5: The complement system Flashcards
What are the seven functional categories of complement components?
- Initiators
- Enzymatic mediators
- Phagocytosis-enhancing components (opsonins)
- Inflammatory mediators
- Membrane attack complex (MAC)
- Complement receptor proteins
- Regulatory components
What are the major pathways of the complement system?
Different activation, but all converge in the generation of an enzyme that cleaves the C3 molecule by C3 convertases.
Classical pathway:
- Ag-Ab immune complexes
Lectin pathway
- PAMP recognition by lectins
Alternative pathway
- Spontaneous hydrolysis
The classical pathway
Part of the adaptive immune response as it begins with Ag-Ab complexes.
Triggered by activation of the C1-complex which binds IgM or more than two IgG complexed
with antigens on a surface.
- IgM/IgG Ab binds Ag
- C1 binds to Ab, activating C1-associated serine proteases => cleavage of C4 and C2 to C4a, C4b, C2a, and C2b.
- C2a + C4b ->C3 convertase (protease) / C2a4b
=> cleavage of C3 to C3a+C3b - C2a4b + C3b -> C5 convertase
=> cleavage of C5 to C5a + C5b
Lead to increment of C3b; important complement protein.
What is the functions of C3b?
- Binds covalently to microbial surface, tagging them for phagocytosis => opsonization
(very similar to C4b) - Can attach to Fc portions of Ab’s -> bind to C3b receptors on phagocytes or red blood cells (transport to liver, destruction)
Similar for C4b - Bind C4b2a => C4b2a3b / C5 convertase => C5 -> C5a+b
The lectin pathway
Innate immunity as it doesn’t rely on Ab’s.
Triggered by mannose binding lectin (MBL/MBP) (or ficolins) which bind to mannose on microbial surfaces. Otherwise homologous to the classical pathway.
Binding of lectin to carbohydrate residues on microbes activates MASP-2 => cleavage of C4 and C2 -> C3 convertase.
End with cleavage of C5
The alternative pathway: thickover pathway
C3(H2O) binds to factor B
Cleavage by factor D: Ba + Bb
Bb binds to C3(H2O) -> fluid-phase C3 convertase (C3(H20)Bb)
=> cleavage of C3
Some C3b binds to microbial surfaces, followed by the binding to factor B. Cleaved by the factor D
=> memb. bound C3 convertase stabilized by properdin.
The alternative pathway:
Properdin-activated pathway
Activation of the alternative pathway by the binding of properdin to a bacterial surface.
Relies on the pre-existence of low levels of C3b (generated by i.e., thickover pathway).
The alternative pathway:
Protease-activated pathway
Generation of the anaphylatoxin C5a can be effected by thrombin cleavage of C5, linking the coagulation and complement cascades.
Functionally meaningful C5b concentrations are not generated by this route.
How can the cleavage of C5 and subsequent steps yiels\d the generation of the membrane attack complex?
Last step of the classical, lectin, and alternative pathway. C5 -> C5a+C5b
C and L: C4b2a3b
A: C3bBbC3b
C5b on the surface of the target cell/immune complex:
binding site for membrane attack complex (MAC).
C5b inactivated unless it is stabilized by C6.
Binding of C7 to C5bC6 => formation of MAC
Cascade of C8 and C9
=> cell death caused by large pores in the membrane (no osmotic integrity)
What is opsonization?
May be most inportant function of complement.
Covalent binding of complement, Ab’s, or other proteins to pathogens, serving as ligands for phagocytic cells with complement/Fc receptors.
C3b and C4b serve as opsonins.
Phagocytic cells:
Complement receptors connect
complement-tagged pathogens
“complement-receptor mediated phagocytosis”.
Ab and complement can create a thick protein coat around virus => prevents it from binding to receptors on host cells.
Complement receptors: CR1
- On leukocyttes and erythrocytes
- Binds C3b (and smaller C3b breakdown prod) with high affinity. Needs to also be bound to C5a to phagocytose cells.
- On erythrocytes: helps to bring immune complexes to the liver for clearance by phagocytes.
- Actor in innate and adaptive immunity.
- On phagocytes, helps bind to complement-coated bacteria to enhance ingestion and
destruction - On B cells: helps bind to complement-coated antigens, enhancing ingestion for processing and presentation to helper T cells
- Cofactor in the protection of host cells against complement attack.
Name some of the functions of complement receptors
- Anaphylatoxin receptors: C3aR and C5aR
- Chemotaxis
- Oxydative burst
- Aids in phagocytosis (CR1)
- Degranulation (Histamine,
Prostaglandins) leads to
secondary effects - Trigger IL-6, TNF aiding in
vasodilation - Modulates (increase or decrease)
the cytokine responses (dual PRR
signals)
MAC-induced cell death
Membrane attack complex is the result of deposition of C5b, C6, C7, C8, and C9 in target cell membranes.
This pore structure (10 Å) disrupts
osmotic integrity, resulting in cell death.
Apoptic necrosis as cell death does not share all the characteristics normally associated with normal programmed cell death.
How can eukaryotic cells recover from a MAC attack?
MACs can be removed from cell surface by shedding MAC-containing memb. vesicles into the ECM, or by internalizing and degrading the vesicles in intracellular lysosomes.
If this is done soon after initial expression on memb. => cell can repair damage and restore osmotic stability.
How can complement promote inflammation?
Key words: anaphylatoxins, C3a, C5a
C3a and C5a fragments of C3 and C5 cleavage.
Promote inflammation, serve as chemoattractants for certain classes of leukocytes.
Binding of anaphylatoxins to their receptors trigger a signaling cascase => secretion of IL-6, TNF-α, etc.
=> localized increases in vascular permeability that facilitate leukocyte migration to the site of infection.
Increase in smooth muscle motility => propel released fluid to site of damage.
Degranulation of granulocytes (signaled by anaph.) promote phagocytosis.
