Complement Flashcards
functions of complement
lysis
opsonization
activation of inflammatory response
clearance of immune complexes
describe the classical pathway
- Ab (IgM or 2 IgG) binds C1q
- C1r C1s (2 of each) bind C1q - Ca2+
- C4, C2 - C4bC2a (C3 convertase) - Mg 2+
- C3 activated & C3b binds = amplification
- C4bC2aC3b = C5 convertase
- C5b678-C9 = MAC
- split off products = C3a, C4a, C5a
describe the alternative pathway of complement
- no Ab involved
- spontaneous hydrolysis of C3
- fluid phase (plasma) and cell bound
- sialic acid on host cell inactivates C3b
- proteins involved = factor B, D (serine protease), Properdin
pathogen activators of alt pathway
gram neg = LIPOPOLYSACCH
gram pos = teichoic acid
fungi & yeast cell wall = zymosan
some viruses
non-pathogen activators of alt pathway
IgG, IgA, IgE
cobra venom
pur carbs (agarose, inulin)
anionic polymers = dextran sulphate
describe the lectin pathway
- lectins acute phase reactants produced in liver = collectins
- mannose-binding lectin (MBL)
> mannose, N-acetyl glucosamine, D-glucose, L-fucose - proteins involved = MBL, MBL-associated serine proteases = MASP1, MASP2, MASP3
what happens in the lectin pathway?
MBL binds CHO residues on microbes
MASP binds and is activated
C4 C2 cleaved to C4BC2a
C3 activated
pathogens with D-mannose, L-fucose
gram neg = Salmonella
gram pos = Streptococci
yeast = C. albicans
viruses = influenza A, HIV
parasites = Leishmania
complement receptors
bind complement coated organisms to aid in clearance
- used in conjunction with regulator proteins (PROTECT HOST CELLS)
- amplify B cell signal
- used by some pathogens to enter cell
examples of complement receptors
CR1
CR2
CR3/4
CR1
- aid phagocytosis by monocytes, macs, and neuts
- binds C3b, C4b
- help with immune complex clearance via rbc delivery to spleen
- required for factor I to function
- receptor for P. falciparum
CR2
- co-receptor on B cell surface
- amplification signalling with associated CD19 and CD81 (TAPA-1)
- EBV uses CR2 as receptor
CR3 and CR4
CD11b/c/CD18 integrins
- aid phagocytosis by monos, macs, neuts
- help neuts and monos with extravasation
- present on NK cells
describe the three components of complement regulation
- inhibitors regulate complement cascade = localize activation, protect host
- soluble (plasma proteins)
- membrane bound (host clls and some pathogens)
list the soluble complement inhibitors
C1-inhibitor (C1-Inh)
factor H
factor I
describe C1-Inh
binds C1r2s2 and dissociates from C1q
describe factor H
- prevent binding of B to hydrolyzed C3 (C3H2O) and C3b
- acts as a cofactor for factor I
describe factor I
- cleaves C3b into C3d + C3c
- cleaves C4b into C4d + C4c
- requires help = cofactor (CR1, factor H, CD46)
- also called C3 inactivator
membrane-bound complement inhibitors
DAF
MIRL
describe DAF
decay-accelerating factor
- CD55
- inactivates C3 convertases
complement needs to bind in close proximity to CD55?
describe MIRL
membrane inhibitor of reactive lysis
- CD59
- binds C5b678 preventing C9 insertion
- AKA protectin
early complement deficiencies
C1q, C1r, C1s, C4, C2
middle complement deficiencies
C3
late complement deficiencies
C5, C6, C7, C8, C9
SLE
systemic lupus erythematosus
- C1, C2, C4-def ppl at risk
- immune complexes not cleared
- build up in tissues (BM, vascular surfaces) = lead to tissue damage (neuts)
C1-Inh deficiency
- hereditary angioedema
- localized edema = subcutaneous tissue, bowel, resp tract
- autosomal dom
- treat with C1-Inh or frozen plasma
C1 esterase inhibitor
Berinert
C1-Inh deficiency leads to _________ formation due to excess kallikrein
bradykinin
factor I and H deficiencies
pts get recurrent infections
CD55/CD59 deficiency
- paroxysmal nocturnal hemoglobinuria
- no PIG-A (phosphatidylinositol glycan A)
- diagnosis = historical Hamm’s test; flow cytometry
- anemia (susceptible to hemolysis), cytopenia, thrombosis
- 10-15 yr survival without treatment => DVT
- treatment = correct anemia, prevent thrombosis, BMT, Eculizumab (anti-C5)
microbial evasion of complement (GPOS)
thick peptidoglycan prevents insertion of MAC
capsule provides physical barrier between C3b and CR2 = S. pneumoniae
microbial evasion of complement (GNEG)
long polysaccharide chains prevent MAC insertion (E. coli and salmonella)
some N. gonorrhoeae have outer membrane protein that MAC will bind to = preventing insertion
P. aeruginosa has elastase which inhibits C3a and C5a
protein mimicry by microbes
microbial membrane bound proteins similar to inhibitor proteins such as CR1, DAF, C1-Inh
- Vaccinia virus, Herpes, EBV, T. cruzi, C. albicans
HIV evasion of complement
- lipid envelope lysed by MAC
- MBL can bind gp41 and 120 (no Abs)
- helps neutralize Ab-coated viral particles = lyse HIV infected cells
BUT
- gp-41 and 120 on lipid envelope binds factor H
- virus incorporates host DAF and MIRL into membrane during budding
- complement coated virus gets picked up by CR1,3,4 = RBC transport virus, bind Mo, dendritic cells which interact with T lymphs, NK rich in CR4
