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BIOL 1010U (101)
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Lecture

IMMUNOLOGY Phagocytic Cells

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School
Department
Biology
Course
BIOL 1010U
Professor
Ani
Semester
Fall

Description
IMMUNOLOGY Phagocytic Cells, Innate Immunity, and Host Defense Recall: TLR transducer signal into macrophage triggering an intracellular signal transduction cascade that activates transcription factors (NFkB) that transactivate the transcription of inflammatory genes Cells of the Innate Immunity (Overview) Neutrophils- shortlived phags that kill microbes w/ ROI and degradative enzymes -roll, attach, diapedesis, fuse lysosomes Macrophages-longlived phags that kill and regulate inflammation and remodeling -attach to bugs via FcR or C3R, fuse lysosomes, produce ROS and RNI Eosinophils -attach to parasite via C3R and release granules Basophils (Mast Cells)-attach to bugs via IgE, release granules, allergic responses (Come from Pluripotential Hematopoietic Stem Cell (Myeloid Progenitor) NEUTROPHILS MACROPHAGES short lived (days) long lived acute inflammation chronic inflammation kill bacteria kill bacteria AND regulate inflammation ROI, degradative enzymes cytokine secretion can present antigens ROI and NO I. Neutrophils -first cells to arrive at inflammatory site (may be called by resident macrophages) -“natural immunity” defense mechanism before lymphocyte driven immune response Bone marrow  circulation (<1day)Tissue (<1day)Effector Functions 2 week differentiation process: Mature Neutrophils do not divide Myeloblastpromyelocte (primary azurophil granules[MP0]myelocytemetamyelocyte (specific 2°granules) 2°granules = complement receptors for chemoattractants and adhesion molecules intracellular stores that are rapidly mobilized during inflammatory response Kills Pathogens (1)phagocytosis (2) oxygen burst/ROS production (3)release of degradative enzymes Neutrophil Dysfunction (Neutropenia = fatal bacteria and fungi) -decrease production (drugs, infefction, tumor) or increase destruction (autoantibodies) -defective adherence (LFA-1, Mac1, gp150) -defective chemotaxis -defective killing (myeloperoxidase deficiency/ chronic granulomatous disease) II. Macrophages-arrive later (chronic inflammation) -Differentiation lasts 2-5 days (ends when promonocytes leave marrow and enter circulation as monocytes) -after 1 day, monocytes leave circulation and differentiate to macrophages (TISSUE SPCIFIC) -Tissue macrophages = larger, more cytoplasm and lysosomal granules, ruffled plasma membrane -Mono. production regulated by cytokines from lymphocytes, macs, endo., fibrobasts (IL-3, M-CSF, GM- CSF) BMcirc <1day)adhesion/diapedesis(life in tissue >1month)Activation(PAMPs TNF) IFN from TEff Fxn -Activation of Macrophage depends upon local stimulieight times more membrane for attachment to substrate  more surface proteins (MHC and FcR) Note: Antigen specific T-lymphocytes can activate macrophages by secreting interferons Protection against parasites (1)ingestion of organisms by macrophages (2)Presentation of microbial antigens on the surface of macrophages (3)Recognition of antigen by CD4+ T cells (4)Release by T cells of mediators (IFNγ)activate macrophages MACROPHAGES MANY FUNCTIONS: INTERACTS WITH ADAPTIVE IMMUNITY 1. Kills pathogens and infected cells: Phag, ROS 2. Remodel tissues: proteases, ECM 3. Present Antigen (ADAPTIVE IMMUNITY) 4. Modulate Immune Response (ADAPTIVE IMMUNITY) III. Leukocyte Circulation and Migration- immune surveillance and immune response to injury or infection RollingActivationAdhesionDiapedesisMigration 1. Rolling Selectins: P, E, L (amino terminal carb binding domain)[on endothelial and neutrophils] Synthesis of E-selectin by endothelial cells is induced by inflammatory stimuli P-selectin is stored in granule like structures mobilized by inflammatory stimuli Ligands: Glycoproteins(glycam, mad-cam, podocalyxin, prot. bound to olig, sulfated silylated olig, SS Lewis tetrasach, post cap or high endo. venule) -Kinetics allows rapid attachment and detachment to provide basis of rolling 2. Activation IL-8, PAF, LTB4, C5a activate neutrophils TNF, IFN activate endothelial cells CAMs 3. Adhesion Neutrophil Integrins (LFA1 or Mac 1) Endothelil Adhesion Molecules (Ig superfamily: ICAM-1, VCAM-1) ICAM2 = constitutive expression ICAM-1=levels increased by stimuli (IL-1, TNF, IFNλ) 4. Diapedesis (migrate btw adjacent endothelial cells) High endothelial venules CD11a/CD18, CD54, CD4-hyaluronic acid 5. Migration and Chemotaxis (to site of infection) -C5a (from complement cascade), IL-8 (secreted by macrophages and Tcells), PAF, LTB4 -PAMPS (N formyl methionine peptides), and archidonic acid metabolites )leukotrienes) -chemotactic factors bind to specific G-protein coupled receptors on neutrophils and monocytes -because of high degree of motility and sensitivity to chemotactic stimuliNeutrophils arrive first (don’t stay long) Leukocyte Adhesion Defeciency Type 2: -defect in fucose transporter -cant produce E selectin -lack of neut. Rolling -recurrent bacterial infections IV. Leukocyte recognition of Pathogens: 1. PRR for PAMPS (innate immunity): specificity, phagocytosis, specialized fxns 2. Complement rec. (innate immunity) 3. Fc receptor for Ab (adaptive imm.): specificity, phagocytosis, specialized fxns -Fc receptors recognize antigens via Ab, transducer signals, activate (or inactivate) leukocytes Through cytoplasmic domain ITIMcoligation to activation partnerInhibition Through cytoplasmic domain ITAMaggregationactivation 1. Fc Receptors -Neutrophils and macrophages do not express clonally distributed antigen receptors (B and T cells do) -multi or single chain, membrane or soluble -bind to specific classes of Ig -phagocytes express FcγR (α subunit Ig superfamily γ subunit TCR family) -activating FcR have cytoplasmic tails with ITAM (immunoreceptor tyrosine based activation motifs) *Crosslinkinjg of multiple FcλR that have bound Ab to a single antigen that leads to triggering! -FcR inconcert with specific Abimmunologic specificity on phagocytic cells and trigger functions Antibody promoting Fc dependent uptake of antigens (1)binding of antigen to cells bearing specific antibodies attached via Fc receptors (2)binding of antibody coated particles to Fc receptors with displacement of bound antibodies (FcγR1 continuasly saturated w/free IgG but are displaced by antibodies bound to an antigen) Activating Fc Receptor Fxn 1. Ab bind to multivalent pathogen via Fab 2. FcR bind to Fc portion of Ab cluster and aggregates 3. Intracellular signals (FcR phosphorylation/ Cytoplasmic Tyrosine kinases) 4. Cell Response FcγRI  macrophages (ROS, cytokines, phagocytosis) high affinity to IgG1 (3 Iglike domains) FcγRIIA  -neutrophil (ROS) (2 Iglike domains, bind antibody-antigen complexes) -macrophage form mediates uptake of antigens via CC pits, phagocytosis of large IgG coated particles, release of inflammatory mediators B cells for
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