Term
What is meant by
1) "C-activation/fixation"
2) "C-inactivation"
3) "Convertase/esterase"
4) "Cascade" |
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Definition
1) Alteration of C' proteins such that they trigger cleavage of many downstream components.
2) Denaturation or proteolytic cleavage of C'-component
3) Altered C'-protein which acts as proteolytic enzyme for the next C'-component
4) Chemical or physiological process that occurs in successive stages, each of which is dependent on the preceding one, often producing a cumulative effect. |
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Term
| Where is Complement made and what are the names of the 3 important complement-mediated pathways? |
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Definition
1) Liver and by Macrophages in situ (at the site of action)
2) Classical (Ab), Lectin/Mannose (Bacteria), Alternative (Microbial surface)
** Can be seen as part of both innate and adaptive pathways ** |
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Term
| Explain how the classical pathway of complement activation proceeds. |
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Definition
Classical= Antibody
Serum C1 composed of C1(qrs) (w/ 6 monomer of each)
C1q (stalk and heads)
C1r (serine protease that cleaves C1s)
C1s mediates interaction of C1q and C1r
1) Ab binds antigen either on surface or immune complex precipitate, with one IgM or enough IgGs close enough together (30-40nnm) such that 2 C1q heads bind Ab-C region
2) C1s cleaves C4 to C4b and C4a
3) C4b/C1 and cleaves C2 to C2a and C2b
4) C4b and C2a cleave C3 into C3a and C3b
5) C3b serves as opsonin and C3a acts as weak anaphylotoxin to induce inflammation
6) C3b stays behind to form C4bC2aC3b complex which cleaves C5 (C5a is anaphylatoxin and C5b BINDS C6 and C7, which insert in membrane of bacteria)
7) C5bC6C7 recruit C8 and lots of C9 to form pore which causes osmotic lysis of:
No Boys Eat Vegetables At Kansas
Gram negative bacteria (Neisseria)
Enveloped Viruses
Nearby cells of host if autoantibodies are made
Kidney cells if immune complexes lodge in kidneys (host CD tries to block this). |
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Term
| What are the 4 main targets of the Complement cascade? |
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Definition
No Boys Eat Vegetables At Kansas
1) gram Negative bacteria (Neisseria)
2) Enveloped Viruses
3) nearby cells of host if Autoantibodies are made
4) Kidney cells if immune complexes lodge in kidneys (host CD tries to block this). |
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Term
| How does the lectin binding pathway differ from the classical complement cascade? |
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Definition
Mannose-binding Lectin (MBL) (similar to C1) with MBL-associated serine proteases, MASP1 and MASP2, in serum bind mannose on bacteria and viruses, and cleave C4.
THE REST IS THE SAME
- C4 goes to C4a and C4b
- C4b and MBL/MASP cleave C2
- C4b/C2a cleave C3 into C3a and C3b
- C3b opsonizes and C3a is weak anaphylotoxin
- C4b/C2a/C3b cleave C5
Late Steps
- free C5a (anaphylatoxin) and free and bound C5b produces
- free C5b BINDS C6 and C7, to recruit C8 and C9 (a lot) to form pore for osmotic lysis |
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Term
| How does the Alternate Pathway of complement activation differ from the classical and lectin-binding pathways? |
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Definition
Some C3 is always breaking in serum, and C3b usually goes on to become iC3b and C3d
1) Bacterial surfaces can stabilize C3b, and factor B can cleave it to Bb.
2) C3bBb can cleave more C3 and form C3bBbC3b complex which cleaves C5
3) Factor D and Properdin stabilize C3bBbC3b complex
4) C5 cleavage leads to LAST STEPS and formation of MAC
LAST STEPS
- free C5a (anaphylatoxin) and free and bound C5b produces
- free C5b BINDS C6 and C7, to recruit C8 and C9 (a lot) to form pore for osmotic lysis |
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Term
| How do the three complement activation pathways converge on C3b? |
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Definition
1) Classical and Lectin-Binding- C3 is cleaved by C4b:C2a
2) Alternative- C3 is cleaved by C3b:Bb and C3bBbC3b (positive feedback loop) |
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Term
Match the physiological result with its complement protein(s)
1) B cell activation
2) Inflammation
3) Membrane attack complex (MAC)- KILLER PATHAY
4) Opsonization/Phagocytosis |
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Definition
1) C3d breakdown product of C3b
2) C5a and C3a release
3) C5b-C9
4) C3b and C4b coat as opsonin. |
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Term
| How does inflammation relate to the complement pathways and how does it occur? |
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Definition
C5a (C4a and C3a to a lesser extent) are anaphylotoxins that:
1) Chemotaxic for neutrophils
2) Activate neutrophil adhesion and emigration from blood stream
3) Activate monocytes to make IL-1 and IL-6
4) Mast cell degranulation (anaphylaxis) |
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Term
| How do Opsonization and Phagocytosis relate to the complement pathways and how does it occur? |
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Definition
C3b (and C4b) deposit surface of microbe (can be broken down to iC3b)
1) CR1 receptor on erythrocytes, macrophages , monocytes, neutrophils, basophils, eosinphils, B cells, Follicular DCs, bind C3b, iC3b, C4b leads to binding and ingestion.
2) CR2 receptor (CD21) present on B cells and follicular DCs bind iC3b, C3d and EBV
Engagement with CR2:C3d and BCR recognizing an epitope on antigen can lead to B-cell activation |
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Term
| How can CR2 (CD21) induce an immune response to Epstein Barr Virus? |
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Definition
Engagement of CR2:C3d and BCR recognized an epitope leads to B-cell activation
In addition to recognizing C3b and iC3b on opsonized targets, CR2 on B-cells and Follicular DCs binds C3d and interacts with BRC recognizing an epitope on an antigen, leading B-cell activation.
EBV acts like C3d and can interact with CR2 to initate an immune response. |
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Term
| Which Regulators of Complement block C3b (convergence point of 3 pathways) |
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Definition
Remember, the goal is to STOP C3b degradation into C3d and iC3b, and prevent chronic complement signaling.
1) Plasma Proteins
Factor I protealitcally cleaves C3b or C4b
Factor H causes dissociation of alternative pathway C3 convertase (C3b:Bb) and is co-factor with Factor I for cleavage of 3b
2) Membrane Proteins
CD46 MCP membrane cofactor protein- works with Factor I for C3b inactivation DAF, decay accelerating protein, stopping cleavage of more C3b
- CR1 cofactor with Factor I for C3b inactivation |
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Term
| Why is a C1 INH deficiency of clinical concern? |
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Definition
C1 INH stops spontaneous C1 activation, which would lead to swelling, inhibition of C' and clotting factors.
Without it, you get swelling, inhibition of C' and clotting factors. |
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Term
| Why is a MCP/Factor H/Factor I deficiency of clinical concern? |
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Definition
These factors inactivate C3b on host cells, to prevent aberrant complement signaling and uncontrolled inflammation.
Deficiencies predispose to hemolytic uremic syndrome and macular degeneration, because you can't dispose of C3b. |
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Term
| Which complement complex inserts itself into bacterial membranes? |
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Definition
This is true of all 3 pathways.
Free C5b associated with C6/C7, and the complex inserts into the bacterial membrane.
This insertion recruits C8 and a lot of C9 to form pore of osmotic lysis. |
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Term
| Why might mutations in the genes encoding Factor D and Properdin be of clinical concern? |
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Definition
These factors bind and stabilize the C3bBbC3b complex that is critical for C5 cleavage in the "Alternate Pathway" of complement activation.
Without them, you get no free C5b, and therefore you get no C5b/C6/C7 poking holes in bacterial membranes. |
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Term
| What is the role of CD59 i complement pathway signaling? |
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Definition
CD59 blocks complement-assocaited kidney cell damage by preventing the formation of MAC by C9
Remember, C3b can break down to iC3b and C3d. Complexes of complement breakdown products can become lodged in the kidney |
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Term
| Why is a Factor B deficiency of clinical concern? |
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Definition
| C3b stabilized by microbial surfaces can cleave Factor B to Bb, which can associated with C3b to cleave more C3- form C3bBbC3b, which can cleave C5 and complete the lytic complement pathway. |
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Term
| Why is a Factor D or Properdin deficiency of clinical concern? |
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Definition
These two molecules stabilize the C3bBbC3b complex, and allow it to cleave C5.
Without them, you can't get to the lytic complement pathway through the Alternate route. |
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Term
| What is the role of CD35 in complement signaling? What does it have to do with C' coating? |
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Definition
CD35 is also called the "CR1" receptor, which is present on erythrocytes, macrophages, ect....
It binds C3b, iC3b and C4b and leads to ingestion, acting as a cofactor with Factor I to cause C3b inactivation.
If an antigen is "coated" with C' molecules, then it will adhere to the CR1 (CD35) receptor more strongly on RBCs, which can get deposited in the kidney (CD59 to prevent) |
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Term
| How does factor H block the alternative pathway of complement activation? |
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Definition
Factor H dissociates the C3 convertase (C3bBb) and prevents it from cleaving further C3.
Factor H also acts as a co-factor with Factor 1 to cleave C3b. |
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Term
| How does CD46 regulation C3b inactivation? What about DAF? |
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Definition
CD46, also called membrane cofactor protein or "MPC" binds C3b and allows FI and FH to cleave it, thereby inactivating it.
DAF stops cleavage of more C3b to iC3b and C3d (you don't want C3d to interact with CR2 and activate B-cells, which might cause autoimmune reactions). |
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Term
| Whh are C3, C2 and C1 deficiencies of clinical concern? |
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Definition
C3= bacterial infections (no downstream signaling of C3b)
C2/C1= Immune complex disorders like autoimmune SLE (lupus) |
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Term
| What are some possible results of over activation of C' |
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Definition
Ag+Ig+C' is not efficiently cleared, Ig either to self or pathogen.
Deposition of complexes in joints, kidneys, organs
Occurs in many autoimmune conditions |
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Term
| What cell type does C5a recruit? |
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Definition
| C5a is a potent anaphylatoxin that activates Mast cells leading to inflammation and RECRUITS NEUTROPHILS |
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