5BBBI203 The Immune System in Health and Disease (5BBBI203)
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L03: Complement
• Complement sits in the innate part of the immune system and is a
non-cellular component
• Complement is collection of soluble proteins (around 50) in blood
and other body fluids. There are 3 different classifications:
activators, receptors and regulators
• Complement is fast
• Complement cascade has 3 steps: recognition, activation, action
• Complement recognizes pathogens, apoptotic bodies and immune
complexes (complex of antibody with corresponding antigen)
• Compliment activation occurs in a 2-step process: complement
cascade and amplification
• Compliment acts differently depending on the situation:
inflammation, recruitment, opsonisation, direct lysis
• Compliment has 3 different recognizing mechanisms: classical,
alternative and Mannan- binding lectin (MBL)- This is not antigen
specific as this is an innate response, this is just for the
determination of whether situation is good or bad for organism
• Classical recognition- complement molecule C1q recognizes the FC
portion of the antibody that is bound to the antigen. When C1q
binds to antibody it activated C1r and C1S bind which promote
catalytic activity
o IMPORTANT: visible link between adaptive and innate
immunity (B cells from adaptive immune system produce
antibodies that lead to activation of complement)
▪ Although the adaptive system has not been activated
body has natural antibodies (IgM) produced during
absence of infection that are used for c1q binding-
often used in the clearance of streptococcus
pneumoniae prior to becoming dangerous
, o C1q is able to recognize DNA, as DNA shouldn’t just be
floating and therefore it’s a danger signal in addition to CRP
and prions
• Manna-binding lectin (MBL) pathway: Complement (PRR)
recognizes pathogen specific patterns (PAMPs) required for
pathogenic survival (therefore it cannot be mutated) that are
evolutionary conserved
o Complement recognizes characteristics that are present in
pathogenic cells. MBL recognizes mannose, collectins Commented [BM1]: asked question in faq
10,11,12 recognize oligosaccharides, Ficolins recognize N-
acetylglucosamine
o Ficolins are actually more abundant that MBL in plasma
o MASP1 and MASP2 are inactive until MBL (PRR) binds to the
carbohydrates on pathogen. MASP1 has a confirmational
change that activated MASP2 which then activates and
cleaves C2 and C4
• Alternative complement pathway: initiated by the spontaneous
hydrolysis of C3
• Alternative pathway can be activated in two ways:
o Action of the lectin or classical pathway- c3b generated by
either of the two pathways linked to a microbial surface can
bind to factor B
▪ This alters the confirmation of factor B enabling plasma
protease factor D to be cleaved into Bb and Ba
▪ Bb remains associated with C3b forming- C3 convertase
o Spontaneous hydrolysis of the thioester bond in c3 to form
C3(H20)
▪ C3(H20) can bind to factor B which is then cleaved by
factor D creating a short lived fluid phase C3 convertase
▪ C3 convertases then cleave C3 into C3a and C3b
• Activation of complement (MBL and classical): after classical or MBL
pathways are activated (activation or either C1q or MBL). C1s and
C1r have enzymatic activity, which then cleaves C2 and C4 resulting
in C4b, C2a (big fragments) and C2a and C4b (small fragments). Big
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, fragment stick to the membrane and small fragments diffuse and
are then part of the anaphylatoxin reaction
o C4b and C2a covalently bind (thioester bond) together to the
membrane of pathogen, creating the c3 convertase – in the
classical and MBL pathways
o Strong bond is required as this is not specicifc and cascade is
extremely aggressive meaning if bounded to wrong results
could be drastic
o C3 convertases cleaves C3 into C3b (large molecule) and C3a
(small molecule) – key step
o C3b binds to C3 convertase stabilizing the molecule and
allowing for the amplification process (opsonisation) of c3b
o C3a diffuses away and gives signals of danger to other parts of
the immune system and c3b starts binding covalently to the
surface of the pathogen
o Some of the C3b binds to c3 convertase forming c5
convertase which cleaves c5 in a similar way to the cleavages
before (c5a and c5b)
• Activation of alternative pathway: C3 opens the thioester bond and
gets filled with water, therefore, generating a partial hydrolyzation.
In the presence of other signals that are danger like factor D then
C3 is able to bind factor B and hydrolyses it
o Factor B is hydrolyse by factor D and generate a small and
large fragment (Ba and Bb)
o Complex of C3 hydrolysed with bB molecules- fluid phase
convertase
o Fluid phase convertase has a level of hydrolysis activity over
C3 and its half-life is really short- dangerous therefore tightly
controlled
o In the presence of danger signal, Factor P, will help the
stabilization of the fluid phase convertase into the membrane
creating the alternative C3 convertase
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, o The outcome is the same as classical and MBL with the
reasons of anaphylatoxins (C3a) and the opsonization of the
pathogen
• After complement activation there’s a massive generation of C3a,
C5a which are the anaphylatoxins and membrane bound
compounds that are doing opsonization therefore giving signs to
immune system that there is in fact something wrong and therefore
it can start killing (inflammatory response)
• There are 4 different ways that complement attacks: inflammation,
recruitment, opsonisation and direct lysis
o Inflammation: through the action of anaphylatoxins cells of
the immune system are recruited to facilitate immune
response
• The main anaphylatoxins are C3a and C5a. C3a is more potent than
c5a. The cells that are susceptible to these actions are cell that have
C3a and C5a receptors (endothelial cells, mast cells, macrophages, T
cells)
• Individuals deficient of MBL or MASP-2 experience more respiratory
infection by common extracellular bacteria during each childhood
indicating importance of lectin in the pathways
o As adaptive system is not fully develop, lack of a functional
working innate can be detrimental. As the antibodies transfer
by mother during placenta only have a life of 6 months
• C3b major function is the opsonisation of pathogens. C4b is also an
opsonin. The receptor of C3b is CR1 and is expressed in
macrophages but b cells (elements of the adaptive immune system)
also contain complement receptors. (CR2). C3b can induce
phagocytosis simply by binding to CR1, it requires C5a.
• Generation of C5 convertase: Lectin and classical
o C5 is formed by binding of C3b and C2a and C4b
o C5 is cleaved into C5a and C5b
• Generation of C5 convertase: alternative
o C5 is formed by binding of C3b and Bb
• C5 is cleaved by C5 convertase generating C5b and C5a.
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