Fundamentals of Pathology PDF

Www.Medicalstudyzone.com 14 FUNDAMENTALS OF PATHOLOGY « 3. Chronic granulomatous disease (CGD) is characterized by poor O2-dependent killing. i. Due to NADPH oxidase defect (X-linked or autosoma...

Www.Medicalstudyzone.com 14 FUNDAMENTALS OF PATHOLOGY « 3. Chronic granulomatous disease (CGD) is characterized by poor O2-dependent killing. i. Due to NADPH oxidase defect (X-linked or autosomal recessive) ii. Leads to recurrent infection and granuloma formation with catalase-positive organisms, particularly Staphylococcus aureus, Pseudomonas cepacia, Serratia marcescens, Nocardia, and Aspergillus iii. Nitroblue tetrazolium 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. 4. MPO deficiency results in defective conversion of H2O2 to HOCl. i. Increased risk for Candida infections; however, most patients are asymptomatic. ii. NBT is normal; respiratory burst (O2 to H2O2) is intact. 5. O2-independent killing is less effective than O2 -dependent killing and occurs via enzymes present in leukocyte secondary granules (e.g., lysozyme in macrophages and major basic protein in eosinophils). G. Step 7 - Resolution 1. Neutrophils undergo apoptosis and disappear within 24 hours after resolution of the inflammatory stimulus. V. MACROPHAGES A. Macrophages predominate after neutrophils and peak 2-3 days after inflammation begins. 1. Derived from monocytes in blood B. Arrive in tissue via the margination, rolling, adhesion, and transmigration sequence C. Ingest organisms via phagocytosis (augmented by opsonins) and destroy phagocytosed material using enzymes (e.g., lysozyme) in secondary granules (O 2- independent killing) D. Manage the next step of the inflammatory process. Outcomes include 1. Resolution and healing - Anti-inflammatory cytokines (e.g., IL-10 and TGF- β) are produced by macrophages. 2. Continued acute inflammation - marked by persistent pus formation; IL-8 from macrophages recruits additional neutrophils. 3. Abscess - acute inflammation surrounded by fibrosis; macrophages mediate fibrosis via fibrogenic growth factors and cytokines. 4. Chronic inflammation - Macrophages present antigen to activate CD4+ helper T cells, which secrete cytokines that promote chronic inflammation. CHRONIC INFLAMMATION I. BASIC PRINCIPLES A. Characterized by the presence of lymphocytes and plasma cells in tissue (Fig. 2.lB) B. Delayed response, but more specific (adaptive immunity) than acute inflammation C. Stimuli include (1) persistent infection (most common cause); (2) infection with viruses, mycobacteria, parasites, and fungi; (3) autoimmune disease; (4) foreign material; and (5) some cancers. II. T LYMPHOCYTES A. Produced in bone marrow as progenitor T cells B. 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 1. T cells use TCR complex (TCR and CD3) for antigen surveillance.  Www.Medicalstudyzone.com Inflammation, Inflammatory Disorders, and Wound Healing 15 2. TCR complex recognizes antigen presented on MHC molecules. i. CD4+ T cells - MHC class II ii. CD8+ T cells - MHC class I 3. Activation of T cells requires (1) binding of antigen/MHC complex and (2) an additional 2nd signal. C. CD4 + helper T-cell activation 1. Extracellular antigen (e.g., foreign protein) is phagocytosed, processed, and presented on MHC class II, which is expressed by antigen presenting cells (APCs). 2. B7 on APC binds CD28 on CD4 + helper T cells providing 2nd activation signal. 3. Activated CD4 + helper T cells secrete cytokines that "help" inflammation and are divided into two subsets. i. TH1 subset secretes IFN-γ (activates macrophage, promotes B-cell class switching from IgM to IgG, promotes TH1phenotype and inhibits TH2 phenotype). ii. T H 2 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). D. CD8 + cytotoxic T-cell activation 1. 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. 2. IL-2 from CD4 + TH1 cell provides 2nd activation signal. 3. Cytotoxic T cells are activated for killing. 4. Killing occurs via i. Secretion of perforin and granzyme; perforin creates pores that allow granzyme to enter the target cell, activating apoptosis. ii. Expression of FasL, which binds Fas on target cells, activating apoptosis III. B LYMPHOCYTES A. 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. B-cell activation occurs via 1. Antigen binding by surface IgM or IgD; results in maturation to IgM- or IgD- secreting plasma cells 2. B-cell antigen presentation to CD4+ helper T cells via MHC class IL i. CD40 receptor on B cell binds CD40L on helper T cell, providing 2nd activation signal. ii. Helper T cell then secretes IL-4 and IL-5 (mediate B-cell isotype switching, hypermutation, and maturation to plasma cells). IV. GRANULOMATOUS INFLAMMATION A. Subtype of chronic inflammation B. Characterized by granuloma, which is a collection of epithelioid histiocytes (macrophages with abundant pink cytoplasm), usually surrounded by giant cells and a rim of lymphocytes C. Divided into noncaseating and caseating subtypes 1. Noncaseating granulomas lack central necrosis (Fig. 2.2A). Common etiologies include reaction to foreign material, sarcoidosis, beryllium exposure, Crohn disease, and cat scratch disease. 2. Caseating granulomas exhibit central necrosis and are characteristic of tuberculosis and fungal infections (Fig. 2.2B). D. Steps involved in granuloma formation