Week 4 - The Complement System

What is the complement system?

A family of ~30 plasma proteins forming an enzymatic cascade that generates antimicrobial and inflammatory molecules.

What percentage of blood serum proteins does complement account for?

5-10%.

Is the complement system heat-stable or heat-labile?

Heat-labile.

When is complement inert and when is it active?

Inert at steady state; activated by PAMPs or antigen-antibody complexes.

What are the three complement activation pathways?

Lectin pathway, classical pathway, alternative pathway.

What do all three pathways share?

Assembly of the membrane attack complex (MAC, C5-C9).

What are the three major consequences of complement activation?

Direct killing (MAC), inflammation (C3a, C5a), opsonization (C3b).

What initiates the lectin pathway?

Mannose-binding lectin (MBL) or ficolins binding carbohydrates on pathogens.

What are MASPs?

MBL-associated serine proteases (MASP-1, MASP-2, MASP-3).

Which MASP activates the pathway by cleaving complement proteins?

MASP-2.

Which complement proteins are cleaved first in the lectin pathway?

C4 → C4a + C4b, then C2 → C2a + C2b.

What is the C3 convertase of the lectin pathway?

C4b2b.

What is the C5 convertase of the lectin pathway?

C4b2b3b.

How many C3 molecules can one C3 convertase cleave?

Up to 1000.

What triggers the classical pathway?

Antigen-antibody complexes (IgM or paired IgG).

Which antibodies cannot activate complement?

IgA, IgD, IgE.

Which complement complex recognizes bound antibodies?

C1 complex (C1q, C1r, C1s).

Which part of the antibody binds complement?

Fc constant region.

Why is IgM more efficient than IgG at activating complement?

IgM is a pentamer; one bound IgM can activate C1, whereas IgG requires two bound molecules.

Which enzyme activity does activated C1s provide?

Cleaves C4 and C2 to form C3 convertase (C4b2b).

What are the convertases of the classical pathway?

C3 convertase = C4b2b; C5 convertase = C4b2b3b.

How can the alternative pathway be activated?

(1) C3b from lectin/classical pathways binding pathogens; (2) spontaneous hydrolysis of C3 → C3(H₂O).

Which proteins are unique to the alternative pathway?

Factor B, Factor D, Properdin (Factor P), Factor H, Factor I.

What is the temporary C3 convertase formed from spontaneous C3 hydrolysis?

C3(H₂O)Bb.

What is the final C3 convertase of the alternative pathway?

C3bBb.

What stabilizes the alternative pathway C3 convertase?

Properdin (Factor P).

What is the C5 convertase of the alternative pathway?

C3bBbC3b.

Which complement protein is the last enzymatically cleaved?

C5.

What initiates MAC formation?

C5b.

Which proteins bind sequentially after C5b?

C6 → C7 → C8 → multiple C9 molecules.

What does polymerization of C9 create?

A pore in the pathogen membrane, causing lysis.

How many C9 molecules polymerize to form a pore?

10-16.

What does MAC do?

Directly kills pathogens by pore formation.

What roles do C3a and C5a play?

Promote inflammation, increase vascular permeability, recruit immune cells.

Which complement fragment is the key opsonin?

C3b.

Why must complement be regulated?

To prevent host cell damage.

Which protein regulates C1 activation?

C1 inhibitor (C1NH).

Which proteins regulate C3 convertase?

DAF (CD55), CR1 (CD35), MCP (CD46), C4BP.

Which factor cleaves C4b and C3b?

Factor I.

Which proteins regulate C3b activity?

Factor H, Factor I, MCP, CR1.

Which proteins regulate C5 convertase?

CR1, Factor H, Factor I.

Which protein regulates MAC formation?

CD59 (protectin).

How does CD59 block MAC?

Prevents C9 binding and polymerization.

What is a complotype?

The inherited pattern of genetic variants in complement genes.

Which dog allele is linked to autoimmune polyarthritis?

C4-4 allele (low serum C4).

What is the effect of autosomal recessive C3 deficiency in Brittany Spaniels?

Homozygous: no C3, increased bacterial infections. Heterozygous: ~50% C3, clinically normal.

What is porcine Factor H deficiency?

Autosomal recessive trait in Yorkshire pigs → deficiency of Factor H → renal failure and death in homozygotes.

How can Factor H deficiency be treated?

Plasma transfusions.

What deposits are seen in Factor H deficiency pigs?

Massive deposits of C3 breakdown products in glomeruli.

What is MBL deficiency?

Mannose-binding lectin deficiency → increased susceptibility to infections (seen in humans, not yet animals).

Are C6 or C7 deficiencies lethal?

No, individuals may remain healthy, showing MAC is not always essential.