Term
| What are the four functions of the products of complement? |
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Definition
1) recruit inflammatory cells
2) Opsonize microbial pathogens
3) Kill microbial pathogens
4) Generate and inflammatory response |
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Term
| Three pathways of activation of complement and their general mechanism |
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Definition
1) Classical pathway: Antigen/antibody complexes
2) MB-Lectin pathway: Lectin binding to pathogen surfaces
3) ALternative pathway: Pathogen surfaces |
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Term
| Classical Pathway: Function of C1 |
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Definition
| - recognizes the antigen-antibody complex by recognizing a part of the antibody Fc region that is exposed only when it binds antigen. |
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Term
| Classical Pathway: What is required to activate C1? |
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Definition
| Either two IgG's in close proximity or one IgM pentamer in the serum |
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Term
| Classical pathway: structure of C1 |
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Definition
C1 = qrs complex
Cq = comprised of 6 globular heads - two heads simulataneously bind antibody Fc for activation
Cs = enzyme
Cr = enzyme |
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Term
| Classical Pathway: What happens after 2 C1q heads bind antibody? |
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Definition
- C1r undergoes a conformational change and becomes active.
- C1r then cleaves C1s, making it active. |
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Term
MB-Lectin Pathway: What protein activates it?
What is it homologous to?
What does it associate with? |
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Definition
mannan binding lectin
- Homologous to: C1q
- associates with two serine proteases MASP-1 and MASP-2 that are similar to C1r and C1s |
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Term
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Definition
| - mannos and certain other complex carbohydrates that are found on the surface of many microbial pathogens |
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Term
| MB-Lectin Pathway: what activates MASP1 and MASP2? |
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Definition
| binding of MBL to pathogen |
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Term
What do the activated MBL/Cqrs do?
What does the product of this bind? |
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Definition
MASP2 or C1s cleaves C4 to C4a and C4b.
C4b becomes bound to cell surface and binds C2 |
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Term
What happens to C2 after binding C4b?
What is the new complex called? |
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Definition
C2 is cleaved by C1s as well to C2a and C2b. C2a remains bound to C4b, forming C4b2a.
- C4b2a is a C3 convertase
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Term
What is the enzymatic function of C4b2a convertase?
How is it a major point of amplification of the pathway signal? |
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Definition
C3 convertase, cleaves C3 to C2a and C3b.
- One C4b2a can cleave up to a 1000 C3's |
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Term
What cleaves C3?
What do it's products do? |
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Definition
- C4b3a cleaves C3 into C3a and C3b
- C3b binds antigenic surfaces and acts as a powerful opsonin and enhances the uptake of antigenic particle by phagocytes. It also joins a complex with C4b2a. |
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Term
What cleaves C5?
What are the products?
What do they do? |
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Definition
C4b2a3b = C5 convertase
It is cleaved into C5 and C5a and C5b
C5a = soluble inflammatory mediator
C5b = initiates final phase of complement activation by forming the Membrane Attack Complex |
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Term
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Definition
- remains soluble and produces a local inflammatory effect
- chemoattractant of neutrophils, eosinophils, basophils and monocytes. |
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Term
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Definition
| - remains soluble and produces a local inflammatory effect |
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Term
What does C5b bind?
What does this complex do?
What joins next? |
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Definition
- C6 and C7
- C5b67 binds the cell membrane via C7
- C8 binds |
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Term
What does C8 bind?
What does it do afterward? |
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Definition
- binds C5b67
- inserts into the cell membrane |
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Term
| What happens after insertion of C8 into membrane? |
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Definition
| - between one and sixteen C9 molecules bind to form a pore in the membrane |
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Term
| What is the alternative pathway for complement dependent upon? |
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Definition
| - slow, spontaneous hydrolysis of C3 in plasma |
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Term
| Alternative pathway: What happens after slow hydrolysis of C3? |
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Definition
| - hydrolyzed C3 can bind Factor B, resulting in C3 (H2O)Bp complex. This ia a C3 convertase and allows for more creation of C3b. |
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Term
Alternative pathway: What is the role of C3b?
What complex does it form after binding cell surface? |
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Definition
- binds to cell surface and Factor B
- Factor B is then cleaved, while bound to C3b, to Bb by Factor D. This results in C3bBb complex, a C3 convertase |
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Term
Alternative Pathway: What is the purpose of creating a C3 convertase from C3bBb
What is the result analagous to in the classical pathway? |
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Definition
| - the binding of another C3b turns it into a C5 convertase, analogous to that of the C4b2a3b of the classical and MB lectin pathway. |
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Term
| What two types of pathogens can be lysed by complement pore complex? |
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Definition
- gram-negative
- membrane coated viruses. |
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Term
What are the consequences of complement activation?
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Definition
1) cell lysis (virus and gram negative bacteria)
2) viral neutralization
3) Opsonization
4) clearnace of immune complexes
5) inflammation |
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Term
| Which two components of the complement pathway is important for opsonization? |
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Definition
1) C3b - assits in ultimate ingestion of the particle by phagocytotic cell
2) C5a - enhances phagocytosis by stimulating phagocytic cells to ingest C3b coated antigens.
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Term
| How does complement assist in clearnace of immune complexes? |
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Definition
| antigen-antibody compelxes bind to complement receptors on circulating RBC's and the complexes are stripped off in spleen and live by phagocytizing cells |
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Term
| Four ways of regulating complement activation ? |
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Definition
1) protease inhibition
2) catalytic cleavage
3) decay acceleration
4) inhibition of lysis |
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Term
What are the C3a, C4a and C5 fragments capable of?
What does this lead to? |
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Definition
binding specific receptors on mast cells and basophils, triggering granule release.
The release of histamine leads to vascular changes including vascular permeability. |
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Term
| Regulation of complement: protease inhibitor |
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Definition
| - C1 inhibitor: destroys enzymatic complex of C1s/C1r |
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Term
Regulation of complement: catalytic cleavage
What inhibits C3b?
What inhibits C4b? |
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Definition
C3b = Factor I, CD46, Factor H:
C3b-> iC3b
C4b = Factor I and CD46 |
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Term
| What does CD46 inhibit? How? |
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Definition
- inhibits C3 converatase and C5 convertase
- how: binds C3b or C4b and promotes inactivation by factor I. |
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Term
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Definition
| - binds C3b and serves as a cofactor for the cleavage of surface bound C3b by factor I. |
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Term
| Regulation of complement: decay acceleration |
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Definition
CD55
C3bBb-> C3b, Bb
C4bC2a-> C4b, C2a |
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Term
| Regulation of complement: inhibition of lysis |
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Definition
CD 59
C5b-C9 -> MAC inhibition by preventing the assembly of this |
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Term
Common deficiencies in the classical pathway
what this leads to?
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Definition
C1, C2, C4
deficiency leads to immune complex disease |
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Term
common deficiencies in the MB-lectin pathway
what these lead to |
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Definition
MBL
MASP1
MASP2
C2
C4
- deficiency of MBL leads to bacterial infections mainly in childhood |
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Term
common deficiencies in the Alternative pathway
and what these lead to |
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Definition
Factor D, Factor P
- deficiecny leads to infection with pyogenic bacteria and Neisseria but no immune complex disease |
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Term
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Definition
leads to infection iwth pyogenic bacteria and Neisseriaxi sp.
sometimes immune-complex disease |
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Term
| Membrane attack component deficiency |
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Definition
C5, C6, C7, C8, C9
- leads to infeciton with Neisseria only |
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Term
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Definition
| - fluid accumulaiton and epiglottal swelling, due to failure to regulate C1 |
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Term
| CD55 and CD59 deficiencies/failure to function |
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Definition
| lack of complement regulation leads to RBC lysis |
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