complement system L8

what pathway is initiated by antigen-antibody interactions?

the classical pathway

what molecules trigger the classical pathway, besides antibodies?

pentraxins (such as c-reactive) can trigger it, by binding to the pathogen to opsonise it

How is the MBL pathway triggered?

By MBL binding to the carb moieties on the pathogens surface

which pathway is part of the innate immune response and amplifies the other two?

the alterative pathway

what is common to all 3 complement pathways?

leads to the formation of the MAC

Besides MAC formation, what other key events occur during complement activation?

recruitment of inflammatory cells

activation of endothelial cells

opsonisation of pathogens

what initiates the classical pathway?

antibody;antigen complexes (Ab:Ag)

(predominantly IgM and IgG)

whats the first molecular event to occur in the classical pathway?

binding of the C1 complex to antibodies attached to the pathogen.

(C1 on antibody, which is on pathogen)

which subunit of the C1 complex is responsible for binding to the antibody?

C1q

what are the three subunits of the C1 complex?

C1q, r and s

How are the subunits of the C1 complex arranged?

one C1q is paired with two molecules of C1r and C1s.

what conformational change occurs upon C1q binding to the antibody?

C1q undergoes a change which activates C1r

after C1q’s conformational change, whats the immediate next step in the cascade?

activated C1r cleaves and activates C1s

which complement protein is cleaved by activated C1s first?

C4 is cleaved into C4a and C4b.

what happens to C4b after it forms?

C4b binds covalently to the pathogen surface

once C4b is attached to the pathogen, what binds to it next?

C2 binds to the attached C4b.

whats created when C1s cleaves the bound C2?

the complex C4b2a, which is the C3 convertase of the classical pathway.

whats the significance of C2 binding to C4b?

it localises C2 for subsequent cleavage C1s

What is the first step in the classical pathway after complement activation?

The C1q subunit of the C1 complex binds to antibodies attached to antigen, resulting in conformational changes that activate C1r.

What happens once C1r is activated in the classical pathway?

C1r activates a second C1r molecule, and both C1r molecules activate C1s, starting the cascade.

how is the C5 convertase generated in the classical pathway?

when additional C3b binds to the C3 convertase, enabling C5 cleavage

what are the products of C5 cleavage?

C5 is cleaved into C5a and C5b

after C5 is cleaved - what does the C5b fragment do?

C5b binds C6, initiating formation of the MAC

what subsequent proteins are involved in MAC formation after C5b binds C6?

C7 is recruited next, followed by C8 binding, then C9 molecules polymerise

how many C9 molecules typically polymerise to form a MAC pore?

between 1-16

whats the main consequence of MAC formation on a cell membrane?

it forms a pore that disrupts ionic balance, leading to cell lysis

why is C3 considered the most abundant complement protein in plasma?

its central to the cascade, with up to 1000

whats the primary function of C3b generated during complement activation?

opsonisation

how does C3 convertase amplification contribute to the complement cascade?

C3 convertase produces more C3b

in turn helps form C5 convertase + amplifies the response

how is the MBL pathway initiated?

by binding of MBL to carb patterns on a pathogen

How do MBL levels change during an immune response?

they increase during acute-phase response

Which enzymes associate with MBL to initiate the lectin pathway?

MASP-1

MASP-2

(MBL-associated serine proteases)

What key events occur after MBL binds to the pathogen’s carbohydrate?

MBL undergoes conformational change, activating MASP-2

In the MBL-pathway, what substrate does activated MASP-2 cleave first?

C4, generating C4b

What is the next step after C4b binds to the pathogen in the lectin pathway?

C2 binds to C4b and is cleaved by MASP-2, forming the C3 convertase

how does the alternative pathway differ from the classical and lectin pathway?

its initiated by antibodies, through spontaneous C3 hydrolysis.

what types of microbial surfaces trigger the alternative pathway?

surfaces from gram-ve and gram+ve bacteria

fungi

yeast

viruses

tumor cells

parasites

what initiates the formation of the alternative pathway’s C3 convertase?

spontaneous hydrolysis C3 generated C3b, which binds to a pathogen surface.

how is factor B involved in the alternative pathway?

factor B binds surface-bound C3b, and is then cleaved by factor D into Bb - forming the C3bBb complex

what role does properdin play in the alternative pathway?

properdin stabilises the C3 convertase complex

how does all three pathwayd ultimately converge?

they converge upon activation of C3, which leads to robust deployment of opsonins and subsequent MAC formation.

what is the central role of C3 activation in the complement cascade?

results in effective opsonisation, formation/amplification of convertases - and initiation of the terminal MAC pathway.

what are the two types of complement regulatory proteins based on their location?

soluble regulators and cell-surface regulators

which soluble regulator primarily controls the classical pathway at its first step?

C1 inhibitor

how does C1inh regulate the classical pathway?

it binds activated C1r:C1s complex

and promotes its dissociation from C1q

limits subsequent C4 and C2 cleavage

which clinical condition is linked to C1inh deficiency?

hereditary angiodema (HAE)

which regulatory proteins target the C3 convertase in the classical and lectin pathways?

C4 binding protein (C4BP)

decay accelerating factor (DAF//CD55)

complement receptor 1 (CR1//CD35)

what additional role does factor I play in regulating these pathways?

Factor I cleaves C4b

into inactive fragments C4c and C4d

thereby inactivating convertase

how is the alternative pathway’s C3 convertase controlled?

regulators such as factor H, DAF + CR1 bind to C3b to dislodge Bb from the convertase

what happens to C3b when factor I acts in the alternative pathway?

its cleaved into iC3b, reducing its ability to form new convertase complexes

which regulatory protein protects host cells by presenting MAC formation?

CD59 (also known as protectin)

How does CD59 inhibit MAC assembly?

It binds to the C5b678 complex, preventing the binding of C9

why is preventing MAC formation on host cells crucial?

it protects host cells from lysis and damage during complement activation

whats the function of S protein in complement regulation?

S protein is a soluble inhibitor that binds to C5b67, preventing its insertion into host cell membranes.

What role does the anaphylatoxin inactivator serve?

It inactivates the anaphylatoxins (C3a, C4a, and C5a) by removing their terminal arginine, reducing inflammation.

In the context of complement regulation, what is the function of CR1 (CD35)?

It is a membrane-bound protein that blocks convertase formation and acts as a cofactor for Factor I-mediated cleavage of C3b and C4b.

What does MCP (CD46) do during complement regulation?

MCP is a membrane-bound regulator that facilitates Factor I cleavage of C3b and C4b, controlling convertase activity.

How does Decay Accelerating Factor (DAF/CD55) function in complement regulation?

DAF accelerates the dissociation of both C4b2a and C3bBb convertases, thereby dampening complement activation.

What is the overall role of Factor I as a regulatory enzyme?

Factor I is a serine protease that degrades active C3b and C4b (with helper cofactors), reducing the continuation of the cascade.

How does the coordinated regulation of complement activation benefit the host?

It ensures efficient pathogen clearance while preventing excessive complement activation that could damage host tissues.