L4 Flashcards
Which complement molecules can make thio-ester bonds? Why don’t these thio-ester bonds bind self?
C4 - classic and lectin pathways
C3 - alternative pathway
Our cells produce inhibitor of these bonds - thioester bonds will only form to antigens
What is the role of C3d?
Breakdown product of C3
Left on antigen
Used for B cell co-activation via CR2
Can also be used for complement binding
What are the options of things that can happen to C3b’s thioester site when exposed or activated via attachment to an antigen?
- Inactivated by water
- Utilized by factor B
- Inactivated by factor i
Explain the steps of the classical pathway.
- Ab binds antigen
- C1 complex binds Fc region of Ab
- Binding creates conformational change in 1q, so 1r can activate 1s
- 1s cleaves 4 in the blood
- 4b thio-ester site exposed - binds antigen
- 4b binds 2, 2 cleaved by 1s
4b + 2a = C3 convertase - 4b+2a bind 3, cleave 3
- 4b+2a+3b = C5 convertase, cleaves 5 into 5a and 5b
Which antibodies activate the classical cascade? Why is conformation important for these Abs?
IgM IgG1 IgG3 (IgG2 = weak activator) Conformation determines if bind C1 - Free in solution conformation will NOT
What are the different molecules of C1? Name the ratio they are present in.
C1q = 6 - non-covalently bind Fc region C1r = 2, serine protease C1s = 2, serine protease r & s are covalently bound
Which complement products activate inflammation (anaphylatoxins)?
C3a & C5a
Which lectin residues are commonly bound as PAMPs?
Mannose
Sialic acid
What are the 2 types of mannose binding proteins?
Mannose binding lectin (made by liver, acute phase reactant)
Ficolin
Describe the steps of the lectin binding pathway.
- MBP + MASP1 + MASP2 bind lectin on antigen
- MASP2 cleaves 4
- 4b thio-ester bonds to antigen
- 4b + 2 cleaved by MASP2
- 4b + 2a = C3 convertase
- 4b+2a+3b = C5 convertase
Explain the steps of the alternative pathway.
- C3 in blood randomly –> 3a & 3b
- 3b thioester binds to antigen, recruits factor B
- Factor D cleaves factor B - Ba & Bb
- 3b + Bb = C3 convertase
Causes more C3 binding to the antigen - proliferation and opsonization - 3b+Bb+3b = C5 convertase
What molecule stabilizes 3b-Bb complex in the alternative pathway?
Factor P
What is the active protease in each of the 2 different C3 convertase enzyme complexes?
2a in 4b2a of classical/lectin
Bb in 3b/Bb of alternative
What is the basis for having different enzymes governing the alternative vs classical and lectin pathways?
Gene duplication at some point in evolution
How does the MAC complex form (lytic pathway)?
C5 cleaved - 4b2a3b5b - 3bBb3b5b 5b recruits C6 & C7 C7 brings the complex into the antigen membrane b/c hydrophobic \+ C8 C9 recruited in multiples to form hole
What is C1INH?
C1 inhibitor
Binds activated C1r & s/MASP2
Removes them from C1q/MBP
What is factor H?
Binds 3b
Can bind Bb
What is factor I? What is its cofactor?
= serine protease
Cleaves 4b & 3b
- 3b –> 3bi & 3d
Uses factor H as cofactor
What is CD59?
Prevents MAC formation
Why do you want complement regulation?
Limit inflam response
Block self responses
Prevent using up all your complement proteins!
What disease results from C1 inhibitor mutation/deficiency?
Hereditary angioneurotic edema
What are the various roles of 3b breakdown products?
3b = opsonizing –> C5 convertase steps
3bi - opsonization ONLY
3d - stimulates B & dendritic cells
What is the role of CR1? What molecule does this receptor bind?
Binds 3b &4bi
On RBCs
Transport complement complex to liver for destruction
How remove immune complexes from the body without clogging up kidneys
What is the fxn of CR2? What molecule does this receptor bind?
Bind 3d & 3bi
B cell coactivation! (on FDC & B cells)
Which complement receptors are important for phagocytosis? What is the difference between them?
CR3 & CR4 - only bind inactive 3
CRIg - bind 3b & 3bi
Where do you find C3a & C5a receptors?
Endothelial cells
Mast cells
Phagocytes
All for inflammatory process!
What are the inflammatory fxns of C5a, C3a, and slightly C4a?
Smooth muscle contraction
↑vascular perm
Mast cell release
Which complement is in highest concentration in the blood?
C3 = 1st C4 = 2nd
