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136 Cards in this Set
- Front
- Back
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List all of the Soluble Mediators
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“The Major Asked His Mom for Eons”
- Interleukin-1,4,6,8,12 and gamma - Tumor Necrosis Factor (TNF) - Transforming Factor Beta (TGFβ) - Major Basic Protein - Anaphylatoxins - Histamine - Monocyte Chemotactic factor/protein (MCP-1) - Eosinophil Cationic Protein - “IL-1,4,6,8,12,G and Double T” |
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What is phagocytosis?
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Process by which organisms are engulfed and destroyed by phagocitic cells.
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What is the major defense mechanism for eradication of invading microorganisms?
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Phagocytosis
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What are the predominant phagocytes?
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Neutrophils and Macrophages
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Which phagocytes comprise 60% of the circulating leukocytes in peripheral blood?
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Neutrophils
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Where do neutrophils mature from?
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Precursor cells in the bone marrow.
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Where is the majority of neutrophils? Minority?
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- Majority circulate in blood.
- Minority are stored in bone marrow. |
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What is the half-life of neutrophils?
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8 hours
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What are the blood borne cells derived from bone marrow proginators?
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Monocytes
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What are the blood borne cells derived from bone marrow proginators?
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Monocytes
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What is the percentage that monocytes comprise of circulating leukocytes?
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4%
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What happens to monocytes when they are recruited into tissue?
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The differentiate into macrophages.
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True/False: Monocytes are more effective at Phagocytosis than macrophages.
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False: Macrophages are more effective at phagocytosis than monocytes.
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Which have a longer half-life, macrophages or moncytes? Which can serve as antigen presenting cells for CD4+T cell activation?
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1. Macrophages
2. Macrophages |
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How does direct recognition of pathogens occur?
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By primitive receptors called primitive pattern recognition receptors or PPRR.
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How do Phagocytes recognize pathogens indirectly?
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By using cell surface receptors that recognize molecules that have bound to, or deposited on, the pathogen cell surface.
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What are opsonins?
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Molecules that have attached to the pathogens.
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What 3 things are opsonins the products of?
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1. Complement activation (C3b)
2. B cell activation (IgG) 3. Cytokine mediated activation of hepatocytes (C-reactive protein, CRP) |
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What triggers phagocytosis?
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Interaction with any of the products of opsonins just mentioned.
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What is the phagocytic vacuole called?
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Phagosome
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What are the 3 phagocitic “weapons” that destroy what the macrophage has engulfed?
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1. Lysosomal enzymes
2. Reactive oxygen intermediates 3. Reactive nitrogen intermediates |
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What is triggered after the recognition and binding of the microorganisms?
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- The assembly of the enzymatic complex NADPH Oxidase
- Formation of the phagosome - Mobilization of glycogen stores |
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What is a phagolysosome?
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The fused product of a phagosome and lysosome in which lysosomal granules are discharged.
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All of the following enzymes are contained in lysosomal granules except: lactoferrin, perforin, lysozyme, and defensin
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Perforin is not in Lysosomal granules.
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How do the lysosomal granule enzymes affect microorganisms?
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They are cytostatic/cytotoxic to them.
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Describe the role that each lysosomal granule enzyme plays in immunity:
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1. Lactoferrin binds iron and removes the essential ingredient for microbial growth.
2. Lysozyme destroys muramic acid in bacterial cell walls. 3. Defensins permeabilize bacterial and fungal membranes. |
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Which enzyme released by lysosomal granules, is required for hypochlorite generation?
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Myeloperoxidase
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What is Hypochlorite?
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A potent antimicrobial agent that mediates its function by halogenating bacterial cell walls.
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What generates Reactive Oxygen Intermediates?
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Activation of NADPH oxidase.
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What is NADPH oxidase?
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A multi-subunit enzyme complex whose components, in the resting phagocyte, are distributed in both the plasma membrane and the cytosol.
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What forms hypochlorite?
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It is formed in the presence of hydrogen peroxide and a chloride ion when myeloperoxidase is available.
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Describe how nitric oxide causes destruction to microorganisms:
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It is a lipid and water soluble gas that is cytotoxic/cytostatic to invading microorganisms.
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Which other ROI’s does the first superoxide anion initiate the generation of?
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- Hydrogen peroxide
- Hydroxyl radical - Hydroxyl ion |
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What triggers the assembly of NADPH oxidase?
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Phagocytosis triggers its assembly on the phagocytic vacuole.
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How does NADPH oxidase function? What is the respiratory burst from?
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Phagocytosis is accompanied by a respiratory burst which is attributable to the activation of NADPH oxidase that uses oxygen with cystolic NADPH to generate superoxide anion.
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What forms hypochlorite?
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It is formed in the presence of hydrogen peroxide and a chloride ion when myeloperoxidase is available.
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Describe how nitric oxide causes destruction to microorganisms:
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It is a lipid and water soluble gas that is cytotoxic/cytostatic to invading microorganisms.
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Which “weapon” targets iron sulfur proteins in the ETC of microbes?
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NO
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Which is most potent/powerful: ROIs, NO or RNIs?
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RNI’s, they are produced when NO reacts with ROIs.
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Name two intracellular organisms that are resistant to ROIs but not RNIs:
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1. Mycobacteria
2. Leishmania |
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What is required in phagocytes for the production of NO?
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Nitric oxide synthase, a cytosolic enzyme that catalyzes the converion of L-Arginine to L-Citrulline and NO in the presence of oxygen.
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Since NO is toxic to microbes and phagocytes, how is the cell protected?
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Because NO has a short half life, i.e. seconds.
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What does induction of nitric oxide synthase (NOS) occur in response to?
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Inflammatory products, microbial product and/or cytokines.
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What are the two signals required for the induction of NOS?
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Priming signal is delivered by bacterial products, or the cytokine tumor necrosis factor.
Second signal delivered by INFγ |
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What does down regulation of NOS occur as a result of?
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Cytokines: Interleukin-10 and 4, as well as transforming growth factor Beta (TGFβ).
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What is the most effective inhibitor of NO synthesis?
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TGF β
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What are eosinophils?
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Bone-marrow derived cells that exist in both circulation and tissues.
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True/False: A large portion of eosinophils are in circulation.
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False: only a small percentage are in circulation.
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What is the half-life of eosinophils?
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8-10 hours.
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What is the role of eosinophils in immunity?
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They kill parasites, especially helminths, which are resistant to destruction by neutrophils and macrophages.
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Even though eosinophils are called innate immune system cells, they need something else to play their role, what is that?
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They need antibodies (IgE) generated in adaptive immunity.
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Is recognition of helminths by eosinophils direct or indirect?
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Indirect
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How do eosinophils recognize helminths?
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- They have FcεR which binds to IgE antibodies.
- The IgE antibodies are bound to epitopes which are bound to the helminths. |
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How do eosinophils kill parasites like helminths after they recognize them?
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- After binding, the eosinophil degranulates and releases some molecules.
- Major Basic Protein (MBP) and Eosinophil Cationic Protein (ECP) which are toxic to helminths and some other parasites. |
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Can a virus be killed by phagocytes?
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Yes, but only when it is outside of a cell.
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How is recognition and destruction of viruses mediated in innate immunity?
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By Natural Killer (NK) cells.
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What makes NK cells recognize cells with viruses in them?
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NK cells have special receptors that recognize a wide array of viral proteins.
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What is the escape mechanism used by viruses to avert NK cells?
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- NK cells have a killer inhibitory receptor, and if this attaches to the ligand I MHC molecule, it will not kill the cell.
- A virus can trigger mechanisms that cause the up-regulation of MHC molecules on the cell surface. Thus, inhibiting NK cells from killing the cell the virus is in. |
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If the virus averts detection from an NK cell because it increased MHC molecules, how can it be killed?
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When MHC molecules are increased, CTL (cells of adaptive immunity) are alerted and they kill the cell with the virus.
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How do eosinophils kill parasites like helminths after they recognize them?
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- After binding, the eosinophil degranulates and releases some molecules.
- Major Basic Protein (MBP) and Eosinophil Cationic Protein (ECP) which are toxic to helminths and some other parasites. |
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How could a tumor escape being killed by CTL cells?
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By decreasing MHC on the cell surface and if there is no viral protein on the cell surface . . . NK cells won’t kill the tumor either.
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Is recognition of virally infected cells by NK cells direct or indirect?
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Both
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How is recognition by NK cells indirect?
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When IgG molecules bind to virally infected cells, the FcγR receptors on the NK cell recognize this and indirect recognition ensues.
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What is the direct recognition referred to as? Indirect?
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Direct = receptor-mediated cytotoxicity.
Indirect = antibody-mediated cellular cytotoxicity (ADCC) |
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How do NK cells ultimately kill the virally infected cell? How is this enhanced?
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The NK cell releases perforin, regardless of how it recognized the cell. Perforin inserts into the cell membrane and induces osmotic cell lysis.
Ability of NK cells to kill is enhanced by exposure to cytokines (IL2,12 and interferon gamma (IFNγ)) |
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Where do NK cells arise from? Where are they found?
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- Arise from bone marrow precursors.
- Found in blood, spleen and peritoneal exudate. |
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Fill in the names of the macrophages.
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What molecular pattern does TLR-2 recognize?
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TLR-2 = Toll Like Receptor 2.
- sometimes recognition is based on cooperation between TLR-2 with TLR-1 and TLR-6. Recognizes: - lipteichoic acid from gram positive bacteria -zymosan from fungi - glycosylphosphatidylinosital anchors from Trypanosoma Cruzi - peptidoglycan from gram positive bacteria |
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What molecular pattern does TLR-3 recognize?
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double stranded RNA. produced by some viruses during replication
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What molecular pattern does TLR-4 recognize?
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Lipopolysaccharide (LPS), a major component of Gram negative bacteria
- requires LPS binding protein, and MD-2 - secreted protein that interacts with extracellular part of TLR-4 |
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What molecular pattern does TLR-9 recognize?
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bacterial unmethylated CpG DNA
(CpG = C connected to G by phosphodieseter bond) |
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Crohn's Disease
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caused by mutation of Nod2
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Nod1 vs. Nod2
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Nod = Nucleotide-binding oligomerization domain-like receptors.
- Nod1 - detects meso-diaminopimelic acid - Nod2 - detects muramyl dipeptide Both: - recognized conserved areas on microbes - interaction with these receptors = leads to activation of NKκB - critical for activation of several immunological processes |
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Opsonin-mediated Phagocytosis
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- phagocytes recognize pathogens INDIRECTLY by cell surface receptors that have bound to pathogen cell surface (opsonin)
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Opsonins are products of:
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1. Complement Activation (C3b)
2. B cell activation (IgG) 3. Cyokine mediated activation of hepatocytes - interaction of any of these = triggers process for phagocytosis |
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What is NO's mechanism of action against microbes?
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- targets proteins in the electron transport chain
- inhibits the respiratory cycle |
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What is MCP-1 a chemoattractant for?
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monocytes and macrophages
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What is IL-8 a chemoattractant for?
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neutrophils
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What cytokines are secreted by activated macrophages? Which on these function both as autocrine and paracrine?
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IL-1, IL-6, IL-12 and tumor necrosis factor (TNF)
IL-1 and TNF - both paracrine and autocrine |
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What receptors are present on macrophages. What do the receptors do?
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The receptors affect the activation or downregulation of the macrophage.
this includes: IFNγ, TNF, IL-10, IL-4, TGFβ, IL-1, MCP-1 and FcγR, CRP-R, and CR1 |
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Where are Natural Killer cells found? Where are the made?
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- NK cells made from bone marrow precursors.
- found in blood, spleen, peritoneal exudate |
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What determines if a cell is protected or destroyed by a NK cell?
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MHC Class 1.
- if the cell expresses self-MHC, it is not killed = tolerance - if not enough self-MHC, then NK cell will start cytolysis. - Viruses and tumors decrease number of self-MHC-1 on cell surface when it infects the cell. Makes viruses and tumors more susceptible. - however, allows it to escape detection from adaptive immune processes (CTL) |
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Antibody dependent cell mediated cytotoxicity
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- antibodies recognize viral proteins embedded in the cell membrane of infected cell
- kill the cell -indirect |
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Perforin
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- lytic granules secreted by NK cells
- inserts into cell membrane - induces osmotic cell lysis |
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What will stimulate NK cells to secrete inferon gamma (IFNγ)?
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- IL-12 and a second cytokine (either IL-15 or IL-18)
- also can be stimulated by activatign receptor |
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Direct Recognition of Pathogens
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Direct - recognize antigens without an intermediary protein
- Pattern Recognition Receptors (PRR) - distinguishes pathogens from self - ie. toll-like receptors |
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Indirect Recognition of Pathogens
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Indirect - needs interaction of intermediatary protein, which binds to an antigen (with a receptor on the phagocyte)
- Opsonin-mediated |
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Which Direct Recognition Receptors are found inside the cell? Which ones are found outside?
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Inside - TLR3, TLR9, NOD1, NOD2
(It's ODD that there are receptors INSIDE) Outside - TLR2, TLR4 |
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What do Direct Recognition Receptors recognize?
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Pathogen Associated Molecular Patterns (PAMPs)
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Name the macrophages associated with the following regions
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How do anaphylatoxins work?
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C3a,b,c bind to cognate R on mast cells/basophils
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CD4
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Recognize antigen fragments presented in association with Class II MHC
- Helper T-cells. (Th) because secrete cytokines required for both innate and adaptive immunity - divided into Th1 - secrete type 1 cytokine Th2 - secrete type 2 cytokine |
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CD8
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Killer T cells. Kills your own cells that have been infected and express antigen fragment in from Class I MHC molecules.
AKA target cells. |
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What is the difference between margination and diapedesis?
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Margination - along the vessel
Diapedesis - through the vessel |
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What are the 2 ways that phagocytes can recognize antigens?
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1. Directly (Pattern Recognition Receptors - PRR)
2. Opsonin-mediated - uses an intermediary protein which binds to the antigen. the protein has a receptor on the phagocyte |
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Opsonins are the products of what 3 things?
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I. Complement Activation - C3b
II. B cell Activation - IgG III. Cytokine mediated activation of hepatocytes - CRP |
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What is the Receptor Opsonin pairing for Fcγ?
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FcγR
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What is the Receptor Opsonin pairing for CRP?
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CRP-BS
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What is the Receptor Opsonin pairing for C3b?
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CR1
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Phagosome
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vesicles that engulf pathogens
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myeloperoxidase
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-released by lysosomal granules
- an enzyme need to generate hypochlorite Hypochlorite = potent antimicrobial agent that breaks down bacterial cell walls |
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NADPH Oxidase
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- triggered by recognition & binding of microorganisms
- in the phagocytic vacuole - generates super anions (reactive oxygen intermediates) to destroy antigens in the vacuole |
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Natural killer cells
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- kill virally infected cells of the body
- enhanced by cytokines (IL-2, IL-12) |
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Antigen presenting cells
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1. endocytose antigen
2. process it into fragments (peptides) 3. display fragments on the cell surface Antigen Presenting Cells are: dendritic cells, b Cells and macrophages |
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What are the 3 inflammatory cells?
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Mast cells, basophils, eosinophils
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Basophils
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circulating counterpart of the tissue mast cells
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lymphocytes
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cells in the adaptive immune system
B cells - antibodies. have cell surface antigen receptors T cells - express alpha and beta cells |
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What are 3 examples of lysosomal granules?
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lactoferrin, lysozyme, defensins
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What does lactoferrin bind to?
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binds to iron, which removes an essential ingrediant for microbial growth
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How does lysozyme kill bacteria?
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destroys muramic acid in bacterial cell walls
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What do defensins attack?
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bacterial and fungal membranes
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Nitric Oxide
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lipid and water soluble gas that is cytotoxic and cytostatic to invading microorganisms
- can kill viruses, intracellular bacteria, parasites, fungi - targets iron sulfur proteins in electron transport chain -> inhibits respiratory cycle - more potent when react with reactive oxygen intermediates to form reactive nitrogen intermediates |
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Reactive nitrogen intermediates
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- when Nitric Oxide reacts with reactive oxygen intermediates (ROIs)
- can eliminate microorganism that are resistant to ROI and lysosomal enzymes (ie. Leishmania and mycobacteria) - targets iron sulfur proteins in electron transport chain -> inhibits respiratory cycle |
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Nitric Oxide Synthase (iNOS)
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enzyme need to make NO
L-Arginine + Oxygen -----iNOS---> L-Citrulline + Nitric Oxide (NO) - To activate: 1. priming signal from bacterial products or cytokine, Tumor Necrosis Factor 2. Second signal from IFNγ To downregulate: - IL-10 and IL-4 or TGFβ |
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MCP-1
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chemoattractant for moncytes and macrophages
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IL-8
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chemoattractant for neutrophils
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Cytokines secreted by activated macrophages
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IL-1, IL-6, IL-12, Tumor Necrosis Factor
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Eosinophils
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- derived from bone marrow
- half life = 8-10 hours - best defense against parasites (esp. helminths) -recognition of helminths = indirect -FcεR bind to IgE antibodies (that are bound to epitopes on helminths) - degranulation of eosinophils = secretes Major Basic protein & Eosinophilic Catonic Protein = both are toxic to helminths and parasites |
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What cell is the immune response to parasites?
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Eosinophils.
-recognition of helminths = indirect -FcεR bind to IgE antibodies (that are bound to epitopes on helminths) - degranulation of eosinophils = secretes Major Basic protein & Eosinophilic Catonic Protein = both are toxic to helminths and parasites |
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Natural Killer Cells
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- from bone marrow precursors
- found in blood, spleen, peritoneal exudate - kill virally infected cells of the body -induced by IFNγ, when stimulated by IL-12 and either IL-8 or IL-5 - enhanced by cytokines (IL-2, IL-12) - innate immune response to viruses - MHC class 1 - some viruses decrease MHC 1 signal - more susceptible to NK cells but avoid detection by adaptive immune system |
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A virus that downregulates specific Class I MHC-self-peptide on the cell surface will escape detection from ______ but be susceptible to _________.
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1. adaptive immune system
2. lytic action of NK cells |
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Where in cell is NADPH oxidase found?
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Cell membrane and cytosol
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Why are glycogen stores mobilized?
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PPP uses it to generate NADPH (needed by NADPH oxidase)
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What is the initiating step for the generation of other ROIs
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Formation of superoxide from oxygen and NADPH
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What does myeloperoxidase catalyze?
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Formation of hypochlorite (an antimicrobial agent)
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What is more potent ROI or RNI?
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RNI
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What organisms are resistant to ROI?
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Mycobacteria, leshmania and intracellular bacteria
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What 2 systems are affected by NO?
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Respiratory (iron sulfur proteins) and DNA synthesis
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What soluble mediator induces NO synthase? what antigens induce NO synthase?
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IFNγ,
phagocytosis mycobacteria or leishmania |
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What soluble mediators inhibit NO?
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TGF-B (most effective), IL-10, IL-4
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How do viruses evade destruction by NK cells
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Induce “killer inhibitory receptors” KIRs (ligand is class I MHC)
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What is receptor mediated cytotoxicity?
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Direct recognition of antigen by NK cell
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What is antibody mediated cellular cytotoxicity?
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Indirect recognition of antigen by NK via FcgR receptor
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How do NK cells kill microbes
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Insert perforins into microbes causing contents to leak
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What 2 substances do eosiniphils secrete?
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Major basic protein (MBP) and eosinophil cationic protein (ECP)
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What is the ½ life of eosinophils?
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8-10 hours
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