I & I - 11 - Compliment
How many Fc regions does IgG have?
1
How is MAC formed?
1. C5b binds to C6 = C5b,6 complex 2. C5b,6 complex binds to C7 = C5b,6,7 complex is hydrophibic and it inserts into the lipid bilalyer of cell membranes. 3. C8 molecule is a trimer of the chains one of which binds to the C5b,6,7 complex and another inserts into the lipid bilyer of the membrane 4. Binding of C9, the final component of the complement cascades, to the C5b,6,7,8 complex creates MAC
What is the diameret of MAC?
10 nm in diameter and they form chanels that allow free movement of water and ions
How many Ig heavy chains does C1q need to bind to to be activated?
2
What are the components of the compliment system?
30 Proteins, 10% of total serum proteins
How many binding sites do the Ig Fc region have?
A single C1q binding site
What is the role of C3a and C5a in inflamation?
Act on mast cells to cause degranulation and release of of vasoactive amines including histamine and 5-hydroxytrptamine which enhances vascular permeability and local blood flow. C5a itself acts directy on receptors on moocytes and neutrophils to enhance their migration to sites of acute inflammation and subsequent activation.
What does the compliment system do to zymogens?
Activate
What is the function of C1s?
Activated C1s cleaves the next protein in the cascade C4
How is the Alternative pathway activated?
Activated on microbial surfaces in the absence of antibody.(Innate immunity)
What is the function of C5 convertase generated by the classical or alternative pathways ?
Activation of the late coponents of the complement system which culminates in the fomratin of the memebrne acttack complex. (and so destruction of the target cell)
To which pathway is C3bBb associated with?
Alternative. (But is able to be done by classical, but is still called the alternative pathway C3 convertase)
What is the function of factor B?
Bb is a serine protease and the active enzyme of C3 and C5 convertases
What is the function of C4b2a?
Bind to and proteolytically cleave C3
What happens to some of the C3b molecules generated by the clasical pthway C3 convertase?
Bind to the convertase and form a C4b2a3b complex this complex functions as the clasical pathway C5
When can C1q bind to IgM?
Binding of IgM to an antigen induces a conforamtional change that allows C1q to bind
How is the Classical pathway initiated?
Binding of complement protein C1 to the C(H)2 domains of of IgG or IgM molecules that have bound anitgen.
how are C1r and C1s activated?
Binding of the C1q globular heads of C1 leads to the activation of C1r which cleaves and activates C1s
After C3b is bound to the microbial surface what happens?
Binds to a plasma protien called factor B and after it is bound, factor B is cleaved by factor D to generate a fragment called Bb that remains attached to C3b (creating C3bBb)
As a summary what is the function of C1q?
Binds to the Fc portion of the antibody that has bound antigen
What are the functions of the different subunits of C1?
C1q binds to the antibiody, and C1r and C1s are proteases
What is C1 composed of?
C1q, C1r and C1s subunits
As a summary what is the function of C2
C2a functions as the active enzyme of C3 and C5 convertase to cleave C3 and C5.
As a summary what are the functions of C3?
C3b binds to surface of microbe where it functions as an opsonin and as a component of C3 and C5 convertases.
What hapens to C3B after its been formed from C3?
C3b is either hydrolsed or forms covalent bonds with woth cell surfaces or with the antibody where complement activation was intiated
What does the cleavage of C4 produce?
C4b and C4a
As a summary what is the function of C4
C4b binds to microbe or cell where antibodyis bound and complement is activated. C4b binds C2 for cleavage by C1s C4a stimulates inflammation
What complex is formed when C2 then complexes with the cell surface bound C4b?
C4b2a (classical pathway convertase)
Other than C5 what are the other proteins involved in the late stages of the cascade?
C6, C7, C8, C9 are structurally related proteins without enzymatic activity.
What complement regulatory proteins bind to C3b to inactivate it?
CR1, H, MCP and DAF bind to C3b. CR1H, and DAF displalces Bb.
How many C1q molecules can IgM bind to, and what does this mean?
Can bind more than two C1q molecules at any on time which makes it a much more effiecient complement antibody tha IgG
How is the classical pathway activated?
Certain isotypes of antibodies bound to antigens (Adaptive immunity)
Which pathways activate the compliment system?
Classical Alternative
What is the function of the C5 convertase (C3bBb3b)?
Cleave C5 and initiates the late steps of the complement activation steps.
What does the C5 convertase do to C5?
Cleave C5 into a small C5a fragment tha is released and a two chain C5b fragment that remains bound to the cell surface
What is the function of C3bBb?
Cleave more C3 molecules, thus setting up an amplification sequence.
What happens when the next complement protein C2 then complexes with the cell surface bound C4b?
Cleaved by nearby C1s molecule to generate a soluble C2b fragment of unknown imortance and a larger C2a fragment which remains physically associated with C4b on the cell surface
As a summary what is the function of C1r?
Cleaves C1s to make it active
As a summary what is the function of C1s?
Cleaves C4 and C2
What is the function of factor D?
Cleaves factor B when it is bound to C3b
What is the function of C4b?
Ensures that the classical pathway proceeds on a cell surface or immune complex.
Why does free IgM not bind to C1q?
Fc regions are inaccessible to C1q.
How do both the alternative and classic pathways initiate the compliment system?
Generation of enzyme complexes that act in the proteolysis of C3 the most abundant complement protein.
What are zymogens?
Inactive enzyme precursors
Once C3b is deposisted on cell surface what is able to happen?
It can bind Factor B and generate more C3 convertase by the alternative pathway (amplification)
What happens if C3bBb binds to a mammelian cell?
It is rapidly degraded and and the reaction is terminated by the action of several regulatory proteins present on these cells
What allowa the activation of the alternative pathaway C3 convertase on microbial cells?
Lack of regulatory proteins
What is the significants of IgG having only one Fc region ?
Multiple IgG molecules must be bruoght together before C1q can bind and multiole IgG antibodies are only brought together when they bind to a multivalent antigen.
What is the C3 Tickover?
Normally C3 in plasma is being continously cleaved at a low rate to generate C3b
What are the functions of the compliment system?
Opsonisation and cell activation, Chemotaxis Lysis of target cells
What is the structure of IgM?
Pentameric
What does the hexamer structure of the C1q subunit function as?
Performs the recognintion function of the molecule and binds specifically to the Fc regions of IgM and IgG molecules.
What can the pores formed by C9 be compared to?
Pore formed by perforin found in t cells and NK cells.
What additional protein of the alternative pathway can bind to stablize C3bBb?
Properdin (this makes sense in welsh)
What does the alternative pathway result in?
Proteolysis of C3 and the stable attachment of C3b to microbial surfaces without a role for antibody.
What inhibits the compliment system?
Regulatory proteins
What happens when C3 is cleaved by C4b2a?
Removal of a small C3a fragment, which leaves C3b
What is C9, and why is it improtant in the formation of MAC?
Serim protei Polymerises at the site of the bound C5b,6,7,8, to form pores in the plasma membrane
What type of proteases are C1r and C1s and in what form do they function?
Serine esterases. Function as a tetramer containing two molecules of each
What is the net effect of the multiple enzymatic steps and amplification?
Single molecule of C3 convertase can lead to the deposistion of hundreds and thousands ofmolecules of C3 b on the cell surface where complement is activated
How is C3bBb3B formed? (also knows as the C5 convertase)
Some of the C3b molecules generated by the alternative pathaway C3 convertase (C3bBb), binds to the convertase itself.
What is the function of properdin?
Stabilizes C3 convertase (C3bBb) on microbial surfaces.
What trait does properdin have that aids in immunity?
The attachment of properdin is favored on micobial as opposed to normal host cells
How does MAC cause the cell destruction?
The entry of water through MAC results in osmotic swelling and rupture of cells.
What is the structure of the C1 subunit C1q?
Umbrella like radial array of six chains, each of which has a globular head connected by a collagen-like arm to a central stalk.
What is C1?
large multimeric protein
