I&I the complement system Flashcards
What type of system is the complement system?
Innate system
What is there activation of in the complement system?
Activation of small soluble heat sensitive protein that can
combine and create complexes with proteolytic activity
What are the 3 steps in the complement system?
- Recognition
- Opsonization
- Effector- inflammation, phagocytosis and membrane attack
What happens in the recognition stage in the complement?
- Innate recognition of non self
- Antibodies
- Apoptotic cells
What are the 3 distinct pathways in the complement system?
3 Distinct pathways:
1. Antibody triggered(classical)
2. Presence of pathogen alone(Alternative)
3. Lectin type protein activation(Lectin)
What is the common pathway in the complement pathway?
Terminal pathway-lysis
What does C1 in the classical pathway interact with?
C1 interacts with Ab (IgM and IgG) bound to microbes
What is the effector mechanism in the classical pathway?
It has an effector mechanism of humoral immunity
What system does the alternative pathway form part of?
Forms part of the innate immune system
What system is the lectin pathway part of?
Part of the innate immune ststem?
Briefly, what is involved in the lectin pathway?
Mannose binding lectin (MBL) recognises terminal mannose residues on microbes, whilst ficolin recognises different microbial residues
What do ‘a’ and ‘b’ in the proteolytic products of the complement protein identify as?
‘a’ is for the smaller products
‘b’ is for the larger products
What does C3 convertase cleave?
C3 convertase cleaves C3 to C3a and C3b
What does C5 convertase cleave?
C5 convertase cleaves C5 to C5a and C5b
What is the classical pathway initiated by?
The classical pathway initiated by the binding of C1 to Ag-bound IgG or IgM
What is the structure of C1 and what does it consist of?
C1 is a multimeric protein complex, consisting of C1q, C1r and C1s
What does C1q bind to?
C1q binds to the antibodies (IgM, IgG1 and IgG3
What does C1 not bind to?
C1 does not bind to soluble (free) Ab molecules; it only binds to Ab bound to Ag
What does the globular head of C1q bind to?
The globular heads of C1q bind to the Fc domains of IgG and IgM, when the Fab domains are bound to A
What must every C1q molecule bind in order to be activated?
Every C1q molecule must bind at least 2 Ig Fc regions to be activated
What is the classical pathway which involves C3 convertase?
-After having bound to 2 or more Ag-bound Ab, the C1q can activate C1r
-C1r cleaves and activates C1s
-The C1s then cleaves C4 into C4b and C4a(the C4 molecules have a similar structure to C3, with an internal thioester bond)
-C4b binds covalently to antigens on the surface of microbes
-It acts as an opsonin, promoting phagocytosis and recruits C2
-C2 is cleaved by C1s into C2a and C2b
-In this case, C2a is the larger fragment and binds to C4b forming the C3 convertase for the classical pathway(C4bC2a)
-C2b is the smaller fragment of C2 and has no biological function
What are the steps involved in the classical pathway involving C5 convertase?
-C3 convertase(C4bC2a) cleaves more C3b molecules producing C3b and C3a
-C3a mediates biological activities
-Newly generated C3b deposits on the microbial surface, where some acts as an opsonin and some binds to the C3 convertase complex
- The resultant C4bC2aC3b is the classical pathway C5 convertase
-The C5 convertase complex cleaves C5, initiating the late steps of complement activation
What are the late steps in the classical pathway?
-The C5 convertase cleaves C5 into large C5b fragments and small C5a fragments
-C5a is a soluble fragment with several biological functions
-C5b remains bound to C5 convertase, where it recruits C6 and C7
-C7 is hydrophobic, therefore inserts into the lipid membranes of the microbes, where it recruits C8
-C8 has three chains, one of which inserts into lipid membranes of the microbe
-The complex formed by C5b-C8 then recruits C9 which polymerises, forming pores(which consist of between 10 and 16 polymerised C9 molecules)
-The C5b-C9 complex is called the MAC(membrane attack complex) which causes lysis of the microbe by allowing H20 entry via C9 pores
What is the lectin pathway initiated in?
The lectin pathway is initiated in the absence of Ab
What is the lectin pathway triggered by?
It is triggered by microbial carbohydrate recognition by PRRs
What are the PRRs that are involved?
The PRRs involved are MBL (mannose binding lectin) and ficolins (which have a similar structure to C1q)
What are the steps invovled in the lectin pathway?
-MBL binds to mannose residues on microbes, whilst ficolin binds to N-acetylglucosamine residues on the microbes
-Like C1q, MBL and ficolin are bound to proteases
-C1q is bound to C1r and C1s, whilst MBL and ficolin are found in a complex with MBL Associated Serine Proteases (MASP1 and MASP2)
-Binding of MBL to mannose and ficolin to N-acetylglucosamine activates the MASPs, which subsequently cleave C4 and C2
-The lectin pathway then continues in a similar way to the classical pathway
What is the initiating event in the alternative pathway?
The initiating event in the alternative pathway is spontaneous cleavage of C3 in the plasma - this is called C3 tick-over
What are the steps involved in the alternative pathway involving C3 convertase?
-C3 contains a reactive thioester bond (which is hidden), making it labile
-C3 cleavage induces a conformational change in C3b, exposing the thioester bond (as well as the binding site for factor B – the next component of the alternative pathway)
-The exposed bond reacts with amino or hydroxyl groups on the surface of microbes
-This leads to ester bond formation, attaching C3b to the surface of the microbe
-In the absence of covalent attachment, C3b remains in the fluid phase, in which it is unstable
-It is rapidly inactivated by hydrolysis therefore further complement activation is stopped
-Notes that when in the fluid phase, complement proteins are inactive or transiently active
-When deposited on microbes, the complement proteins are stable (i.e. they are constantly activated)
-Once bound to the surface of the microbe C3 B binds factor B
-The factor B is then cleaved into factor Ba and factor Bb by factor D (a plasma protease)
-This leaves us with C3b bound to factor Bb, the C3 convertase complex of the alternative pathway (C3bBb)
-The C3 convertase is stabilised by properdin and functions to cleave more C3 molecules, amplifying complement activation
-New generated C3b deposits on microbial surfaces act as opsonins, promoting phagocytosis
-C3a functions to mediate biological activity
What are the steps involved in the alternative pathway involving C5 convertase?
-As the C3 convertase cleaves more C3 and, some of the C3b molecules produced bind to the C3 convertase
-This produces C3bBbC3b, the alternative pathway C5 convertase
-C5 convertase cleaves C5 into C5a and C5b, initiating the late steps of complement activation
What are the late steps in the alternative pathway?
-The C5 convertase cleaves C5 into large C5b fragments and small C5a fragments
-C5a is a soluble fragment with several biological functions
-C5b remains bound to C5 convertase, where it recruits C6 and C7
-C7 is hydrophobic, therefore inserts into the lipid membranes of the microbes, where it recruits C8
-C8 has three chains, one of which inserts into lipid membrane of the microbe
-The complex formed by C5b-C8 then recruits C9 which polymerises, forming pores (which consist of between 10 and 16 polymerised C9 molecules)
-The C5b-C9 complex is called the MAC (membrane attack complex), which causes lysis of the microbe by allowing H2O entry via C9 pores
What is the function of C3b and C4b?
Act as opsonins
What do C3b and C4b deposit on and what does this cause?
Deposit on microbial surfaces, coating them. This opsonisation promotes phagocytosis
What is the function of C3a, C4a and C5a?
Trigger acute inflammation
What do C3a, C4a and C5a bind to?
Bind to mast cells, causing degranulation, which releases histamine
Why are C3a, C4a and C5a also known as anaphylaxtoxins?
They’re also known as anaphylatoxins because mast cell degranulation is similar to anaphylaxis
What does C5a act as and what does this do?
C5a acts a chemotactic agent, attracting neutrophils and promoting ROS production
What does C5a do to permeability and what does it promote and what does this lead to?
C5a increases the permeability of endothelial cells and promotes neutrophil adhesion to the endothelium, leading to WBC recruitment at inflammation sites
Why is complement activation tightly regulated?
Compliment activation is tightly regulated to prevent activation affecting healthy cells, and to limit the duration of complement activation on microbes or Ag-Ab complexes
What are the 3 mechanisms of complement regulation?
-Inhibiting the formation of C3 convertase
-Degrading or inactivating C3 or C5 convertase
-Inhibiting the formation of the MAC
What is C1 INH and what does it do?
C1 INH is a complement regulator that inhibits C3 convertase formation
How does C1 INH inhibit the formation of C3 convertase formation?
-It dissociates the proteases (C1r and C1s) from C1q
-This in turn blocks of the proteolytic activity of C1r and C1s
What is CD59 and where is it found?
CD59 (protectin) in a complement regulator that is found on the surface of healthy cells
What does CD59 inhibit and how?
It Inhibits MAC formation on healthy cells by binding to C5-C8
What does the inhibition of MAC formation inhibit and what happens as a result?
-Inhibits the recruitment and polymerisation of C9
-As a result, no pores are formed in the cell membrane, so cell lysis cannot occur
What does staphylococcal inhibit?
Staphylococcal inhibits C3 convertase assembly
What does staphylokinase cleave?
Staphylokinase cleaves antibodies bound to pathogen surface
and avoids complement and phagocytosis
What does staphylococcal complement inhibitor inhibit?
Staphylococcal complement inhibitor inhibits C3 convertase
activity
What does Staphylococcal Superantigen inhibit?
Inhibit Fab
fragment binding to C1 complex
How does N.meningitis block complement?
Factor H binding protein recruited to pathogen
surface to inactivate c3b
What disease/manifestations arise due to a deficiency of Complement regulation
Factor I and Factor H?
Atypical haemolytic uraemic syndrome +
recurrent bacterial infections associated with
low C3
What does a deficiency in DAF lead to?
Paroxysmal Nocturnal haemoglobinuria
What is the triad in atypical haemolytic uraemic syndrome?
- Thrombocytopenia
- Microangiopathic haemolytic
anaemia - Acute renal failure
What is there failure to control of in atypical haemolytic uraemic syndrome?
Failure to control the alternative
pathway
What mutation leads to paroxysmal nocturnal haemoglobin(PNH)?
Mutation in PIG-A gene
What is there a lack of in host cell walls in PNH and what does this reduce?
Lack of glycosylphosphatidylinositol
protein in host cells walls reduces
anchoring of CD55 and CD59 control
factors on erythrocytes
What is the erythrocyte more susceptible to in PNH?
Susceptible to lysis
What accumulates on the surface of erythrocyte in PNH?
C3b accumulates on Erythrocyte Surface
What pathway is activated and leads to the destruction of what in PNH?
-Activation of complement Terminal/ Mac
pathway
-Destruction of Erythrocytes
What is the treatment of PNH?
Eculizumab
