more specific immune response compared to acute inflammation
    • Stimuli include:
      • Persistent infections
      • Infections with viruses, mycobacteria, parasites, and fungi
      • Autoimmune diseases
      • Foreign materials
      • Some cancers

    T lymphocytes

    • Originate in bone marrow as progenitor cells
    • Mature in the thymus where their T-cell receptor undergoes rearrangement, resulting in CD4+ helper T cells and CD8+ cytotoxic T cells.
    • T cells use TCR complex (TCR and CD3) to detect antigens
    • TCR complex recognizes antigens presented on MHC molecules:
      • CD4+ T cells recognize MHC class II
      • CD8+ T cells recognize MHC class I.
    • Activation of T cells requires:
      • Binding of antigen/MHC complex
      • A second signal

    CD4+ Helper T-Cell Activation

    • Extracellular antigens are phagocytosed, processed, and presented on MHC class II by antigen-presenting cells (APCs).
    • B7 on APCs binds to CD28 on CD4+ helper T cells, providing the second activation signal.
    • Activated CD4+ helper T cells secrete cytokines, further stimulating inflammation. These cells are categorized as:
    • TH1 subset secretes IFN-γ (activates macrophages, promotes IgG antibody production, promotes TH1 phenotype, inhibits TH2 phenotype).
    • TH2 subset secretes IL-4 (promotes IgE antibody production), IL-5 (eosinophil chemotaxis and activation, promotes IgA antibody production), and IL-13 (functions similar to IL-4).

    CD8+ Cytotoxic T-Cell Activation

    • Intracellular antigens are processed and presented on MHC class I, expressed by all nucleated cells and platelets.
    • IL-2 secreted by CD4+ TH1 cells provides the second activation signal.
    • Activated cytotoxic T cells kill target cells via:
      • Secretion of perforin and granzyme: perforin creates pores, enabling granzyme entry and apoptosis.
      • Expression of FasL, which binds to Fas receptors on target cells, inducing apoptosis.

    B Lymphocytes

    • Immature B cells produced in bone marrow undergo immunoglobulin rearrangements to become naive B cells that express surface IgM and IgD.
    • Activation of B cells occurs through:
      • Antigen binding by surface IgM or IgD, leading to maturation into IgM- or IgD- secreting plasma cells.
      • B-cell antigen presentation to CD4+ helper T cells via MHC class II:
        • CD40 receptor on B cells binds CD40L on helper T cells, providing the second activation signal.
        • Helper T cells secrete IL-4 and IL-5, promoting B-cell isotype switching, hypermutation, and maturation to plasma cells.

    Granulomatous Inflammation

    • Subtype of chronic inflammation
    • Characterized by granulomas: collections of epithelioid histiocytes (macrophages with abundant pink cytoplasm), often surrounded by Langhans giant cells and a rim of lymphocytes.
    • Two main types:
      • Noncaseating granulomas lack central necrosis. Common causes include reactions to foreign materials, sarcoidosis, beryllium exposure, Crohn's disease, and cat scratch disease.
      • Caseating granulomas exhibit central necrosis, characteristic of tuberculosis and fungal infections.

    Granuloma Formation

    • Accumulation of macrophages at the site of inflammation.
    • Macrophages differentiate into epithelioid histiocytes, characterized by their abundant pink cytoplasm.
    • Fusion of macrophages may form giant cells, which have multiple nuclei.
    • The granuloma forms a wall of lymphocytes surrounding the central area of necrosis (caseating granulomas) or inflammatory cells (noncaseating granulomas).

    Fundamentals of Pathology

    • Chronic granulomatous disease (CGD) results from a NADPH oxidase defect, which is X-linked or autosomal recessive.
    • CGD leads to recurrent infections and granuloma formation with catalase-positive organisms, including Staphylococcus aureus, Pseudomonas cepacia, Serratia marcescens, Nocardia, and Aspergillus.
    • The Nitroblue tetrazolium (NBT) test is used to screen for CGD.
    • Leukocytes are incubated with NBT dye, which turns blue if NADPH oxidase can convert O2 to O2ꜙ, but remains colorless if NADPH oxidase is defective.
    • MPO deficiency results in defective conversion of H2O2 to HOCl.
    • MPO deficiency increases risk for Candida infections, however, most patients are asymptomatic.
    • NBT is normal in MPO deficiency, and the respiratory burst (O2 to H2O2) is intact.
    • O2-independent killing is less effective than O2-dependent killing and occurs via enzymes present in leukocyte secondary granules.
    • Neutrophils undergo apoptosis and disappear within 24 hours after resolution of the inflammatory stimulus.

    Macrophages

    • Macrophages predominate after neutrophils and peak 2-3 days after inflammation begins.
    • Macrophages are derived from monocytes in the blood.
    • They arrive in tissue via margination, rolling, adhesion, and transmigration sequence.
    • Macrophages ingest organisms via phagocytosis (augmented by opsonins) and destroy phagocytosed material using enzymes (e.g. lysozyme) in secondary granules.
    • Outcomes of macrophage activity include resolution and healing, continued acute inflammation, abscess formation, and chronic inflammation.
    • Macrophages mediate fibrosis via fibrogenic growth factors and cytokines.

    Chronic Inflammation

    • Chronic inflammation is characterized by the presence of lymphocytes and plasma cells in tissue.
    • Chronic inflammation is a delayed response, but more specific (adaptive immunity) than acute inflammation.
    • Chronic inflammation can be caused by persistent infection, infection with viruses, mycobacteria, parasites, and fungi, autoimmune disease, foreign material, and some cancers.

    T Lymphocytes

    • T lymphocytes are produced in bone marrow as progenitor T cells.
    • T cells further develop in the thymus where the T-cell receptor (TCR) undergoes rearrangement, and progenitor cells become CD4+ helper T cells or CD8+ cytotoxic T cells.
    • T cells use TCR complex (TCR and CD3) for antigen surveillance.
    • TCR recognizes antigen presented on MHC molecules:
      • CD4+ T cells recognize MHC class II
      • CD8+ T cells recognize MHC class I
    • Activation of T cells requires binding of antigen/MHC complex and a second signal.

    CD4+ Helper T-cell Activation

    • Extracellular antigen is phagocytosed, processed, and presented on MHC class II, which is expressed by antigen-presenting cells (APCs).
    • B7 on APC binds to CD28 on CD4+ helper T cells providing the second activation signal.
    • Activated CD4+ helper T cells secrete cytokines that "help" with inflammation and are divided into two subsets:
      • TH1 subset secretes IFN-γ (activates macrophages, promotes B-cell class switching from IgM to IgG, promotes TH1 phenotype and inhibits TH2 phenotype).
      • TH2 subset secretes IL-4 (facilitates B-cell class switching to IgE), IL-5 (eosinophil chemotaxis and activation, and class switching to IgA), and IL-13 (function similar to IL-4).

    CD8+ Cytotoxic T-cell Activation

    • Intracellular antigen is processed and presented on MHC class I, which is expressed by all nucleated cells and platelets.
    • IL-2 from CD4 TH1 cells provides the second activation signal.
    • Cytotoxic T cells are activated for killing via:
      • Secretion of perforin and granzyme: perforin creates pores that allow granzyme to enter the target cell, activating apoptosis.
      • Expression of FasL, which binds Fas on target cells, activating apoptosis.

    B Lymphocytes

    • Immature B cells are produced in the bone marrow and undergo immunoglobulin rearrangements to become naïve B cells that express surface IgM and IgD.
    • B-cell activation occurs via:
      • Antigen binding by surface IgM or IgD, resulting in maturation to IgM- or IgD-secreting plasma cells.
      • B-cell antigen presentation to CD4+ helper T cells via MHC class II.
        • CD40 receptor on B cell binds CD40L on helper T cell, providing the second activation signal.
        • Helper T cell then secretes IL-4 and IL-5 which mediate B-cell isotype switching, hypermutation, and maturation to plasma cells.

    Granulomatous Inflammation

    • Granulomatous inflammation is a subtype of chronic inflammation.
    • It is characterized by a granuloma, which is a collection of epithelioid histiocytes (macrophages with abundant pink cytoplasm), usually surrounded by giant cells and a rim of lymphocytes.
    • Granulomas are divided into noncaseating and caseating subtypes.
    • Noncaseating granulomas lack central necrosis.
    • Caseating granulomas exhibit central necrosis and are characteristic of tuberculosis and fungal infections.

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    Description

    This quiz covers key concepts related to Chronic Granulomatous Disease (CGD) and Myeloperoxidase (MPO) Deficiency. You'll explore the mechanisms of O2-dependent killing, the implications of NADPH oxidase defects, and the significance of the NBT test. Test your knowledge of these conditions and their clinical relevance.

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