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31 Cards in this Set
- Front
- Back
How does the complement system work and what are the 3 outcomes? |
It is a biochemical cascade that:
1. releases inflammatory and chemotactic mediators 2. opsonization (coats microbes with a "tag") 3. directly lyses microbes |
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Which immune systems activate the complement system? |
BOTH innate and adaptive immune responses |
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Why is the complement system so important?
**Consists of 16 different serum poteins and glycoproteins (mostly made in liver) that comprise about 10% of total serum protein (a lot!!)** |
-small inciting stimulus can cause the biochemical cascade to amplify a huge, billion-fold response
-many effects to happen at the same time in a coordinated fashion |
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What are the 3 complement activation pathways? |
1. Classical - initiated by IgG or IgM (acquired immune system)
2. Lectin - initiated by mannose-binding lectin (an extracellular PRR) (innate immune system)
3. Alternative - initiated by microbial surface vicinity (innate immune system) |
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What are 3 common features of the complement activation pathways? |
1. proteolytic cascade that allows for signal amplification
2. result in creation of a C3 and a C5 convertase which can cleave C3 and C5 complement proteins respectively
3. all end in a common terminal pathway (membrane attack pathway) |
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Is the C3 convertase used in alternative pathway is different than the C3 convertase used by classical and lectin pathways? |
YES |
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What does the C in C3a/C5a stand for? What is the number? What is the second letter? |
Complement Historical order of cascade Cleavage product or subunit (a is the soluble one and is usually smaller than b) |
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How is the classical pathway triggered? |
Antigen-antibody complex produced after adaptive humoral immune response (IgG₁, IgG₃ and IgM)
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How many antibodies need to be bound close on the surface microbe in the classical pathway? What does this cause? |
-two antibodies -C1 complex recognizes this using it's C1q subunit
- This causes conformational changes in C1 complex = triggers autocatalysis (cleaves its own proteins)
**This is all Ca²⁺ dependent! |
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What are the next steps in the classical pathway after it has been activated? |
1. Cleaved proteins from the C1 complex (C1s) cleaves C4 and C2 to form C4b and C2a
2. These two join together to form the C3 convertase C4b2a
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What does C3 convertase cleave?
What are the products attached to? |
- This cleaves C3 into C3a and C3b - Both C4b and C3b covalently attach to activating surface (e.g. microbe) via thiolester linkage |
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What does C3b form?
Which goes where? |
- Part of C3b will form C5 converting complex
- Will go on to the terminal membrane attack pathway |
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How is the Lectin pathway triggered and what does the binding cause? |
Antibody Independent (non-specific) Mannose-binding lectin (MBL) is similar C1
1. MBL binds to PRR's found on microbial surfaces (mannose, fucose and N-acetyl glucosamine (NAG))
2. Conformational change in MBL that induces autocatalysis of MBL associated serene proteases that then cleave C4 and C2
**these first steps differ from the classical pathway** |
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How is the alternative pathway triggered? |
-Antibody and lectin independent (non-specific)
-Relies on low-level serum hydrolysis of C3 (steady state, there is always a low level of C3 cleavage happening all the time)
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Hydrolyzed C3 must be really close to an activator surface (bacteria) to do what..?
This binding causes what?
What is C3b used for? |
- to binds serum factors to form C3 convertase (different convertase than the lectin/classical pathways)
- C3 convertase hydrolyses C3 into C3a and C3b, = amplification loop (no regulators)
- C3b can be used to form C5 convertase which is used to make membrane attack complex |
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How does the host control the alternative activation pathway?
-example of factors that inactivate... |
- Host cells possess surface carbs and regulators that inactivate C3b
- Factor H and Factor I inactivate and degrade inappropriately bound C3b
**Spontaneously bound C3b on host cells is destroyed as fast as it is deposited** |
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How is the alternative pathway inherent to the classical and lectin pathways? |
It can activate the other pathways => C3 is the main player in all the pathways => the alternative pathway provides an amplification loop for C3 deposition |
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Since Classical, Lectin and Alternative pathways all end with formation of C5 convertase complex, how does the terminal membrane attack pathway work?
(what does the pore allow?) |
- C5 convertase cleaves, initiates a pathway involving C6, C7, C8 and C9 to form a rigid pore (the membrane attack complex - MAC)
-pore allows influx of solute and electrolytes across the microbe membrane which causes osmotic swelling and sometimes lysis |
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Examples of proteins (inhibitory factors) that help regulate the complement system?
(prevents inappropriate targets - 'stop mechanism') |
Decay accelerating factor (CD55) regulates alternative pathway - accelerates decay of C3 convertase
Complement Receptor 1 (CD35) regulates alternative, lectin and classical pathways - inhibits C3 convertases
Protectin (CD59) regulates terminal membrane attack - prevents MAC formation |
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Why is cobra venom so toxic? |
-Forms a stable C3 convertase that is not recognized by regulatory proteins such as Factor H and I
= continuously hydrolyzes C3 and C5 which leads to complement depletion and severe local tissue damage |
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What are the 4 outcomes of complement activation? |
1. Inflammation and chemotaxis
2. Enhancement of phagocytosis (opsonization)
3. Promoting humoral immunity (talking to adaptive immune system)
4. Clearance of immune complexes |
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What are the 6 outcomes of Complement Activation? |
1. Opsonization (C3b) 2. Chemotaxis (c3a, C5a) 3. Vascular permeability (C3a, C5a) 4. Target osmodysregulation and lysis (MAC) 5. Enhances adaptive immunity (C3b) 6. Immune Complex Clearance |
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What is opsonization? |
-Making microbes "more tasty"
-C3b deposition enhances binding and uptake of microbes via CR1 and CR3 in professional phagocytes
- causes highly enhanced clearance |
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What is chemotaxis and how does it work in the complement system? |
-Polymorphonuclear leukocytes and macrophages migrate along C3a and C5a gradients to site of C' activation
(C3a and C5a are small and not part of the MAC complex - their job is to increase vascular permeability) |
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How does complement activation cause increased vascular permeability? |
- C3a and C5a trigger degranulation of Mast cells
- Mast cells release vasoactive amines which are vascular dilaters
- this causes increased vascular permeability and blood flow so blood cells can get to the inflamed tissue |
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How does complement activation enhance adaptive immunity?
(C3b broken down into C3dg - what does C3dg do on B cells?) |
- B-cells find an antigen, they are activated and C3dg helps to significantly enhance their activity = antibody production -C3dg = prolonged antigen - B-cell interaction, enhancing the humoral response to that antigen even more |
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How does the complement system work in clearing immune complexes? |
- C3b can bind to the immune complexes, which allows them to be bound to the surface of erythrocytes
- removed by phagocytosis or erythrocytes in the liver and spleen |
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Why are C3a and C5a considered anaphylotoxins? (anaphylactic shock) |
-help recruit circulating leukocytes by prompting endothelial cells lining local vasculature to express adhesion molecules
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What happens if there are deficiencies in the classical activation pathway?
**Little or no increased risk of infection but what is there a increased risk for? |
-alternative and lectin pathways are sufficient for controlling infection (compensatory mechanisms)
- Increased risk of SLE-like autoimmune disease, probably due to impaired clearance of immune complexes by monocyte-macrophage system
*SLE = systemic lupus erythematosus
(can cause kidney problems) |
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What happens if there is a factor H deficiency?
(alternative pathway - regulates complement activation that blocks formation of C3 convertase and is a cofactor for cleavage of C3b with factor I) |
= unregulated activation of alternative pathway
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Example of animal with Factor H deficiency and what do they develop? |
Norwegian Yorkshire pigs -develop type II membranoproliferative glomerulonephritis due to deposition of C3 components in glomerulus of kidney |