L4 - A Kelly - Complement Flashcards
complement consists of…
Comprises 30 different soluble and membrane bound protiens – made in the liver and distributed as inactive zymogens
complemetns naming conventions?
Naming…. C1, C2 ect.
C1 cleaves to C1a and C1b (b subunit tends to be larger)
4 functions of complement
- Opsonisation
- Lysis
- Inflammation
And it clears immune comoplexes and apoptotic cells.
whats the main player in complement
C3
why is C3 so importnat - why is it special?
Cleaved to C3a and C3b. exposing C3b’s internal thioester bond – links hydroxyl or amino groups on pathogens
C3a = anaphylotoxin – stimulates inflammation
which complement receptors are important for dealing with C3b tagged bacteria?
CR1 and CR3
CR1 and CR3 picture
describe features of CR1
CR1 binds directly to C3b – macrophage also needs C5a to phagocytose
CR1 also highly expressed on erythrocytes – removed complexes from the blood – clearance in liver
3 major pathways for complemetn activation
alterantive pathway
lectin pathway
classical pathway
complement activation pathways image
do all complement activation pathways converge on C3 cleavage?
yep
describe the alternative pathway
which complement pathway is the first to act?
alternative pathway
the first step in the alternative pathway is
spontaneous conformational changes in C3 that expose the internal thioester group
in the alternative pathway, the exposed thioester group does what?
In an aqueous environment this will most likely react with water to generate C3H2O
alternative pathway- C3H2O associated wihtwhat?
factor B
C3H2O + factor B is cleaved by what in the alternative pathway?
factor D (a serine protease).
its only factor B thats cleaved at this stage
in the alternative pathway- what happens after factor D has cleaved factor B?
The large fragment Bb remains associated with C3(H2O) to generate C3(H2O)Bb, a protease that can cleave C3 into C3a and C3b. This is called the aqueous or fluid phase C3 convertase
in the alternative pathway - whats the role of the fluid phase C3 convertase?
the aqueous or fluid phase C3 convertase. It’s role is to produce enough C3b so that some will attach to the “activating” surface of a pathogen. Microbial surfaces by default are “activating” as they generally lack regulatory mechanisms to deactivate complement.
Describe how the membarne attack complex is generated
C3b + C3bBb = C3b2Bb = alternative C5 convertase
C5 lacks thioester group
C5b + C6 and C7 = C7 inserting into lipid membrane.
Binding of C8 to C5b67 allows insertion into the membrane and subsequent polymerisation of C9 subunits to form a membrane pore. This is effective against many gram negative bacteria and enveloped viruses.
describe the lectin pathway (image)
Classic pathway picture
desxribe the classic pathway
- activated if the surface of the pathogen can be recognised by antibody or C-reactive protein (which recognises bacteria, fungi, yeast and parasites)
- Binding of antibody to a surface exposes a binding site for C1q present in the Fc region of some antibody isotypes.
- When a molecule of C1q binds to several antibody Fc regions the induced conformational change activates the C1r and C1s subunits.
- C1s is able to cleave C4 to expose a reactive thioester group which can covalently attach C4b to the pathogen surface.
- Activated C1 then associates with and cleaves C2 depositing the C2a fragment on C4b forming C4bC2a, the Classical C3 Convertase.
- It cleaves C3 and deposits C3b on the microbial surface.
- Membrane associated C3b generated by the classical or the lectin pathway can utilise the alternative pathway amplification loop by binding to factor B to generate C3bBb.
describe Properdin (Factor P),
only known positive regulator of the alternative pathway stabilises C3bBb and increases activity 5-10 fold. It also stabilises the C5 convertase complex assisting MAC complex formation
describe Membrane cofactor protein (MCP)
- Expressed on host cell membranes
- induces dissociation of C4bC2a and MCP C3bBb (shown) and cleavage of C3b/C4b by factor I.
- Complement Receptor 1 (CR1) functions in a similar way.
- It has both decay accelerating capacity and factor I cofactor activity.
describe factor H
- Regulated complememnt activation in solution
- Soluble cofactor for factor I
- Binds host sialic acid
- causes dissociation of C3bBb complex and makes C3b susceptible to cleavage by factor I.
describe decay accelerating factor
present on the surface of host cells, dissociates the classical and alternative (shown) C3 convertases (C3bBb/C4bC2a).
describe protectin
Protectin is a host cell surface protein that binds the MAC intermediate C5b678 and prevents its insertion into membranes. It also interacts with C9 and prevents its recruitment to the MAC complex.
example picture
