Pathoma 2023 PDF_p21-22.pdf

Www.Medicalstudyzone.com Inflammation, Inflammatory Disorders, and Wound Healing 13 D. Fever 1. Pyrogens (e.g., LPS from bacteria) cause macrophages to release IL-1 and TNF, which increase cycloox...

Www.Medicalstudyzone.com Inflammation, Inflammatory Disorders, and Wound Healing 13 D. Fever 1. Pyrogens (e.g., LPS from bacteria) cause macrophages to release IL-1 and TNF, which increase cyclooxygenase activity in perivascular cells of the hypothalamus. 2. Increased PGE2 raises temperature set point. IV. NEUTROPHIL ARRIVAL AND FUNCTION A. Step 1 - Margination 1. Vasodilation slows blood flow in postcapillary venules. 2. Cells marginate from center of flow to the periphery. B. Step 2 - Rolling 1. Selectin "speed bumps" are upregulated on endothelial cells. i. P-selectin release from Weibel-Palade bodies is mediated by histamine. ii. E-selectin is induced by TNF and IL-1. 2. Selectins bind sialyl Lewis X on leukocytes. 3. Interaction results in rolling of leukocytes along vessel wall. C. Step 3 - Adhesion 1. Cellular adhesion molecules (ICAM and VCAM) are upregulated on endothelium by TNF and IL-1. 2. Integrins are upregulated on leukocytes by C5a and LTB4 3. Interaction between CAMs and integrins results in firm adhesion of leukocytes to the vessel wall. 4. Leukocyte adhesion deficiency is most commonly due to an autosomal recessive defect of integrins (CD18 subunit). i. Clinical features include delayed separation of the umbilical cord, increased circulating neutrophils (due to impaired adhesion of marginated pool of leukocytes), and recurrent bacterial infections that lack pus formation. D. Step 4 - Transmigration and Chemotaxis 1. Leukocytes transmigrate across the endothelium of postcapillary venules and move toward chemical attractants (chemotaxis). 2. Neutrophils are attracted by bacterial products, IL-8, C5a, and LTB4. E. Step 5 - Phagocytosis 1. Consumption of pathogens or necrotic tissue; phagocytosis is enhanced by opsonins (IgG and C3b). 2. Pseudopods extend from leukocytes to form phagosomes, which are internalized and merge with lysosomes to produce phagolysosomes. 3. Chediak-Higashi syndrome is a protein trafficking defect (autosomal recessive) characterized by impaired phagolysosome formation. Clinical features include i. Increased risk of pyogenic infections ii. Neutropenia (due to intramedullary death of neutrophils) iii. Giant granules in leukocytes (due to fusion of granules arising from the Golgi apparatus) iv. Defective primary hemostasis (due to abnormal dense granules in platelets) v. Albinism vi. Peripheral neuropathy F. Step 6 - Destruction of phagocytosed material 1. O2-dependent killing is the most effective mechanism. 2. HOCl generated by oxidative burst in phagolysosomes destroys phagocytosed microbes. i. O2 is converted to O 2 ꜙ by NADPH oxidase (oxidative burst). ii. O2ꜙ is converted to H2O2 by superoxide dismutase (SOD). iii. H2O2 is converted to HOCl (bleach) by myeloperoxidase (MPO).  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.