Complement System Part II

Amplification pathway

increases complement effect by creating more C3a and C5a

C3a and C5a

induce contraction of smooth muscles in blood vessels

C3a and C5a effect on endothelium

increase vascular permeability and adhesion molecule expression

excessive C3a and C5a

can lead to anaphylactic shock

MAC (Membrane Attack Complex)

forms a pore in target cell membranes causing lysis

MAC/TCC composition

C5b, C6, C7, C8, and 12–18 C9 molecules

C1 inhibitor

a serine protease inhibitor that binds to C1r:C1s and prevents C2 and C4 cleavage

C1 inhibitor function

prevents activation of classical pathway

CD55 (Decay-accelerating factor)

glycoprotein that protects cells by competing with Factor B

CD55 action

inhibits alternative complement activation

Factor H

plasma protein that binds C3b on host cells to prevent self-attack

Factor H vs. Factor B

Factor H outcompetes Factor B for C3b

Factor H function in C5 convertase

displaces C3b from forming C5 convertase

Protectin (CD59)

blocks MAC formation by preventing C5b678 insertion and C9 polymerization

Vitronectin and Clusterin

inhibit MAC by blocking membrane insertion

complement gene locations

scattered throughout the genome

complotype

genetic variations in complement proteins

complement gene variation effect

influences susceptibility to infection and inflammation

bovine Factor H

has 3 alleles

equine C3

has 6 alleles

canine C3

has 2 alleles

canine C6

has 7 alleles

porcine C6

has 14 alleles

canine C7

has 11 alleles

canine C4

has 5 alleles

feline and equine C4

have at least 4 alleles

canine C3 deficiency

autosomal mutation leading to no/low C3 production

homozygous C3-deficient dogs

have no detectable C3

heterozygous C3-deficient dogs

have ~50% of normal C3

C3 deficiency antibody effect

reduced IgG, more IgM, less specific immunity

C3 deficiency clinical signs

recurrent sepsis, pneumonia, pyometra, wound infections

bacteria involved in C3 deficiency

Clostridium spp., Pseudomonas spp., E. coli, Klebsiella spp.

complication of C3 deficiency

amyloidosis and immune complex kidney diseases

C3 deficiency mutation

cytosine deletion → frameshift → premature stop codon

porcine Factor H deficiency

failure to regulate C3b → uncontrolled complement activation

porcine FH deficiency trait

autosomal recessive (Yorkshire pigs)

FH-deficient pigs

born healthy, stop growing, become anemic, and die of renal failure

FH function in pigs

inactivates C3b to prevent overactivation of complement