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89 Cards in this Set
- Front
- Back
What are macrophages derived from?
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Peripheral blood monocytes
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What happens when monocytes differentiate?
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They leave the peripheral vasculature and differentiate into tissue macrophages.
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What are 2 things that trigger macrophage activation?
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-Ingestion of bacteria or bacterial products
-Cytokines or chemokines |
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What are lung macrophages?
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alveolar
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What are connective tissue macrophages?
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histiocytes
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What are liver macrophages?
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kupffer cells
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What are kidney macrophages?
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Mesangial cells
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What are brain macrophages?
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microglial cells
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What are bone macrophages?
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osteoclasts
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What are 3 types of uptake macrophages can do?
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-Phagocytosis of large particles
-Endocytosis of small particles -Endocytosis of receptor/ligands |
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What is Endocytosis of small particles called?
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Pinocytosis
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What is endocytosis of receptors and their ligands called?
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Receptor mediated endocytosis
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What changes occur in the macrophage to allow for phagocytosis?
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The underlying cytoskeleton changes to loop out and around the particle being ingested.
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What are 5 main functions of macrophages?
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DRARE
-Detect microbial invasion -Restrict microbial spread -Assist in lymph activation -Recruit immune cells -Effect cell-mediated immunity |
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What are the 5 functional steps of phagocytosis?
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1. Recognition
2. Uptake 3. Maturation 4. Killing 5. Antigen presentation RUMKA |
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What is involved in bacterial recognition?
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Antigen-receptor interactions
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Do macrophages have only one receptor specific for each microbe?
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NO - they can recognize bugs with many different host receptors.
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What are 2 main ways that bacteria can be recognized by macrophages?
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-PAMPS/PRRs
-Opsonization and Fc receptor |
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What does the specificity of interaction determine?
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The subsequent steps that will occur in phagocytosis.
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What will the binding of complement coated microbes to the C3b receptor on macrophages result in?
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Induction of INOS and Phox activation to stimulate killing
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What will binding of Mannose residues on microbes to the Mannose binding receptor (TL4) on macrophages result in?
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Pathways that may allow the bacteria to survive within the cell.
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What are 4 surface structures on bacteria that influence their being recognized by macrophages?
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1. Pili
2. Surface proteins 3. Capsule 4. Flagella |
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How do pili influence bacterial recognition? What is an example of a bug that uses this mechanism?
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Pili can undergo phase variation in response to variations in their environment - as in E. coli
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How do surface proteins influence bacterial recognition? What is an example of a bug that uses this mechanism?
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Changes in surface proteins can completely change the antigenic appearance of bugs like Borellia recurrentis
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What disease is caused by borellia recurrentis?
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Relapsing fever
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How do Flagella influence bacterial recognition?
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Flagellar expression can be regulated by the bacteria.
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How do Capsules influence bacterial recognition? What is an example of a bug that uses this mechanism?
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Capsules can mask the epitopes of LPS and PG on some Gram pos bacteria and allow them to resist phagocytosis.
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So the 4 main types of macrophage receptors for bacteria are:
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-PRRs
-LPS/LTA -Plasma derived -Membrane derived |
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What bugs have LPS?
What bugs have LTA? |
LPS = gram neg
LTA = gram pos (lipotechoate) |
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How do extracellular pathogens avoid recognition?
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By capsules
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What are 3 examples of plasma derived receptors on macrophages?
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-Collectins
-Pentraxins -Complement |
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What are 4 examples of membrane-derived receptors on macrophages?
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-C-type lectins
-Leucine rich protiens -Scavenger receptors -Integrins |
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What is an example of a C-type lectin?
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Macrophage mannose receptor
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What are 4 microbes that have mannose?
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-Candida albicans
-Mycobacterium tuberculosis -Pneumocystis carinnii -HIV1 |
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What is an example of a Leucine rich protein surface receptor on macrophages?
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CD14
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What are the microbial ligands for CD14?
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LPS and LTA
Peptidoglycan E. coli |
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What is an example of a Scavenger receptor on macrophages?
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Scavenger receptor A type I
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What are the microbial ligands for Scavenger receptor A type I?
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LPS and LTA
B. subtilis E. coli |
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What is an example of an integrin receptor on macrophages?
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CR3
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What are the microbial ligands for CR3?
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-M. tuberculosis
-B. pertussis -Leishmania -H. capsulatum |
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What step occurs in phagocytosis after bacterial recognition?
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Bacterial uptake
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What are the 3 general steps of bacterial uptake?
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1. Microbe/receptor induces signal transduction cascade
2. Cytoskeletal remodels by actin depolymerization and repolymerization 3. Bacterium internalized into a phagosome |
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What type of process is bacterial uptake normally?
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Passive
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What is required for non-phagocytic cells to take up bacteria?
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The bugs have to actively induce their own uptake.
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How does Salmonella typhimurium induce its uptake?
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By a trigger mechanism
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What is the active mechanism utilized by L. monocytogenes?
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Zipper
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What is involved in the Trigger mechanism?
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-Major cytoskeletal remodeling
-Effector proteins |
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What is involved in the Zipper mechanism?
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-Receptor mediated process
-Minimal cytoskeletal remodeling -Bacterial sliding into cell |
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How does Francisella tularensis get into macrophages?
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By looping phagocytosis
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How does Legionella pneumophilia get into macrophages?
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By coiling phagocytosis
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What does Rickettsia do once it is phagocytosed?
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It escapes the phagosome by degrading it.
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What step occurs after bacterial uptake?
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Maturation of the phagosomes that contain the bacteria.
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What is the fun description of phagosome maturation?
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It's like a train that rides around on microtubule train tracks, picking up cars that alter the phagosomal pH as it goes from periphery to perinuclear region.
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What does the phagosome fuse with?
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Endocytic vesicles
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What do early endosomes display?
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-Rab5
-Transferrin receptor -Fluid phase markers (FPMs) |
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What do late endosomes display?
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-Rab7
-EEA1 -M6PR -Lamp1 and Lamp2 -H ATPase -other FPMs |
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What do Phagolysosomes display?
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-Cathepsin D
-LAP -H ATPase |
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What is the pH of the phagosome at ingestion?
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7
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What is the pH of the phagosome after fusion with early endosomes?
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6.5 - 6
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What is the pH of the phagosome after fusion with late endosomes?
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6 - 5
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What is the final pH of the phagolysosome?
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4-5
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What are Intracellular bacteria able to do in macrophages?
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Block or alter the steps in phagosome maturation
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What are the 4 mechanisms for altering phagosome trafficking?
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1. Survive/replicate in phagolysosomes
2. Escape/replicate in cytosol 3. Modulate endocytosis 4. Modulate membrane trafficking |
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What organism survives and replicates in phagolysosomes?
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Coxiella
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Is anything altered about the phagosome maturation with Coxiella living in it?
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No - in fact maturation is accelerated!
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What does Coxiella do within the phagolysosome?
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Replicates to high numbers
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How can Coxiella survive the phagolysosome?
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It has mechanisms to resist the low pH and antimicrobial products, and actually they activate genes that allow the bug to survive.
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What are 5 bugs that can escape from phagosomes?
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-Rickettsia
-Shigella -E. coli -Listeria -Francisella tularensis |
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Why do those bugs have to escape from phagosomes?
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In order to be able to replicate.
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How do the bugs escape from their phagosomes?
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By expressing dedicated enzymes that degrade the phagosomal compartment
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How do the microbes survive intracellularly?
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-avoid fusing with lysosomes
-Cytosol is nice and nutrient rich |
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What 2 organisms exhibit cell-to-cell spread, and how?
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Shigella and Listeria - by making actin comet tails
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What 2 microbes alter the phagocytic pathway?
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-Mycobacterium
-Salmonella |
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Why do Mycobacterium and Salmonella alter the phagocytic pathway?
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To establish themselves a unique niche within the phagocyte.
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How do mycobacteria establish a niche?
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By preventing acidification by arresting the phagosome at an early stage.
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How does Salmonella establish a niche?
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It allows acidification of the phagosome, but survives the acid.
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What are the stipulations for when alteration of the phagocytic pathway will work?
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-Bacteria must be alive
-Macrophage must remain inactivated |
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How do bacteria arrest the phagosome at early stages?
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By expressing proteins that subvert the normal maturation process.
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How does Salmonella remain intracellularly?
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By the formation of a spacious vacuole
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What microbes survive intracellularly by entering different phagocytic pathways?
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-Legionella
-Brucella -Chlamydia |
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How is the phagocytic pathway utilized by Legionella/Brucella and Chlamydia different?
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-It is not accessible to the endocytic network or lysosome fusion events
-It remains closely interacting with ER and golgi |
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What are the mechanisms of bacteria killing by lysosomes?
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-iNOS
-NADPH oxidase -Acidic pH -PHox -Defensins/Lysozyme |
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What can macrophages do after bacteria are killed?
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-Activate and ahieve effector functions
-Process and present the microbe as antigen |
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What do activated macrophages secrete?
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Cytokines
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What cytokines do activated macrophages secrete?
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IL1, TNF-alpha
IL6, 8, and 12 |
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What are the effects of macrophage cytokine secretion?
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-Lymphocyte recruitment and activation
-Cross activation of other immune cells -Increased vascular permeability |
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What are the systemic effects of IL1 and IL6 production?
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Fever and APR production
Wasting Shock |
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What happens when macrophages are continuously stimulted?
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Tissue injury and disease
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How does mycobacterium cause so much damage to the host?
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By inducing so much chronic inflammation.
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