Complement Flashcards
innate immunity definition
immunity that is naturally present and is not due to prior sensitisation to an antigen from infection or vaccination.
generally non specific
when does innate defence begin?
as soon as the pathogen penetrates the epithelial barrier and begins to live in the human tissue
what is the complement system?
part of the immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells from the organism, promote inflammation and attach the pathogen’s cell membrane
can be recruited by antibodies
what does the complement system consist of?
31 small proteins that are synthesised by the liver and macrophages and circulate in the blood as inactive precursors (zymogens)
what are the three steps to achieve complement activation?
- generation of C3 splitting enzymes- convertases
- the cleavage of complement protein C3
- terminal lytic events- MAC attack
Three main complement pathways + what they all have in common
classical, MBP lectin, alternative
all lead to the cleavage of C3 to form C3b and C3a
three main outcomes
recruitment of inflammatory cells
opsonisation
killing pathogens
What is the most important stage of complement activation?
The cleavage of the protein C3 to form C3a and C3b
function of C3b
binds to pathogens, which tags the pathogen for destruction by the phagocytes
known as complement fixation
function of C3a
the C3a molecule is smaller, and more soluble
acts as a chemoattractant to recruit effector cells from blood, such as phagocytes
Important feature of C3b explained
high-energy thioester bond within the glycoprotein
when C3 is made and enters circulation, the zymogen is stabilised by sequestering the thioester
when C3 is cleaved, the bond is exposed and becomes subject to nucleophilic attack by carbohydrates on the pathogen, which binds C3b to it
Determine whether each pathway is innate or adaptive
alternative- completely innate
MBP lectin- innate, however require inflammation
classical- innate and adaptive- requires an antibody-antigen complex to activate it
stages of alternative pathway
- C3 is hydrolysed by water molecules to form iC3
- iC3 binds to inactive complement factor , making factor B susceptible to cleavage by protease factor D
- protease factor D cleaves factor B. This produces a small factor Ba which is released and a large factor Bb which remains bound to iC3
- Bb has protease activity. The iC3bBb complex efficiently cleaves C3 into C3a and C3b respectively
- iC3bBb diffuses away, C3b becomes bound
how is the alternative pathway able to take place?
the pathogen surface creates local environments that are conducive to complement activation-
it increases the rate at which C3 is hydrolysed to iC3- known as tickover
what is iC3bBb an example of?
a soluble C3 converts
lectin definition
a group of cell-surface receptors and plasma proteins that recognise carbohydrates
What is MBL?
Mannose binding lectin, a C type lectin that binds to mannose containing carbohydrates of bacteria, protozoa, fungi and viruses
What is the MBL structure + significance?
resembles a bouquet of flowers
triple helix formed of three identical polypeptides contributes a carbohydrate recognition domain- around 5 or 6 of these so have either 15 or 18 potential binding sites
even though the individual binding is very weak, the large number increases the strength
lectin pathway of complement activation stages
- mannose of pathogen binds to MBL, which circulates in the plasma as a complex with two serine protease zymogens: MASP 1 and 2- 2 molecules of each in complex
- once the MBL complex binds to the mannose in the pathogen, one molecule of MASP 2 is induced to become enzymatically active and cut itself
- the MASP 2 then cuts the other MASP 2
- the activated MASP 2 proteases cleaves C4 molecules into C4b and C4a
- the cleavage exposes a thioester bond of C4b which fixes some C4b fragments onto the pathogen surface. C4a acts as an anaphylatoxin and weakly recruits leukocytes
- C2 interacts with an activated MASP 2, which is cleaved into a larger fragment C2a and smaller inactive C2b.
- the C2a binds to C4b on the pathogen surface. The complex C4bC2a is a C3 convertase
What antibodies are the most effective at initiating the classical pathway?
IgM and IgG
Important protein in the classical pathway + structure
C1- bouquet of 6 flowers, formed of 18 C1q polypeptides and 2 molecules each or C1r and C1s which are inactive serine proteases.
classical pathway stages
- C reactive proteins bind to the C1q stalks
- this causes C1r to cut itself, the other C1r and the C1s
- C1s becomes the active protease and cleaves C4, leaving the covalent attachment of C4b
- C1s cleaves C2
- C2a binds to C4b, forming the C4bC2a C3 convertase
how can IgM activate this process?
binds to the surface of a pathogen and undergoes a conformational change to a staple form, which enables the binding to C1q on the Fc part of each antibody
How can IgG activate the process?
C1q crosslinks two IgG molecules bound to antigens on the pathogen’s surface.
C1 is then activated and the classical pathway proceeds
