lecture 7 Flashcards
zymogens
pro enzymes
components exist as this
highly conserved bw specifies
complement system initiated through 4 distinct pathways
w identical end results
- classical
- alternative
- MBL
- C2 bypass pathway: intracellular activity
complement system plays a role in both
innate and adaptive immunity
complement proteins secreted in Liver by Macrophages as
zymogens and are found in normal serum
innate pathway
includes alternative and lectin pathways
activated by recognizing PAMPS
adaptive pathway
includes classical pathways
activated by presence of antibody bound to antigen
complement components (C3b) bind
covalently to invading microbes and opsonize them
membrane attack complex
complement components that punch holes in microbes
chemoattractants trigger
inflammation through C3a C5a
deficiences of some components can lead to
increased susceptibility to infections
major proteins designated as
C1-C9
lectin pathway
triggered by mannose-binding lectin - MBL
revognizes mannose on microbial glycoproteins and glycolipids
uses C4 & C2
creates C3 components (C3b and C3a)
C3 deposited on microbe and opsonization/phagocytosis starts
C5 converts to C5a and b - comes in and form attack on membrane
C3a
inflammation
C5a
inflammation
alternative pathway
triggered by direct recognition of certain microbial surface structures (ex: spontaneous cleavage of thioester bond in C3)
B and C3
creates C3a and b components which generate C5a and C5b
attack on membrane by complement proteins!
classical pathway
uses C1 protein to detect IgM, IgG1, or IgG3 antibodies bound to the microbe
uses C4 and C3
creates C3a and b components which generate C5a and C5b
attack on membrane by complement proteins!
MAC formation
C6 + C5b + C7 + C8 binds C9 units together to make membrane attack complex to cause cell lysis
initiated by lectin, alternative and classical pathways
C1q
complement activating protein
binds w C1r2s2 onto microbial surface antigen bound to IgM antibody
mannose binding lectin
complement activating protein
binds MASP1/2 to mannose on microbe surface
MASP
MBL- associated serine protease
Ficolin
complement activating protein
binds MASP1/2 to N acetylglucosamine on bacterial cell wall
mannose binding lectin
complement initation mechanisms
mannose binding lectin (MASP1/2) binds mannose/similar sugars on bacteria, fungi, protozoa & viruses -> conformational change -> C4 and then C2 cleavage -> generates C4a + C2a -> generate C4bC2b convertase -> cleave C3 -> makes C3a + C3b
antibodies as complement initiation mechanism
antibodies bind to epitopes on pathogens surface -> conformational change -> C1q (like MBL) binds to complement binding site on antibodies w C1r & C1s which are serine proteases -> C4 & then C2 cleavage -> make C4a + C2a -> generate cell bound C4bC2b convertase -> cleaves C3 -> makes C3a + C3b
C1r & C1s
serine protease - cuts C4 and C2
spontaneous C3 cleavage as complement initation mechanism
C3 spontaneous breakdown -> C3b + C3a -> C3b surface bound -> a. normal circumstance (no avtivating surfaces) -> Hv binds and creates C3bH -> I inactivates C3b
b. in presence of activating surface B binds to create C3bB -> D acts on it and makes C3bBb + C3bBa -> P acts on it and makes C3bBbP
C3 convertases as complement initiation mechanism
- C4b2b
2. C3bBb
C5 convertases as complement initation mechanism
- C4b2b3b
2. C3bBb3b
regulation of complement activation
C1, decay accelerating factor (DAF) (CD55), CD59, factor H and I
C1 inhibitor
disrupts C1 and the classical pathway
decay accelerating factor
DAF, CD55
dissociates C3 convertases and lectin pathway
factor H and I
destroy C3b on sialic acid experssing cells
disrupts alternative pathway
CD59
blocks C9
prevents C5b678 + poly C9 so no MASP or membrane attack
C3b and sialic acid
C3 breaks down spontaneously into C3a and C3b, if it is bound to sialic acid factor H will bind to C3b
-> activates factor 1 which creates a complex that degrades C3b -> a. iC3b b. C3c and C3d
C3c, C3d and iC3b are opsongens that are unable to initiatiate complement pathway
CR1
CR1 + C3b in RBC, monocytes, macrophages, neutrophils and T cells
immune adherence receptor
removal of C3b opsonized immune complexes by liver
neutrophil phagocytosis
inhibition of classical and alternative pathways
CR2
CR2 + iC3b/C3d (g) in B cells
enhances B cell immunity
CR3
CR3 + iC3B dimer in NK cells, monocytes, macrophages, neutrophils and T cells
adherence receptor cell-cell interaction and binding phagocytosis leukocyte trafficking and migration outside in signaling promote inflammation
CR4
CR4 + iC3b dimer in neutrophils, NK cells, monocytes, macrophages, dendritic cells
same as CR3 adherence receptor cell-cell interaction and binding phagocytosis leukocyte trafficking and migration outside in signaling promote inflammation
consequences of complement activation
- complement mediated cytolysis
- opsonization and phagocytosis
- stimulation of inflammatory reactions
- regulate B cell responses
complement mediated cytolysis
binding of C3b to microbe surface and activate late components of complement
formation of MAC
osmotic lysis of microbe
opsonization and phagocytosis of complement activation
binding of C3b (or C4b) to microbe - opsonization
recognition of bound C3b by phagocyte C3b receptor (CR1)
phagocytosis of microbe!
stimulation of inflammatory responses as result of complement activation
proteolysis of C3, C4, C5 to release C3a, C4a, and C5a
recruitment and activation of leukocytes by C3a, C4a and C5a
microbe is DESTROYED by leukocytes
B cell responses regulated as consequence of complement activation
C3d bound to antigen, binds to BCR and CR2
C3b cleaved by factor 1
C3c + C3d regulate B cell responses
complement deficiencies
- canine C3
2. procine factor H
canine C3 deficiency
brittany spaniels
autosomal recessive C3 deficiency
experience recurrent sepsis, pneumonia, wound infections - recurrent bacterial infections
organisms: clostridium, pseudomonas, e coli, klebsiella species
treatment: antibiotics and monitoring
porcine factor H deficiency
yorkshire pigs
factor H inactivates C3b -> prevents excessive alternative pathway activation
autosomal recessive deficiency
renal failure at early age (glomerulonephritis)
treatment: infusion of normal swine serum
C3 will deposit in glomerulus - causing renal failure
Neisseria meningitides
resistance to complement activation (alternative pathway)
mechanism of immune evasion: sialic acid expression inhibits C3 and C5 convertases
streptococcus
resistance to complement activation (alternative pathway)
mechanism of immune evasion: M protein blocks C3 binding to organism, and C3b binding to complement receptors
evasion of innate immunity by microbes
- salic acid expression
- M protein block
- capsule preventing interation w C3b
- some bacter inactivate C3a and C5a
- produce molecules that mimic regulatory proteins
