complement

functions of complement

inflammation by anaphylatoxin production
opsonisation
lysis via MAC

classical complement pathway

1. antibody binds antigen

2. C1 binds

3. C4 and C2 cleaved by C1r/s

4. C4b2a is C3 convertase

5. C3 cleaved

6. C4b2a3b is C5 convertase

lectin pathway

1. PAMP containing mannose binds MBP

2. MASP1 conformational change activates MASP2 to cleave C4 and C2

3. C4b2a is C3 convertase

4. C3 cleaved

5. C4b2a3b is C5 convertase

alternative pathway - via classical or lectin

1. C3b binds factor B

2. factor D cleaves factor B

3. C3bBb is C3 convertase

4. C3 cleaved

5. C3b2Bb is C5 convertase

alternative pathway - spontaneous

1. C3 undergoes spontaneous hydrolysis

2. C3H2O binds factor B

3. factor D cleaves factor B

4. C3H2OBb is fluid C3 convertase

5. C3 cleaved

role of properdin

stabilises C3bBb
made by neutrophils and stored in granules

MAC formation

1. C5b recruits C6 and C7

2. C5b-7 inserts into membrane

3. C8 and C9 recruited

4. C9 forms pore and leads to osmotic lysis

complosome

1. C3H2O binds CTSL which cleaves

2. C3a binds C3aR = low level mTOR activation

3. C5 cleaved in lysosome and C5a binds receptor on mitochondria = increases ROS production

4. C3b binds CD46 = induces GLUT1 and LAT1 transporters expression, mTORC1 activation

5. after peak activity CD46 switches to regulatory

negative regulators of complement

C1INH
DAF
FH
FI
protectin

C1INH

inhibits C4b2a formation
dissociates C1r/s from active C1 complex to stop C4/2 cleavage

DAF

inhibits C4b2a formation by displacing C2a and Bb

FH

binds sialic acid and dissociates Bb from C3b

FI

serine protease that cleaves C3b and C4b

protectin

prevents C8 and C9 joining MAC

N.meningitidis evasion of complement

FHBP inactivates C3b

S.aureus evasion of complement

Spa binds fc to prevent classical pathway activation
SCIN inhibits C3 convertase formation

VCV evasion of complement

VCP co factor for FI binds C3b and C4b
dissociation of C3 and C5 convertases
KO VCP = decrease in VCV virulence

CMV evasion of complement

uses host DAFs and CD59 in virion envelope

flavivirus evasion of complement

NS1 leads to C4 degradation and FH recruitment

T.cruzi evasion of complement

binds factor H and C4BP
inhibits all pathways

leishmania complement evasion

gp63 protease cleaves C3b so can’t form convertase
still can bind CR3 on macrophages to allow uptake

T.gondii evasion of complement

interferes with C1q binding

disorders of proteins that activate complement

greater susceptibility to infections and immunodeficiency
C3 deficiency - susceptible to severe recurrent infections, poor IC clearance
MAC deficiency - neisseria infections, can’t lyse gram negative bacteria

disorders of proteins that inhibit complement

hereditary angioedema - C1INH deficiency, excess bradykinin production, vascular leak and swelling
paroxysmal nocturnal hemogloninuria - loss of GPI anchored proteins so rbcs become sensitive to complement