Complement Flashcards
What is complement?
It allows a cascade of enzymes to be stimulated by previous cleavage of precursors.
How is complement activated?
Complement can be activated by either pathways
Classical
Lectin
Alternative
What occurs in all pathways?
The C3 (which is a central component of complement) is cleaved to produce C3b and C3a. C3b- this is the larger fragment and is deposited onto the surface of microorganisms which marks it out for destruction. This causes lysis and opsonisation.
C3a- smaller fragment- anaphylaxis
How is the C3 cleaved?
C3 convertase cleaves C3 into a larger fragment of C3b which causes destabilisation of a thioester (S) converts to (S-) bond which makes it susceptible for nucleophilic attack.
When this occurs, thioester bond becomes exposed and unstable and once the nucleophilic attack occurs, it allows it to anchor into the membrane and results in the pathogen elimination.
What is the main component of the classical pathway?
The classical pathway is directly associated with immunoglobulins.
Once the IgG is attached to the antigen surface.
The C1q (with 6 collagenous bases and 6 globular heads) attaches to the antibody IgG.
This produces 2 molecules of C1r and C1s which cleaves C4.
The C4 produces C4b which attaches to the membrane and C4a which is a smaller fragment.
Simulateanously C2 is being cleaved off producing C2a and C2b.
Attached of C2a to C4b forms the C3 convertase enzyme.
How is C3 convertase enzyme produced?
This occurs when C1r and C1s are produced when C1q joins the IgG. This produces cleavage of C4 into C4a and C4b. C4b attaches to the membrane and simultaneously C2a attaches to it forming C3 convertase.
This leads to the production of C3b and C3a. C3b is used for lysis and opsonisation.
What differs in the lectin pathway?
Lectin pathway is similar to the classical pathway but the main component is the mannose binding lectin- MBL and this has sugars on the microbial surface that cleaves the C4
Describe the alternative pathway?
It works immediately and it is the major line of defence against systemic infections.
The unstable C3 is prone to hydrolysis of the thioester bond forming iC3. Factor B attaches to iC3 which causes factor D to cleave factor B. Factor Bb and iC3 combine forming and unstable C3b which attaches to the pathogen surface.
Now the C3b attaches to Bb and a factor P which forms a stable C3 convertase
What does the C3b do next?
The C3b cleaves C5 into C5b and C5a. C5b combines with C6, C7, C8, C9 which creates a membrane attack complex (MAC). This creates a funnel shaped hole into the cell membrane which allows solutes to flow in and out hence the more the holes, the easier it is to kill.
What is MAC?
Membrane attack complex
What is opsonisation?
Coating of microorganisms with antibodies or complement components so that phagocytosis can occur more efficiently.
Anaphylaxis
C3- C3b+ C3a.
C5- C5b+ C5a
C3a/C5a- known as anaphytoxins
C3a/C5a- bind to receptors of mast cells causing the release of histamine which increases the vascular permeability and blood flow- this allows the recruitment of other components of inflammatory response into the infection site.
What is C3a and C5a referred to
anaphytoxins
Phagocyte chemotaxis
C5- C5b+ C5a
C5a binds to the receptors of the phagocytes which causes them to migrate up a concentration gradient to the infection site and they become sticker
Neutrophils are also transmigrated in this process causing rolling and tethering, adherence and transmigration.
Complements also need to be controlled, how?
1) Classical pathway is controlled by- C1 inhibitor. Delay acceleration factor (DAF) and complement receptor 1 (CR1).
2) Alternative pathway is controlled by factor I, factor H and CR1.
