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Why are people with Factor I deficiency more susceptible to infection? They have been depleted of C3b in a single attack because there is no Factor I to inactivate C3b (into iC3b). What condition does impaired lipid tails of CD59, HRF and DAF lead to? Paroxysmal nocturnal hemoglobinuria (because it increases complement-mediated lysis of host erythrocytes) Name 2 cell surface proteins that deactivate convertase activity. Decay-accelerating factor (DAF) Membrane co-factor protein (MCP) a.) What 2 factors/proteins inhibit the membrane-attack complex (MAC)? b.) How? a.) Protectin and HRF b.) Inhibit MAC by preventing polymerization of C9 into the membrane, which would complete the MAC pore protein structure and induce leakiness, resulting in cell death. What two cell types fuse in order to capture and destroy pathogens? Macrophages and lysosomes Forming phagolysosomes How are phagolysosomes destroyed? By membrane-attack complex pores. What components induce local inflammation? C3a and C5a How do complement proteins, monocytes, and neutrophils get through tissue to the site of infection? C3a and C5a dilate capillaries to separate endothelial cells and induce leakiness. What does the lack of a spleen cause increased susceptibility of? Bacterial blood infections If no spleen, what alternative action will provide an adaptive immunity to a specific pathogen? Vaccinations What system does Warfarin target? Coagulation cascade What system induced vasodilation and increases blood flow to the infected site? Kinin system (via bradykinin, a vasoactive peptide) What is the action of proteases? Break down tissue to allow pathogens into the body. Name a protease inhibitor. alpha-2 macroglobulins Name a human antimicrobial, and explain where it works and why. Defensins - work in low ionic strength environments such as sweat, tears, and the gut. Are toll-like receptors (TLRs) innate or adaptive? Innate Explain why there only needs to be a set number of TLRs in the body. Can form homo-/hetero-dimers and monomers. Why aren't defensins harmful to human cells? Expressed as inactive peptides, and must be cleaved to become activated. Which cell lineages carry TLRs? (toll-like receptors) **hint: think whether TLRs are part of innate/adaptive immunity. Lymphoid (NK) and Myeloid Can TLRs recognize proteins, lipids, carbohydrates, or nucleic acids? All of the above. What would a TLR recognizing a viral infection lead to? Production of antiviral cytokines. What would a TLR recognizing a bacterial infection lead to? Activation of transcription factors, which transcribe genes encoding inflammatory cytokines. What do macrophages express and secrete? Inflammatory cytokines Describe the actions of cytokines: a.) act as chemokines that direct flow of leukocytes (via chemokine gradient) b.) activate leukocytes c.) cause endothelial changes to help recruit leukocytes from the blood d.) trigger blood clotting cascade e.) cause fever (calor) f.) induce acute-phase response protein secretion What causes death in ICUs that is induced by cytokine activity happening "globally," as opposed to locally? Septic shock List a possible cause of septic shock. Gram- bacteremia What proteins do hepatocytes produce and secrete in response to cytokine activity? Mannose-binding lectin (MBL) What does lectin bind to? Mannose-containing carbohydrates of microorganisms (features NOT present on human cells) Pyogenes Produce pus (ex., Streptococcus pyogenes) Main function of Neutrophils and Macrophages: phagocytosis - engulf and kill microorganisms Function of "activated endothelium:" Sticky and leaky to allow transmigration of phagocytes. What are the most abundant leukocytes; 40-70%? Neutrophils Where is the largest reserve of mature neutrophils? Bone marrow What is pus at the site of infection due to? Neutrophil death. Pyogenic Infection Infection that induces a strong neutrophil response, producing pus. List the ways neutrophils migrate to an infected area: a.) rolling adhesion b.) tight binding to adhesion molecules c.) diapedesis - movement between endothelial cells d.) migration - movement to basal side of endothelium and into tissue e.) secretion of proteases to dissolve basement membrane of endothelium f.) chemokine gradients in extracellular spaces g.) expression of different types of receptors capable of recognizing different pathogens/foreign substances h.) cytoplasmic granules contain "weaponry" What do cytoplasmic granules consist of? Proteolytic enzymes and defensins What is formed when a neutrophil engulfs a pathogen? Phagosome Upon neutrophil death, what happens to the granule contents that cannot be replenished? Apoptosis, and then phagocytosis by macrophage. How does a neutrophil degrade a phagocytosed pathogen? Respiratory burst Respiratory Burst Superoxide and hydrogen peroxide formed (toxic oxygen species) Name a genetic defect leading to lack of respiratory burst capability: Chronic Granulomatous Disease Granuloma Organized collection of macrophages resulting from the immune system's attempt to segregate an infection that it cannot control (b/c of chronic granulomatous disease, body is not able to destroy phagocytosed pathogens) Describe the first step in the Lectin Complement Pathway: Mannose-binding lectin (MBL) circulates in plasma; binds to mannose of pathogen surface; becomes activated and catalyzes cleavage of C4 (into C4a and C4b) What is the purpose of C4b? Opsonizes pathogen and acts as C3-convertase to cleave C3 into a+b; induces C3b opsonization, which then leads into the alternative complement pathway. What protein initiates the Classical Complement Pathway? C-reactive protein (CRP) Describe Steps in Classical Complement Pathway: Initiated by CRP; CRP binds to phosphocholine on pathogen surface, interacting with C1; C1 cleaves C4 into C4a+b; C4b cleaves C3; continues to follow the Alternative Complement Pathway Interferons (IFN) Antiviral cytokines State the 2 ways Type-I interferons achieve their antiviral effects: Inhibiting viral replication; Activating host defenses (ex. activating NK cells for destruction of virus-infected cells). What is a Type-I interferon binding to cell surface receptors on the cell that made it called? Autocrine fashion What is a Type-I interferon binding to cell surface receptors on nearby cells called? Paracrine fashion How is IFN gene transcription/translation triggered? Triggered by virus that is infecting a cell; Triggered by TLRs sensing some foreign substance (ex. nucleic acids not common to human cells, like double-stranded viral RNA). What responses do the autocrine/paracrine functions of IFN generate? Inducing resistance to viral replication by destroying viral mRNA and inhibiting translation of viral proteins; Increasing expression of ligands for NK cell receptors on infected cells. How are NK cells different from B/T-lymphocytes? NK cells contain cytotoxic granules. NK cell function is similar to what adaptive immune response cell's function? T-lymphocytes What effect do cytokines have on NK cells? Enhance NK cell cytotoxicity; Induce NK cell proliferation. What is the principle NK-produced cytokine? Type II interferon (INF-gamma) Macrophages secreting cytokines that help activate T-cells initiates which immune response? Adaptive immune response.