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Immunity to bacteria Antimicrobial Defenses for Infectious Agents Neutrophils Macrophages Complement NK cells CD4 TH1-DTH CD8-CTL Antibody Bacteria Intracellular Viruses Fungi Parasites bacteria ++ + + ++ ++ ++ + + + ++ ++ + + + ++(IgE) Barrier defenses of human body Antibacterial Responses “Protection is initiated on activation of innate responses on a local basis and progress to acute-phase and antigen specific responses on a systemic scale” major events in acute inflamation 1. Expansion of capilaries to increase blood flow (seen as blushing or a rash) 2. Increase in the permeability of the microvasculature structure to allow escape of fluid, plasma proteins, and leukocytes from the circulation edema 3. Exit of leukocytes from the capillaries and their accumulation at the site of injury Bacterial components that activate Protective Responses I • Direct activation – LPS – Lipoteichoic acid – Lipoarabinomannan – Glycolipids and glycopeptides – Polyanions – N-Formyl peptides Bacterial components that activate Protective Responses II • Chemotactic – Peptidoglycan fragments – Cell surface activation of alternative pathways of complement (C3a, C5a) Complement in antibacterial response • Alternative and Lectin pathways activated by bacterial surfaces • Classic pathway activated later by antibody-antigen complexes • Production of chemotactic and anaphylotoxic proteins (C3a, C5a) • Opsonization of bacteria (C3b) • Promotion of killing of gram-negative bacteria • Activation of B cells (C3d) Complement cascade Neutrophil diapedesis in response to inflamatory signals Phagocytes & Phagocytosis • PMNs, monocytes, and eosinophils are the first cells to appear in response to acute inflammation; they are followed later by macrophages Neutrophils • major antibacterial response • an increased number of neutrophils in the blood, body fluids or tissue indicates: “bacterial infection” • “left shift” Steps in Phagocytosis • Attachment – bacterial carbohydrates (lectins) – receptor for opsonins – fibronectin receptors – Fc receptors • Internalization (phagocytic vacuole) • Digestion (phagosome) Antibacterial compounds of the phagolysosome I • Oxygen-dependent compounds – Hydrogen peroxide: NADPH oxidase and NADH – Superoxide – Hydroxil radicals (OH) _ _ _ – Activated halides (Cl , I , Br ): myeloperoxidase – Nitrous oxide Antibacterial compounds of the phagolysosome II • Oxygen-independent compounds – Acids – Lysosome (degrades bacterial peptidoglycan) – Lactoferrin (chelates iron) – Defensin and other cationic proteins (damage membranes) – Proteases, elastase, cathepsin G Phagocytosis & killing of bacteria Macrophages in antibacterial response • Important antibacterial phagocytic cells – Killing by oxygen-dependent and oxygenindependent mechanisms – Production of IL-1, IL-6, and IL-12; TNF-a and TNF-b, and interferon-a – Activation of acute-phase and inflammatory responses – Presentation of antigen to CD4 T cell Antibacterial responses Acute-Phase Reactants • • • • • a1-antitrypsin a1-glycoprotein Amyloid A & P Antithrombin III C-reactive protein C1 esterase inhibitor C3 complement • • • • • • • Ceruloplasmin Fibrinogen Haptoglobulin Orosomucoid Plasminogen Transferrin Lypopolysaccharidebinding proteins Specific Immune Responses to Bacteria I • Macrophages move to lymph nodes and interact with CD4 T cells after ingestion of bacteria • initially: Macroph(APC). CD4 TH0 cells antigenic peptides + class II MHC TCR + CD4, on TH0 Specific Immune Responses to Bacteria II • costimulatory signals from the interaction of CD28 (T cells) B7 molecule (macrophage) + IL-1, IL-12 • TH0 produce IL-2, IFN-g and IL-4 • B cells produce IgM • LPS and cell wall polysaccharides activate B cells Specific Immune Responses to Bacteria III • TH0 TH1 (IL-12 & IFN-g) – activation of Macrophages, T cells, B cells – important for intracellular infections • CD4 TH2 T-cell response – occur later – initiated by the B cell presentation of antigen – presentation to TH2 cell (Ag + class II MHC) – TH2 IL-4, IL-5, IL-6, IL-10 , Plasma-cells, memory cells IgG T cells in antibacterial response • TH1 CD4 responses important for intracellular bacterial infections • TH2 CD4 response important for all bacterial infections • CD8 cytolytic T cells not very important Antibody in antibacterial response • primary protection against extracellular bacteria and reinfection • Binding to surface structures of bacteria (fimbriae,lipoteichoic acid, capsule) – Blocking attachment – Opsonization of bacteria for phagocytosis – Promotion of complement action – Promotion of clearence of bacteria – Neutralization of toxins and toxic enzymes Bacterial Immunopathogenesis • • • • “tissue and systemic damage” IL-1, IL-6 and TNF-a life-threatening in systemic infection endotoxin macrph. TNF-a in the blood symptomes of sepsis antibodies which share determinants with human proteins post-streptococcal glomerulonephritis and rheumatic fever superantigens STSS Bacterial Evasion of Protective Responses 1. the inhibition of phagocytosis and intracellular killing in the phagocyte 2. inactivation of complement function 3. cleavage of IgA 4. intracellular growth (avoidance of antibody) 5. change in bacterial antigenic appearence