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421 Cards in this Set
- Front
- Back
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Efficacy of chemical antimicrobial agents is reduced or entirely neutralized in the presence of what? |
Organic materials and biofilms |
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What should any disinfection procedure begin with? |
Physical removal of organic material and cleansing of the surface or wound with detergent |
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What are endospores and how does their response to chemical inactivation compare with vegetative cells? |
They are desiccated structures of low metabolism They are far more resistant to chemical inactivation than vegetative cells |
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What is a kind of bacteria that has a waxy cell wall that resists common disinfectants? |
Mycobacterium tuberculosis |
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What are synthetic antimicrobial drugs? |
Chemically manufactured compounds that have been chosen for their selective toxicity |
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What is selective toxicity?
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The ability to inhibit or kill pathogens without damaging the host |
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What does selectivity of an antimicrobial depend on? |
Targeting a metabolic function that differs between the target pathogen and the host or other microbes (to avoid impacting the normal flora too much) |
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Which kind of antimicrobials require a functional immune system in the host to finally eliminate an infection? |
Bacteriostatic |
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What kind of bacteria are Chlamydia and Rickettsia? |
Obligately parasitic bacteria |
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Bacteria can be broadly classified into which 4 groups? |
Mycobacteria Gram positive Gram negative Obligately parasitic |
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What is the spectrum of tetracycline? |
It's a broad spectrum antibiotic (kills G+, G-, and obligately parasitic bacteria) |
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What is an integral component of mycobacterial cell walls? |
Mycolic acid |
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What antibiotic can target mycobacteria? |
Isoniazid |
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What is another name for growth factor analogues? |
Anti-metabolites |
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What are growth factor analogues? |
Compounds that are structurally similar to a natural growth factor required by the pathogen but which are different enough to disrupt function of the natural growth factor, usually by competitive or noncompetitive inhibition of an essential enzymatic activity |
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List some growth factor analogues |
Sulfa drugs Isoniazid Nucleoside analogues |
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What does "antibiotic" mean? |
A compound that is produced by MICROORGANISMS that inhibit the growth of bacteria |
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Sulfa drugs are analogues of what? Describe how they work |
They are analogues of p-aminobenzoic acid that block synthesis of folic acid, inhibiting nucleic acid synthesis |
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Why are sulfa drugs selectively toxic to bacteria? |
Because bacteria must synthesize their own folic acid, whereas animals get folic acid from their diet |
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Why is folic acid important? |
It is needed as a cofactor in the synthesis of DNA and other enzymatic reactions |
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Isoniazid is active only against what? |
Mycobacterium |
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Isoniazid is a what analog? |
Nicotinamide analog |
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Describe how Isoniazid works |
It is a nicotinamide analog that interferes with myconic acid synthesis, which is an essential component of mycobacteria cell walls |
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Nucleoside analogues are typically used for what? |
Anti-viral compounds (they mimic nucleosides like thymidine) |
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Why is selective toxicity against viruses more difficult to achieve? |
Because viruses use the host cell metabolic machinery to replicate |
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Describe the margin of safety for a lot of antiviral drugs |
It is low |
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What do nucleoside analog drugs target? |
They target the elongation of nucleic acids produced by RNA-dependent (reverse transcriptase) or DNA-dependent DNA polymerases |
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What does the D in DAMNIT stand for? |
Degenerative, developmental |
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Drugs that use integrase are specific for what? |
Retroviruses |
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What are some examples of fungal cell wall inhibitors? |
Azoles Polyenes Allylamines |
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What do fungal cell wall inhibitors (the azoles, polyenes, and allylamines) target? |
They inhibit ergosterol synthesis, which is an essential component of fungal cell membranes |
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What do fungal cell wall inhibitors (echinocandins) target? |
They inhibit 1,3-beta-D-glucan synthase, which is an enzyme that creates fungal cell wall glucan polymers |
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What are inhibitors of chitin synthesis? |
Polyoxins (but they aren't suitable for clinical use) |
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What are some specific molecules that can be targeted in fungal cell walls that are not components of mammalian cells? |
Ergosterol, glucan polymers, and chitin |
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How do quinolones work? |
They interfere with bacterial DNA gyrase, which is an enzyme essential for supercoiling |
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Quinolones are derivatives of what? |
Nalidixic acid |
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Describe the fluoroquinolones |
(like ciprofloxacin) They are broad-spectrum, being effective on both G+ and G- bacteria (they interfere with supercoiling and are derivatives of nalidixic acid) |
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By definition, what are antibiotics? |
Compounds made by microorganisms, either fungi or bacteria, to kill or inhibit other microorganisms |
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Are any antibiotics anti-viral? |
Nope |
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Why is it that <1% of antibiotics are clinically useful? |
Due either to host toxicity or suboptimal pharmacologic characteristics such as poor absorption |
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What is the main structural component of gram positive organisms? |
Peptidoglycan |
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Penicillin is produced naturally by what? |
The fungus Penicillium chrysogenum |
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Antibiotics that target cell wall synthesis target which type of bacteria mainly? |
Gram positive bacteria (but their spectrums have been broadened through modifications to include Gram negative) |
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Describe how penicillin works |
It binds to and inactivates the bacterial enzyme responsible for extracellular transpeptidation during peptidoglycan synthesis |
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What part of penicillin is the active structural component? What does it inhibit? |
The beta lactam ring (it inhibits transpeptidation) |
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How does resistance to penicillin occur? |
It occurs when a bacterial strain harbors beta lactamase, which is an enzyme that cleaves the beta lactam ring |
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How can penicillin be given different properties? |
Through substitutions to the R group (artificial chemical modifications) |
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How can coupling amoxicillin with clavulinic acid be helpful? |
Clavulinic acid is a beta lactamase inhibitor, so that will reduce the MIC |
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What are some benefits elicited by artificial chemical modifications? |
-Broadening the spectrum of activity to include some of many G- bacteria -Making the molecule acid stable -Making the drug more resistant to beta lactamase degradation |
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How can beta lactam drugs be made more effective? |
Combined drug therapy with beta lactamase inhibitor Artificial chemical modifications to make the drug have a more broad spectrum, acid stable, or more resistant to beta lactamase degradation |
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Are antibiotics that target bacterial cell wall synthesis bacteriocidal or bacteriostatic? |
Bacteriocidal |
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What is another group of antibiotics that is produced naturally by the Cephalosporium fungi? |
Cephalosporins |
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Describe cephalosporins |
Have the beta lactam ring that binds and inhibits the transpeptidase enzyme Are more beta lactamase resistant Have undergone modifications to enhance various characteristics |
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Both cephalosporins and penicillins do what? |
Inhibit the transpeptidase which helps form the peptidoglycan cell wall |
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What is vancomycin? |
A glycopeptide antibiotic (it is a disaccharide plus a cyclic peptide) that blocks peptidoglycan biosynthesis |
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How does vancomycin work? |
It binds to the intracellular peptidoglycan precursors and blocks their transport to the cell exterior |
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What is vancomycin synthesized by? |
Amycolatopsis orientalis |
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Which peptidoglycan synthesis blocking antibiotic is a drug of last resort? Which kinds of infections are this drug normally used against? |
Vancomycin MRSA and Clostridium difficile |
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What are some types of antibiotics that target protein synthesis? |
Aminoglycosides Tetracyclines Macrolides |
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Why are antibiotics that target protein synthesis selectively toxic? |
Because they act by binding bacterial 30S or 50S ribosomal subunits but may also interfere with mitochondrial ribosomes (the bacterial ribosomes are different from eukaryotic ribosomes but the mitochondrial ones are the same so eukaryotic ones may be harmed) |
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So, antibiotics that target protein synthesis target bacterial __________ machinery |
Translation |
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Why are antibiotics that target protein synthesis broad spectrum? |
The translation machinery is shared across both G+ and G- bacteria |
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What does the A in DAMNIT stand for? |
Anomalous, autoimmune |
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What do aminoglycosides target? |
The 30S ribosomal subunit (they halt protein translation) |
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Are aminoglycosides bacteriostatic or bactericidal? |
Bactericidal |
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Amino glycosides are effective against which kind of organisms? |
G- mostly |
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What do tetracyclines target? |
The 30S ribosomal subunit (but they target a different site on the subunit than the aminoglycosides) |
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Are tetracyclines bactericidal or bacteriostatic? |
Bacteriostatic |
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Tetracyclines have a broad spectrum, but which organisms are they particularly useful against? |
Non-cell walled obligate intracellular pathogens such as Chlamydophilia, Ehrlichia, and Rickettsia (these organisms live inside cells and use their cellular machinery to replicate) |
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Which antibiotics bind to the 50S ribosomal subunit? |
Macrolides Lincosamides Chloramphenicol |
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Describe the spectrum of macrolides, lincosamides, and chloramphenicol and whether they are bactericidal or bacteriostatic |
They are broad spectrum Bacteriostatic |
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Which antibiotic types target the 30S ribosomal subunit? Describe whether they are bactericidal or bacteriostatic |
Aminoglycosides--bactericidal Tetracyclines--bacteriostatic |
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Which antibiotic types target the 50S ribosomal subunit? Are they bactericidal or bacteriostatic? |
Macrolides Lincosamides Chloramphenicol Bacteriostatic |
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Why isn't chloramphenicol used much in humans any longer? |
Due to idiosyncratic reactions of fatal aplastic anemia |
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What does idiosyncratic mean? |
We don't know why it happens so we can't predict it |
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What does the M in DAMNIT stand for? |
Metabolic, mechanical, mental |
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What does the N in DAMNIT stand for? |
Nutritional, neoplastic |
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What does the I in DAMNIT stand for? |
Inflammatory (infectious or noninfectious) Ischemic Immune Inherited Iatrogenic Idiopathic |
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Which antibiotic has been associated with fatal aplastic anemia? |
Chloramphenicol |
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What are some antibiotics that target RNA transcription? |
Rifampin and streptovaricins |
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How do antibiotics target RNA transcription? |
They bind the beta subunit of RNA polymerases to inhibit RNA synthesis in bacteria and mitochondria |
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What also binds DNA and prevents RNA elongation? |
Actinomycin |
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Which kind of antibiotic can target DNA repair? |
Imidazoles (i.e. metronidazole) |
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Describe the use and usefulness of antibiotics that target DNA repair |
They interfere with DNA repair systems and also introduce DNA breaks They are useful for infections due to G- anaerobic rods (found in the gut) and some protozoa like Giardia |
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Why is it more difficult to have selective toxicity for antivirals? |
Because the viruses often use the eukaryotic host cell for replication and completion of its life cycle |
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What are some simple, common antivirals for external use? |
Cold disinfectants and moist heat (bleach and autoclaving) |
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What are some virus-specific activities that can be targeted by anti-viral compounds? |
Uncoating and reverse transcription |
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Describe the spectrum of anti-viral drugs |
Very narrow |
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What are some types of anti-viral drugs? |
Nucleoside analogues Viral protease inhibitors Neuraminidase inhibitors Interferons |
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How do nucleoside inhibitors work as anti-viral drugs? |
Some act as viral polymerase inhibitors (primarily active against herpes and cytomegaloviruses--like acyclovir and ganciclovir) Others inhibit reverse transcriptase (are active against HIV and FIV) |
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Describe viral protease inhibitors |
(e.g. lopinavir and indinavir) Have anti-HIV activity and are typically included in combination therapy |
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Describe how neuraminidase inhibitors work as anti-viral drugs |
They specifically block the activity of influenza virus neuraminidase, which is an enzyme required for the release of new virion particles, so this blocks their replication Others block the M2 ion channel which is required for uncoating |
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What does the T in DAMNIT stand for? |
Traumatic (internal or external) Toxic (endogenous or exogenous) |
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How do synthetic amines work as neuraminidase inhibitors? |
They block the M2 ion channel of the influenza virus envelope that is required for uncaring |
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What are interferons and when are they secreted? What do they do when they're secreted? |
They are small secreted proteins produced by host cells when infected by a virus They induce resistance to virus infection, generally in adjacent uninfected cells (so, they could be good antiviral drugs) |
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What is a drawback to interferons? |
They are species specific No company will develop a feline IFN or equine IFN mainly because the market for them is small |
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What things must happen for a drug to be effective? |
A drug must permeate into the target microorganism, must not be degraded or exported rapidly, and must bind to a particular functional structure. Not all organisms harbor the structure targeted by a particular drug. |
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Why are mycoplasma bacteria resistant to penicillin and cephalosporin derivatives? |
Because they don't have a cell wall |
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How do many organisms modify a drug molecule? |
Through acetylation or phosphorylation after it has been permeated through, which makes the drug inactive They could otherwise use a transporter to move it out of the cell |
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How do many bacteria degrade penicillins? |
They have beta lactamase and degrade it |
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What is a substance that can help antibiotics penetrate better? How does it do this? |
EDTA It chelates Ca to prevent coagulation; for some bacteria, it binds Ca to make them more permeable |
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What happens to other bacteria in a population when you kill off susceptible strains? |
They remain with less competition to proliferate |
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What is the selective pressure for antibiotic resistance? |
The antibiotics we use |
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How can multiple genes be spread quickly to other bacteria? |
Horizontal transfer |
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What should you first do if presented with an animal that "ain't doing' right"? |
Collect its history and conduct a thorough physical exam |
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What should you do, based on your history and physical findings? |
Define a set of the animal's "problems" and develop a list of possible diagnoses (hypotheses) |
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When should you collect samples for specific lab tests to rule out or confirm hypotheses? |
After defining a set of the animal's "problems" and developing a list of possible diagnoses (hypotheses) |
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Why is accurate diagnosis crucial? |
Because it allows one to design appropriate specific therapy and to give a rational prognosis |
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What is the DAMNIT scheme? |
A list of the familiar pathophysiologic disease processes to consider during the diagnostic process |
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What is the generalized response caused by the innate immune system in response to most infections? |
Inflammation |
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What does the overall "sick feeling" comprise? |
Fatigue Depression Lethargy Wanting to sleep Loss of appetite Muscle and joint soreness Fever |
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What is the "sick feeling" an effect of? |
The innate immune responses on the CNS, liver, and bone marrow |
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What do infectious organisms FIRST interact with in the body? |
Sentinel immune cells |
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What are the sentinel immune cells? |
Mast cells, macrophages, and dendritic cells |
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What do sentinel cells DO when they interact with a foreign organism? |
They secrete pro-inflammatory cytokines |
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What is the purpose of pro-inflammatory cytokines? |
To alert other immune cells that a danger exists and affect local capillaries surrounding the site of infection |
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What global effects do pro-inflammatory cytokines cause from their action on the hypothalamus? |
Fever, anorexia, sleepiness, and depression |
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What global effects do pro-inflammatory cytokines cause from their action on the bone marrow? |
Increased production and release of white blood cells |
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What global effects do pro-inflammatory cytokines cause from their action on the liver? |
Increased synthesis of "acute-phase proteins" that enhance phagocyte actions and sequestration of iron |
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What global effects do pro-inflammatory cytokines cause from their action on the muscle? |
Enhanced protein catabolism and release of a pool of available amino acids |
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What global effects do pro-inflammatory cytokines cause from their action on the adipose tissue? |
Release of stored fats |
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If inflammation is chronic, what will be two visible signs? |
Muscle and fat wasting |
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What are the signs of acute local inflammation? |
Redness, heat, swelling, pain, and loss of function |
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What causes the signs of local, acute inflammation? |
The effects of pro-inflammatory cytokines on local capillaries surrounding a site of infection |
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What determines whether an inflammation- inciting insult causes systemic signs? |
The amount and chronicity of pro-inflammatory cytokine production |
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What is a potential life-threatening result of massive pro-inflammatory cytokine release? |
Shock |
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What are some results of a cytokine storm leading to shock? |
Fever Acidosis Global hypotension Disseminated intravascular coagulation Endothelial damage resulting in multiple organ system failure and death |
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__________ arises from the collective, integrated mechanisms for preventing and/or eliminating an infection |
Immunity |
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What is the FUNDAMENTAL basis of immunity? |
The ability to discriminate self from non-self |
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What is the first line of defense? |
The genetically determined aspects of normal anatomy and physiology that prevent infection in a nonspecific fashion (called innate immunity) |
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Describe some non-specific barriers to infection |
Physical barriers (skin, mucus, airway turbulence, cilia, and intermittent or constant flow across surfaces that inhibit microbial adherence) Chemical barriers (stomach acid, low pH of urine, free fatty acids on skin, defenses, products of normal flora that inhibit pathogens, microbiome) |
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Describe some components of the "second line of defense" (after physical and chemical barriers) |
Inflammation Complement Phagocytosis Interferon Natural killer cells |
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Describe what inflammation can be defined as |
The acute response that causes local dilation and increased leakiness of capillaries allowing plasma proteins and immune cells to access the site of infection |
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What is inflammation initiated by? |
Sentinell cells' TLRs binding to PAMPs |
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What are PAMPs? |
Pathogen-associated molecular patterns |
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Describe what the complement is |
A group of plasma proteins that participates in an enzyme cascade that results in enhanced destruction of pathogens |
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What are 3 objectives of the complement cascade? |
1) Better uptake and destruction of microbes by immune cells 2) Damage to microbial membranes (death) 3) Enhanced inflammation |
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What is the final common pathway of immune reactions? |
Phagocytosis |
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Describe what phagocytosis is |
Where cells engulf and digest microbes and microbial debris; also used to dispose of apoptotic host cells without inducing inflammation |
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Describe what interferon does |
It is secreted in a paracrine manner from virus-infected cells that creates changes in neighboring cells to inhibit their infection |
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Describe what NK cells are/what they do |
They are cells that constantly circulate and migrate through tissues monitoring for signs of viral infection or cancerous transformation When found, they kill the cells showing those signs |
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What is acquired (adaptive) immunity? |
Those activities of immune cells learned by prior exposure and responses to infectious agents by mechanisms which either neutralize the infectious agent directly or enhance the effectiveness of some aspect of innate immunity such as the complement reaction or phagocytosis |
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Which acts more quickly--innate or adaptive immunity? |
Innate immunity |
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How is the phenomenon of immunologic memory evident in adaptive immunity? |
In that this kind of immunity is more rapid in onset and more effective upon second and subsequent exposures to the same infectious agent |
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What are humoral responses? |
Those resulting in the production of antibodies |
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What are antibodies? |
Soluble proteins designed to bind tightly to infectious agents |
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What are cell-mediated responses? |
Those resulting in the production of cells that use direct cell-cell contact to kill a target cell |
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Which kind of immunity uses humoral and cell-mediated responses? |
Acquired immunity |
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What is an antigen? |
Any molecule that an animal can make an antibody to bind to it |
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What is the smallest that peptides can be to be an antigen?
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8 amino acid residues |
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What does the immune system "see"? |
Molecular shapes NOT organisms |
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When does an immune response end? |
When the foreign antigen is eliminated |
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What are antigen-presenting cells? |
Cells specialized to "see" antigens and initiate acquired immune responses |
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What are effector cells? |
Those that secrete antibodies in the humoral response or do the killing in cell-mediated responses |
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What are some characteristics that acquired immunity exhibits? |
Humoral and cell-mediated responses Antigen specificity (and is antigen-driven) Antigen recognizing cells (APCs) and effector cells Immunologic memory |
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Blood is about what percent extracellular fluid? |
60% |
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Blood is about what percent red blood cells? |
40% |
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Blood is about what percent white blood cells? |
1% |
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What is another name for the white blood cell layer? |
The buffy coat |
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What are the white blood cells (functionally)? |
All of the cells in blood that participate in immune responses |
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How are white blood cells measured? (what per what?) |
Thousands of WBCs/microliter of blood |
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Describe where the WBCs in blood are in transit to or from |
They are in transit from the bone marrow to tissues or recycling from one tissue to another |
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What is the site of production of WBCs? |
Bone marrow |
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What reside in the bone marrow? (that all immune cells in circulation are progeny of) |
Pluripotent stem cells |
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What does initial differentiation of pluripotent stem cells produce? |
It divides the family into myeloid/monocytic (gives rise to phagocytic cells) and lymphoid stem cells (gives rise to lymphocytes) |
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What do myeloid/monocytic cells give rise to? |
Phagocytic cells |
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What do lymphoid stem cells give rise to? |
Lymphoid cells |
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What do phagocytes do? |
Engulf, inactivate, and hydrolyze particles of foreign and endogenous nature for disposal |
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What are the "professional" phagocytes? |
Neutrophils and macrophages |
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Describe the shape of neutrophils' nucleus |
Polymorphonuclear |
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What percent of the total WBC are neutrophils in small animals? In ruminants? |
60-80% of total WBCs in small animals 20-30% of total WBCs in ruminants |
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What is the most numerous WBC in small animals? |
Neutrophils |
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What is the most numerous WBC in large animals? (and what percent of the total WBC are these) |
Lymphocytes 50-75% of total WBC |
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What is the half-life circulation of neutrophils? |
About 12 hours |
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How long do neutrophils live? |
Only a few days |
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Neutrophils are highly responsive to ____________ infections |
Bacterial |
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Why don't neutrophils need to be long-lasting? Won't they deplete really quickly? |
The bone marrow production can increase quickly to replace their numbers |
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Which cell is a major constituent of pus? |
Neutrophils |
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Where are monocytes/macrophages produced? |
In bone marrow |
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What are macrophages called while they are in circulation?
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Monocytes |
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What are macrophages called in the: Liver Brain Connective tissue Lungs ?? |
Liver--Kupffer cells Brain--microglia Connective tissue--histiocytes Lungs--alveolar macrophages |
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How long do monocytes stay in circulation for? |
~3 days |
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How long can tissue macrophages stay? |
For months unless activated by inflammation |
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What is the approximate ratio of tissue macrophages to blood monocytes? |
~400:1 |
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What is the % of WBCs of monocytes circulating in blood? |
~5% of WBCs |
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Which cells are also polymorphonuclear but are less phagocytic than neutrophils? |
Eosinophils and basophils |
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What is the major function of eosinophils and basophils? |
Secretion of their granule contents |
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Where do eosinophils mature, and what is their half-life in circulation? In tissues? |
Mature in the spleen Half-life in circulation is about 30 minutes Half-life in tissues is about 12 days |
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What do eosinophils' granules contain? What are they very effective against? |
Cationic proteins that are highly toxic to parasites Eosinophils dump the contents of their granules into surrounding fluid for extracellular destruction of large organisms |
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Which WBC is the least in number? Where is it mostly found? |
Basophils In circulation |
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What do basophils' granules contain? |
Potent mediators of inflammation |
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What do lymphoid cells include? |
Lymphocytes (B cells and T cells) Plasma cells NK cells |
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What is it that lymphocytes are produced and begin to differentiate? |
In bone marrow |
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What are the largest % of WBCs in large animals? |
Lymphocytes (50-75% of WBCs) |
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What do B-lymphocytes do in the bone marrow? |
Complete antigen-independent differentiation |
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Where do B-lymphocytes complete antigen- independent differentiation complete some antigen-independent differentiation in large animals? In birds? |
Large animals--Peyer's patches Birds--bursa of Fabricius |
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What do B-lymphocytes do after they leave the bone marrow? |
Move to populate secondary lymphoid organs |
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What do B-lymphocytes do upon antigen
stimulation? |
They differentiate into antibody secreting plasma cells |
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Where are T-lymphocytes produced? |
In the bone marrow |
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What do T cells do in the thymus? |
Undergo subsequent steps of differentiation |
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Where do T cells go after they leave the thymus?
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To secondary lymphoid organs |
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What are the two types of mature T cells? |
T helper cells Cytolytic T cells |
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What do T helper cells do? |
They respond to antigen stimulation by secreting an array of cytokines which act on surrounding cells to enhance both humoral and cell-mediated responses to antigen |
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What to cytolytic T cells do? |
They are activated in response to specific antigens and destroy transformed (cancer) or virus infected cells displaying foreign molecules |
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NK cells are involved in ________ immunity |
Innate |
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How do NK cells work? |
They have targets and killing mechanisms similar to cytolytic T cells but they recognize signs that a cells is infected that are not antigen-specific They also secrete cytokines that enhance the activities of other immune effector cells (like macrophages) |
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What is the main difference between how NK and cytolytic T cells work? |
Cytolytic T cells are activated in response to SPECIFIC antigens NK cells have similar targets and killing mechanisms as the cytolytic T cells but recognize signs that a cell is infected that are NOT antigenspecific |
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Are NK cells phagocytic? |
Nope |
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Which immune cells have a round nucleus? |
Monocytes, lymphocytes, and NK cells |
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Which cells arise from lymphoid stem cells? |
B cell T cell NK cell |
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List the general characteristics of innate responses |
Nonspecific Occur locally Have rapid onset but short duration Do not display immunologic memory |
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What is the most important innate response to infection? |
Acute inflammation |
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Why is acute inflammation so important for combatting foreign materials? |
It focuses phagocytic cells and soluble defensive molecules from plasma on a local region of tissue |
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Acute inflammation is a local, temporary response to infection or tissue damage resulting in _________ blood flow and leakage of __________ from capillaries allowing escape of ______________ from the bloodstream |
INCREASED blood flow Leakage of FLUID from capillaries Allowing escape of NEUTROPHILS AND LARGE MOLECULES, SUCH AS ANTIBODIES AND COMPLEMENT COMPONENTS from the bloodstream |
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Describe chronic inflammation |
It is a prolonged, local or generalized, and sometimes unregulated process caused by a persistent inflammatory stimulus that may cause pathology in the host |
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What are the 3 main sentinel cells? |
Macrophages, dendritic cells, and mast cells |
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Where are sentinel cells mainly distributed? |
In common avenues of invasion, like skin, epithelial linings of the gut, airways, urogenital tract, mammary glands, lymph nodes, liver, and spleen |
|
|
Describe the surface receptors on sentinel cells |
They have toll-like receptors, which recognize highly conserved molecular patterns that are found on different classes of pathogens |
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|
What are the 4 main pro-inflammatory cytokines that are released in response to TLR binding to a PAMP? |
TNF alpha, IL-1, IL-6, and IL-12 |
|
|
Besides sentinel cells, which other immune cells have TLRs on their surface? |
Neutrophils and eosinophils |
|
|
How are responses partially tailed to the invading organism when TLRs bind to pathogens? |
If the TLRs bind to bacteria--cytokines are secreted that stimulate antibacterial responses (like an influx of neutrophils) If the TLRs bind to viral products--cytokines are secreted that stimulate secretion of interferons that enhance neighboring cell resistance to viral infection |
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|
What is another term for activating the complement cascade? |
Complement "fixation" |
|
|
What initiates the alternative pathway? |
Presence of non host cell membranes |
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|
What initiates the lecithin pathway? |
Binding of mannose binding protein to mannose on the foreign surface |
|
|
What does the complement result in? |
Direct disruption of microbe membrane or enhanced destruction by immune cells |
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|
What are C3a and C5a? What do they do? |
By-products of the complement cascade They are chemotaxins that enhance the inflammatory reaction by causing mast cell degranulation and further influx of immune cells |
|
|
What are the cardinal signs of acute inflammation? (locally) |
Heat, redness, swelling, pain, and loss of function |
|
|
What do sentinel cells do when they detect pathogens in a tissue? |
Secrete pro-inflammatory cytokines |
|
|
So, within minutes of insult in a tissue, what happens? |
Capillaries dilate and blood flow increases |
|
|
How does leakiness result from dilation? |
Dilation stretches endothelial junctions, which leads to leakiness |
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|
Why is it important that vasculature becomes leaky from acute inflammation? |
Because it allows antibodies and complement proteins and other large molecules to diffuse through to the site of infection |
|
|
What are the two main kinds of phagocytic cells? |
Polymorphonuclear (neutrophils) and macrophages |
|
|
What effect do pro-inflammatory cytokines have on the liver? |
It signals them to secrete acute-phase proteins |
|
|
What do acute-phase proteins do? |
They aid in the phagocytic process Sequester iron |
|
|
Most of what is seen in the beginning of the inflammatory process is caused by what? |
Pro-inflammatory cytokines |
|
|
What are granulomas? |
An effect of chronic inflammation that is a structure that will form inside an infected tissue-often the lungs-where a collection of immune cells come together and lay down collagen to wall themselves off |
|
|
Describe how acute local inflammation starts and occurs |
*Started by sentinel cells' release of cytokines *The response is dilation of arterioles that control capillary beds so you get some swelling and heat *Focuses where you need it so soluble proteins like Abs and the complement cascade proteins can reach the site of infection *Then neutrophils arrive to phagocytize things as well as macrophages *If these are sufficient to eliminate the threat, it stops |
|
|
Where do complement proteins localize? |
At the site of infection |
|
|
What do complement proteins do? |
*They are a group of proteins that cause an enzyme cascade *This cascade creates protein molecules that call in more phagocytic cells into the area (bring more neutrophils and macrophages in) *They also cover up the foreign material in a protein that helps other things engulf it *They can also create a protein complex in the wall of the bacteria to poke holes in it |
|
|
What is the final common pathway of immune reactions? |
Phagocytosis (where cells engulf and digest microbes and microbial debris) |
|
|
Are interferons part of the innate response? |
Yep |
|
|
Is the complement cascade part of the innate response? |
Yep |
|
|
What do NK cells mainly analyze for? |
Viral-infected cells and cancer |
|
|
What do NK cells do when they find unacceptable cells? |
They cause them to undergo apoptosis (This is good because it just lets the bad cell shrivel up and get phagocytized, so keeps it from causing inflammation) |
|
|
How long can it take to make specific antibodies on a first exposure to something? |
10 days to 2 weeks |
|
|
What separates innate from adaptive immune responses? |
Immunologic memory |
|
|
Which immunity is something you're born with? |
Innate immunity |
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|
What does it mean to be an antigen-driven process? |
It means that the response will continue as long as the antigen is present When the antigen is destroyed, the process will stop |
|
|
What are the "eyes" of the immune system? |
The receptors on immune cells (They recognize particular shapes) |
|
|
About what is the limit of smallness for an
antigen? |
8 amino acids |
|
|
Which cells are specialized to "see" antigens and initiate acquired immune responses? |
Antigen presenting cells |
|
|
Which cells secrete antibodies in the humoral response or do the killing in cell-mediated responses? |
Effector cells |
|
|
How are macrophages and dendritic cells important as APCs? (Roughly, what do they do?) |
They present bits of pathogens to T cells |
|
|
"Myeloid" refers to what? |
White blood cells (but red blood cells also come from the myeloid stem cell) |
|
|
Does gaining of functionality for lymphocytes occur in the bone marrow? |
Nope |
|
|
If blood didn't clot before it was centrifuged, what will the fluid component be? |
Plasma (It will contain all of the clotting factors and will have all of the Abs, growth factors, etc.) |
|
|
If blood clotted before it was centrifuged, what will the fluid component be? |
Serum (It won't have any clotting factors in it) |
|
|
What is a normal range for % RBCs in centrifuged blood? |
32-50% (~40%) |
|
|
40% RBC is about how many per microliter? |
5 million/microliter |
|
|
How many WBCs do we expect per microliter? |
10,000 |
|
|
What is the "munitions factory" for lymphoid cells in the body? |
Bone marrow |
|
|
All of the immune cells in blood that participate in immune responses are what? |
WBCs |
|
|
Initial differentiation of pluripotent stem cells result in which cells? |
Myeloid/monocytic stem cells and Lymphoid stem cells |
|
|
What are the "professional" phagocytes? |
Macrophages and neutrophils |
|
|
What are the PMNs? |
Neutrophils, eosinophils, and basophils |
|
|
Formation of lobes in the neutrophil nucleus is indicative of what? |
The pyknotic process (the nucleus becomes metabolically less active) |
|
|
What do young neutrophils look like? |
They look banded |
|
|
What color do basophils stain? |
Dark blue |
|
|
What is the differentiated form of a B lymphocyte? |
Plasma cell |
|
|
Where do B cells wait around until they're
activated? |
The spleen |
|
|
Where are T cells "educated"? |
The thymus |
|
|
What are the 3 MAIN pro-inflammatory cytokines? |
IL-1, IL-6, and TNF-alpha |
|
|
Which kinds of cells are located in the lamina propria? |
Macrophages, dendritic cells, and mast cells |
|
|
TLRs are on which kinds of cells, mainly? |
Dendritic cells, mast cells, and macrophages |
|
|
What is the primary function of sentinel cells? |
To initiate inflammation upon engagement of their TLRs (by secreting pro-inflammatory cytokines) |
|
|
What is secreted from host cells when they're damaged? |
Alarmins |
|
|
What do TLRs recognize? |
PAMPs |
|
|
What happens when TLRs bind to PAMPs? |
A signal cascade from the sentinel cells are initiated, which is started by the secretion of pro-inflammatory cytokines (IL-1, IL-6, and TNF alpha) |
|
|
What local effect do IL-1, IL-6, and TNF-alpha have? |
They act locally on capillaries to cause capillary dilation and increased blood flow |
|
|
Besides secreting pro-inflammatory cytokines, what do mast cells do when they are stimulated by a pathogen? |
They dump the contents of their granules (which have a local effect on capillaries) |
|
|
What substances are in the granules of mast cells (that get dumped when the mast cells encounter a foreign organism)? |
Histamine Prostaglandins and leukotrienes Polypeptides (include C3a and C5a) |
|
|
Why don't prostaglandins and leukotrienes act as rapidly as histamines? |
Because they need to be made by the cell when it's stimulated, whereas histamines are pre-formed |
|
|
Which COX-specific inhibitors do we want and why? |
We want COX-2 specific inhibitors Inhibition of COX-1 can cause gastric ulcers |
|
|
What are C3a and C5a? What do they do? |
Byproducts of the breakdown of complement proteins; are chemoattractants for phagocytic cells |
|
|
What effect do histamines have on the pulmonary vessels in herbivores? |
It causes constriction of them So, fluid will back up into the lungs |
|
|
What effect do histamines have on most vessels?
|
It dilates them |
|
|
What effect do histamines have on the hepatic vein in dogs? |
It constricts it This leads to increased fluid leakage around the liver and the gut The liver and abdomen can engorge with blood because they can't drain well back into the heart |
|
|
What is the most common cause of shock? |
A G- infection form which a lot of LPS is suddenly dumped LPS binds to sentinel cells and causes them to dump their granules, which includes histamine |
|
|
What do you call LPS-induced shock? |
Endotoxic shock |
|
|
Where does arachidonic acid come from? |
The inner leaflet of cell membranes |
|
|
What effect do NSAIDS have on the release of sentinel cell granules? |
They inhibit prostaglandins and leukotrienes from being a component of them (They don't inhibit histamine or other proteins though) |
|
|
Which cells are the "first responders"? |
Neutrophils |
|
|
Mature neutrophils are dependent on what for energy? |
Glycogen stores
|
|
|
What are the main cellular component of acute inflammation? |
Neutrophils |
|
|
What determines the lifespan of a neutrophil? |
Their lifespan is only as long as it can generate ATP from the glycogen stores |
|
|
What effect do pro-inflammatory cytokines have on endothelial cells? |
It causes them to up-regulate the expression of an adhesion molecule called P-selectin |
|
|
What effect do pro-inflammatory cytokines have on neutrophils? |
It causes them to up-regulate the expression of an adhesion molecule called L-selectin |
|
|
What does P-selectin (on endothelial cells) do? |
It starts to grab onto passing neutrophils (attaching to their L-selectin; it SLOWS the neutrophil down so it starts rolling along) |
|
|
The neutrophil rolling along the endothelium causes the endothelium to express what? |
ICAMs (a new adhesion molecule) |
|
|
The neutrophil rolling along the endothelium causes the neutrophil to secrete what? |
CD11/CD18 (it's a heterodimer that binds to the ICAM) |
|
|
What happens next with the ICAM (on the endothelium)? |
It binds to the CD11/CD18 on the neutrophil and causes it to STOP |
|
|
What happens as a result of the P-selectin/ L-selectin interaction? |
The endothelial cells start secreting platelet activating factor |
|
|
What happens once the neutrophil comes to a stop? |
It pushes one of its pseudopodia (feet) between the endothelial cells and streams its cytoplasm through the foot to the other side of the endothelium (It undergoes diapedesis) |
|
|
Describe the bovine leukocyte adhesion defect |
Calves (esp. Holsteins) are born and have multiple infections and normally die within a few months They have weird infections with really high numbers of neutrophils (and a very thick buffy coat) but no pus despite clear infection Their neutrophils can't get out of the vasculature because of a defect in CD18 |
|
|
What does endothelial secretion of platelet activating factor do? |
Causes increased neutrophil secretion of CD11a/CD18 and CD11b/CD18 |
|
|
What causes increased endothelial secretion of P-selectins? |
Proinflammatory cytokines Bacterial products Products of damaged tissue |
|
|
How do neutrophils know where to go once they're outside of the endothelium? |
They undergo chemotaxis (move up the concentration gradient of a chemotaxin--i.e. particles shed by a pathogen--or complement products, components of cells that have been damaged and released, etc.) |
|
|
How do neutrophils leave trails for cytolytic T cells to follow? |
As the neutrophils leave the blood vessel and enter the CT around it, bits of the neutrophil break off and are left behind, clinging to the CT In those bits is a chemokine (a protein that signals) called CXCL12, that is a chemokine for cytolytic T cells to follow |
|
|
What is the end of the antibody called that sticks out from the antigen? |
The Fc domain |
|
|
How do neutrophils bind to antibodies? |
Through their Fc receptors binding to the Fc domain on the antibodies |
|
|
How do neutrophils bind to complement proteins? |
Through their complement receptors |
|
|
What is opsonization? |
The process whereby a pathogen is targeted for phagocytosis (by coating it with different molecules, like antibodies); opsonization greatly improves the adherence of the phagocyte to the foreign organism |
|
|
Which complement component often binds to the surface of foreign particles? |
C3b |
|
|
When an endosome is formed and the particle is moving inside the phagocytic cell, what else happens? |
Granules move through the cytoplasm toward the endosome |
|
|
What are a lot of the cytosolic granules in a phagocytic cell? |
Lysosomes |
|
|
What is formed when the cytosolic granules join the phagosome? |
The phagolysosome (a lot of the cytosolic granules are lysosomes) |
|
|
What are secreted by the lysosome to try to destroy the pathogen? |
Hydrolytic enzymes |
|
|
What is a killing mechanism that is initiated by the adherence of the foreign particle to the phagocytic cell?
|
The oxidative burst |
|
|
What are some particles that can opsonize a foreign particle? |
Antibody Complement C-reactive protein Serum amyloid |
|
|
What improves adherence of the phagocytic cell to the foreign particle? |
Opsonization |
|
|
Production of reactive oxygen intermediates is called what? |
The respiratory burst |
|
|
What triggers the respiratory burst? |
Adherence of the phagocytic cell to the foreign particle |
|
|
What is a common complement protein that opsonizes foreign particles? |
C3b |
|
|
Describe the components of the respiratory burst |
*NADPH oxidase is activated by the adherence *It generates superoxide radicals from O2 *Superoxide dismutates converts some superoxide radical with water to form H2O2 *Myeloperoxidase then splits some H2O2 to form hypohalide ions |
|
|
Where do the components of the respiratory burst come from?
|
Primary granules and NADPH oxidase (which is a membrane protein) |
|
|
What do secondary granules in the phagocytic cell secrete? (And what do the components of these granules do?) |
Hapicorrin--sequesters vitamin B12 Lactoferrin --sequesters iron Bacteria need both of these for replication Also, defensins--attack membranes of bacteria, fungi, and enveloped viruses |
|
|
What comes out of the lysosome? |
(Hydrolytic enzymes) Lysozyme (which degrades peptidoglycan) Acid hydrolyses Collagense Elastase |
|
|
How does "necrotaxis" work? |
As stuff is broken down in the phagocytic cell, some components can be dumped out Many of these degradation products are chemotactic factors (they then amplify the inflammatory reaction as some of the destruction of the damaged organism or tissue occurs) |
|
|
What is a defense mechanism used by neutrophils as they die? Describe it |
Extracellular trapping They release their nucleic acids (DNA) as they die, and that is very sticky and highly viscous As they die, this forms a net that can entrap bacteria that are there and dying. This makes them more easily phagocytize by more neutrophils that are infiltrating the lesion |
|
|
As neutrophils are working and dying.. What happens if there are only a few bacteria to neutrophils? If you have a high ratio of bacteria to neutrophils? |
Few bacteria: the neutrophils eat them up but stay resistant to apoptosis Many bacteria: as the neutrophils eat them up and use up their glycogen stores, they undergo apoptosis (macrophages can consume an entire apoptotic cell |
|
|
What happens if there is low O2 and low pH as neutrophils are working? (like in an abscess) |
The neutrophils die by necrosis and essentially burst, which makes pus and is chemotactic for more neutrophils as well as macrophages |
|
|
If neutrophils do not succeed in eliminating foreign material rapidly (the stimulus persists), what happens? |
They die, releasing elastase and collagenase that are chemotactic factors for macrophages (and they can be phagocytized intact as they die by macrophages to prevent spillage of their lysosomal contents) |
|
|
What do dead neutrophils and microbial debris create? |
Pus |
|
|
Neutrophils are most responsive to what kind of infections? |
Bacteria |
|
|
Which phagocytic cells are drawn more slowly (within hours) to sites where phagocytosis of foreign material is needed but have more prolonged phagocytic activity? |
Macrophages |
|
|
Why are macrophages longer-lived? |
Because they are less dependent on glycogen stores |
|
|
The function of any of these immune cells is largely determined by what? |
Their cell surface receptors |
|
|
What happens when a neutrophil's TLR is bound? |
They phagocytize whatever is bound to their TLRs (they don't secrete pro-inflammatory cytokines) |
|
|
Which phagocytic cells have opsonin receptors for byproducts of complement activation? |
Neutrophils and macrophages |
|
|
What is a MAJOR complement opsonin? |
C3b |
|
|
What does C3b do? |
It coats the surface of foreign organisms and is an opsonin that is recognized by opsonin receptors on neutrophils |
|
|
List the main cell surface receptors on neutrophils |
TLRs Opsonin receptors (including Fc receptors) CD11 a, b, c and CD18 (are complement receptors and bind ICAMs to allow diapedesis) |
|
|
What are acute phase proteins? |
Soluble plasma proteins produced by the liver that inhibit inflammatory mediators and thereby regulate acute inflammation, keeping it under control (They down-regulate the inflammation that is produced) |
|
|
C-reactive proteins are an example of what? |
Acute phase proteins |
|
|
Macrophages' _____ can bind to ______ on pathogens, which causes secretion of ___________ |
TLRs PAMPs Pro-inflammatory cytokines (IL-1, IL-6, and TNF alpha) |
|
|
When you have a CD18 defect, are only
neutrophils prevented from getting out of the vasculature? |
Nope, also macrophages |
|
|
Why do neutrophils have such a short life? |
They burn out quickly since they rely on degrading glycogen that's stored and they can't regenerate it |
|
|
How do macrophages have a more sustained energy source? |
They have an intact respiratory apparatus--intact mitochondrial respiration so can regenerate ATP (They aren't dependent on glycogen stores and can function for an extended period of time) |
|
|
How do macrophages kill bacteria when they consume them? |
They use nitric oxide synthase (to ultimately generate reactive nitrogen species) as well as through the respiratory burst |
|
|
What kind of cell surface receptors do macrophages have? |
TLRs Opsonin receptors (FcR and CR) Mannose-binding receptors MHCII for antigen presentation |
|
|
What is a major difference in the function of
macrophages and neutrophils? |
The ability to present antigens |
|
|
Presentation of antigens by macrophages to T lymphocytes causes what to happen? |
An acquired immune response which results in antibody or cytolytic T cell formation |
|
|
Which receptor allows macrophages to present antigens? |
MHC II |
|
|
For macrophages to change, what happens when their TLRs are engaged? |
*They secrete pro-inflammatory cytokines like normal *They also up-regulate their opsin receptors and increase their MHC II expression *They also secrete more proteases to degrade necrotic host tissue or foreign material |
|
|
What can really increase the killing ability of macrophages? |
Interferon gamma |
|
|
What specifically does interferon gamma do to macrophages? |
It activates them It causes them to start making the reactive nitrogen intermediates and make more reactive oxygen intermediate |
|
|
Which immune cells can secrete interferon gamma? |
Main source is T helper cells Some also comes from NK cells |
|
|
How long does it take for cells to secrete much interferon gamma? |
5-10 days |
|
|
What are the 3 stages of macrophage activation? |
1. Inflammatory macrophages 2. Activated macrophages 3. Epitheloid cells |
|
|
What creates "inflammatory" macrophages? Describe the changes |
Upon movement into inflamed tissue, it is when their TLRs engage They gain increased phagocytic activity, up-regulated opsonin receptors, increased MHC II expression, and have increased protease secretion |
|
|
What creates "activated" macrophages? Describe the changes |
Exposure to interferon gamma (from helper T cells or NK cells) Increased bacterial killing via nitrogen oxidative species |
|
|
What creates "epitheloid" macrophages? Describe the changes |
Long-term persistence of foreign material (like asbestos fibers of mycobacterium) The cell walls between the macrophages around the particle will break down and they'll form a multinucleate giant cell...it becomes epitheloid because it's a layer around the particle |
|
|
Epitheloid/giant cells are an indication of what? |
Chronic inflammation |
|
|
What do macrophages secrete to help clean up necrotic or damaged tissues? |
Collagenase and elastase |
|
|
What does exposure to IL-4 and IL-13 do to macrophages? |
It suppresses their microbial killing functions (by forming less ROS) and enhance their wound healing functions (increase protease production) |
|
|
What do collegians and elastase from macrophages do? |
Help clear away damaged tissue and promote wound healing |
|
|
What can macrophages also secrete to promote healing? (particularly for forming new capillaries) |
VEGF |
|
|
Describe the various secretory functions of macrophages |
*Collagenase and elastase for wound healing *Some complement proteins and clotting factors *Pro-inflammatory cytokines (IL-1, IL-6, TNF alpha, and IL-12) |
|
|
Which kind of shock is mediated by the secretion of histamines by mast cells? |
Anaphylactic shock |
|
|
G- mastitic shock is mediated by what? |
Macrophages' release of TNF-alpha This will send you into septic shock |
|
|
Describe septic shock |
*It is a runaway infection with G- bacteria *These will stimulate macrophages and cause a huge release of TNF alpha *This causes fever and hypotension *This leads to kidney, liver, and lung injury then death |
|
|
What do lower chronic doses of TNF alpha cause? |
Atrophy of muscle and loss of adipose tissue |
|
|
Where is process antigen presented on macrophages? |
On MHC II |
|
|
Who do macrophages present their antigens to? |
T lymphocytes |
|
|
Which cells present antigens? (of what we've talked about) |
Macrophages and dendritic cells |
|
|
What effect do macrophages have on fibroblasts after foreign material has been removed? |
They stimulate them to produce collagen and help with wound healing |
|
|
What is excessive collagen called? |
Fibrosis |
|
|
What happens with macrophages if the stimulus is persistent? |
More macrophages come in Fibroblasts synthesize an excessive amount of collagen (fibrosis) and loose connective tissue New blood vessels permeate it A granuloma is formed |
|
|
What do lymphocytes in a granuloma indicate? |
That whatever is inside the granuloma is immunogenic |
|
|
What effect do pro-inflammatory cytokines have on the liver? |
It causes it to secrete acute phase proteins to reduce the inflammatory response and to scavenge nutrients to prevent them from being available to the foreign organism |
|
|
What are C reactor protein and serum amyloids? |
They are both opsonins that come from the liver They coat the foreign material and make it easier for phagocytic cells to engulf them |
|
|
What is amyloidosis? |
Infiltration of tissues with deposition of partially degraded proteins as insoluble beta-pleated sheets This leads to loss of organ function |
|
|
What causes amyloidosis? |
Chronic inflammation |
|
|
How are particles usually cleared? |
By phagocytosis |
|
|
How are soluble antigens normally cleared?
|
In a triphasic process of: DISTRIBUTION CATABOLISM IMMUNE ELIMINATION (they are too small for phagocytosis in general) |
|
|
Describe the distribution phase in clearing of soluble antigens |
It is the time when the antigen is dispersing into the whole vasculature and is leaking out of capillaries to disperse into the extracellular volume |
|
|
Describe the catabolic phase in clearing of soluble antigens |
The soluble antigen is in contact with cells that are doing pinocytosis and it's being degraded (it would go along this way until it's all gone except that the immune system kicks in) |
|
|
Describe the immune elimination phase in clearing of soluble antigens |
It is where antibodies are produced to bind to it and produce a protein complex with the foreign material with Fc molecules sticking out which bind to Fc receptors on phagocytic cells |
|
|
How does the complement cascade exemplify a classic cascade phenomenon? |
The product of one reaction is the enzymatic catalyst of the next reaction |
|
|
Why are there intrinsic controls involved in the complement cascade?
|
Because the events of complement activation are potentially damaging to host tissues |
|
|
What is the central enzymatic reaction in the complement cascade?
|
The conversion of C3 to C3b |
|
|
What is another name for C3bBb? |
C3 convertase It has enzymatic activity--it will catalyze the conversion of C3 to C3b |
|
|
What happens if the C3b formation occurs on the host membrane? What is this pathway called? |
The binding of factor H and I occur (in the presence of the sialic acid on host cell surfaces) This halts the enzymatic activity This is called the alternative pathway |
|
|
Activating the complement cascade means making what? |
A C3 convertase (C3bBb) It converts C3 to C3b |
|
|
What is there an abundance of on bacterial membranes? |
Mannose |
|
|
What is a lectin?
|
A protein that binds to a sugar |
|
|
How does the lectin pathway occur? |
*An acute phase protein comes from the liver and is called mannose binding protein *It recognizes mannose *It recruits some other proteins that are called mannose binding protein serine protease *Once the mannose binding protein serine proteases are there, they act on a plasma protein called C4 and cleave it to make C4b *Additionally, C2 will bind to it and that's cleaved by the same proteases into C2b...now we have C4b2b, which has enzymatic activity C4b2b also has C3 convertase activity |
|
|
What are C3a and C5a chemotactic for? |
Neutrophils |
|
|
What is the other enzymatic activity of C4b2b and C3bBb other than being C3 convertase? |
They convert C5 to C5a, which is a chemotaxin for neutrophils |
|
|
Complement proteins are products from where? |
The liver (as acute phase proteins) and macrophages |
|
|
How do the complement proteins get into the tissues where they're needed? |
They are soluble proteins that are normally present in plasma They readily leak from the plasma into tissues during inflammation |
|
|
What is the result of all complement activation pathways? |
Generation of a membrane-associated enzyme complex (A C3 CONVERTASE) that cleave C3 to C3b + C3a on FOREIGN cells |
|
|
Which two complement activation pathways are innate?
|
The alternative and lectin pathway |
|
|
Which complement activation pathway is adaptive? |
The classical pathway |
|
|
Describe the alternative pathway |
*Under normal circumstances, a slow but constant spontaneous breakdown of C3 to C3b is countered immediately by the binding of factors H and I and proteolytic inactivation of C3b to C3d *Factor H binding to C3b is enhanced by sialic acid, which is only present on host membranes |
|
|
Activation of the classical pathway is dependent on what? |
Antibodies |
|
|
Describe how the classical pathway works |
*Activation of the classical pathway is antibody-dependent *Complement activation is a biological function of the Fc portion of antibodies binding to C1qrs *C1qrs binding to adjacent antibody molecules frees a C1 inhibitor from the C1qrs complex |
|
|
What do the classical and alternative pathways result in formation of? |
Surface-bound C3 convertase |
|
|
What C3 convertase is generated with the classical pathway? |
C4b2b |
|
|
What C3 convertase is generated with the
alternative pathway? |
C3bBb |
|
|
What does C3 convertase do? |
It amplifies C3b production on that surface when the surface has no way to protect itself |
|
|
What (very generally) happens on host cell membrane if C3 convertase is on it? |
C3b is rapidly degraded into C3d and C3 convertase is inactivated (by the binding of factors H and I) |
|
|
What does conversion of C3 to C3b initiate? |
The terminal complement pathway |
|
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Describe how the terminal pathway is formed |
*Conversion of C3 to C3b initiates it *C5 binds to membrane-bound C3b and is split by either C3bBb or C4b2b (they are also C5 convertases); this releases C5a *C5b remains bound to C3b on the activating surface and recruits C6, C7, and C8 from the ECF *The C5b678 complex induces polymerization of C9 into a membrane attack complex, which forms pores in the cell membrane and kills the target |
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Which complement molecule will opsonize the foreign antigen?
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C3b |
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What initiates the lectin pathway? |
Mannose |
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What does the alternative pathway start with? |
Random cleavage of C3 into C3b and C3a |
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Describe how the alternative pathway proceeds if on a bacterium |
*C3 is randomly cleaved into C3b and C3a *Without inhibition by factors H or I (as they would if on a host cell membrane), C3bBb makes more and more C3b |
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What does C3b also attract? What ends up happening? |
C5 and can convert C5 to C5b So, C3bC5b6789 forms and 9 keeps polymerizing to form the membrane attack complex and bore some holes into the foreign membrane |
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What binds to C3b when sialic acid is present? |
Factor H When H binds to C3b, I also binds I is an enzyme that degrades C3b to C3d So, it prevents C3 convertase from being formed |
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What is the central reaction of complement activation? |
The cleavage of C3 to C3b (and C3a) C3a is a chemotactic factor C3b is an opsonizing agent |
