Complement Flashcards
The complement system is a group of more than 30 plasma and membrane proteins that play a critical role in host defense. When activated, complement components interact in a highly regulated fashion to generate products that:
Recruit inflammatory cells (promoting inflammation).
Opsonize microbial pathogens and immune complexes (facilitating antigen
clearance).
Kill microbial pathogens (via a lytic mechanism known as the membrane attack complex).
Generate an inflammatory response.
Describe complement activation:
Where does it take place?
What are the pathways?
Complement activation takes place on antigenic surfaces. However, the activation of
complement generates several soluble fragments that have important biologic activity.
There are three distinct pathways of activation of complement: the Classical, the Lectin, and the Alternative Pathways. See Figure 1, p 3.
Classical pathway (antigen: antibody complexes) Lectin pathway (lectin binding to pathogen surfaces) Alternative pathway (Pathogen surfaces) ... all lead to complement activation
Describe activation of classical pathway.
When is it initiated?
What component recognizes antigen-antibody complex?
What happens?
Classical pathway activation is initiated after immune complex formation.
Complement component C1 recognizes the antigen-antibody complex.
The binding of antibody to antigen induces a conformational change in the antibody constant region. This exposes a site on the Fc portion (of the antibody molecule) that can
be bound by the first complement component of the classical pathway, C1.
Describe the structure of C1.
When does activation of C1 occur?
C1 is a macromolecule that consists of C1q (comprised of 6 globular heads and extended
tails) in complex with C1r and C1s (the C1qrs complex). See Figure 3.
p 5
Activation of the C1qrs complex occurs when at least two of the C1q globular heads are simultaneously bound to antibody. See Figure 4. p 6
Describe the activation of the C1qrs complex. What must occur in order for activation to take place?
(How will IgG differ from IgM?)
Activation of the C1qrs complex occurs when at least two of the C1q globular heads are simultaneously bound to antibody. See Figure 4.
For this to occur, two Fc portions need to be in within close molecular proximity of each other on the antigenic surface. (C1q binds to at least 2 IgG molecules) p 6
In contrast to IgG, the pentameric nature of IgM allows a single molecule of antigen bound IgM to activate C1. See Figure 4.
What happens once C1q is bound to the antibody?
Once C1q is bound to antibody, C1r undergoes a conformational change and becomes enzymatically active.
C1r then cleaves C1s, which after cleavage is enzymatically active as well.
Describe the activation of the lectin pathway. How does it differ from the classical pathway?
Activation of the Lectin pathway is similar to the classical pathway.
Except that the Lectin pathway is initiated by a protein, Mannan Binding Lectin (MBL) or ficolins.
Describe MBL. What do they bind specifically? What about ficolins?
What proteases are MBL/ficolins associated with? How do these become activated?
MBL binds to mannose and certain other complex carbohydrates that are found on the surface of many microbial pathogens (like Candida albicans, a fungus with surface
mannose residues). See Figure 5.
Ficolins bind oligosaccharides.
MBL/ficolins are physically associated with two serine proteases, MASP-1 and MASP-2
(mannan binding lectin-associated serine protease-1) that are similar to C1r and C1s.
When MBL/ficolins bind to surfaces, MASP-1 and MASP-2 become activated.
Describe what happens once C1qrs is activated (or MBL/ficolines activated MASP-1 and MASP-2)?
Activated C1qrs, see Figure 6 (or separately MBL/ficolins activated MASP-1 and MASP-2 see Figure 7) cleave C4, and the C4b fragment becomes bound to a cell surface
(e.g. microorganism). Bound C4b fragment binds C2.
Activated C1qrs, see Figure 6 (or separately MBL/ficolins activated MASP-1 and MASP-2 see Figure 7) cleave C4, and the C4b fragment becomes bound to a cell surface
(e.g. microorganism). Bound C4b fragment binds C2.
What happens next?
Once bound to C4b, C2 is also cleaved by C1s, forming the C4b2a complex, which
remains bound to the cell surface. (For Lectin Pathway activation, MBL/ficolins can be
substituted for C1, substitute MASP-1 and MASP-2 for C1r and C1s in Figure 4).
Once bound to C4b, C2 is also cleaved by C1s, forming the C4b2a complex, which
remains bound to the cell surface. (For Lectin Pathway activation, MBL/ficolins can be
substituted for C1, substitute MASP-1 and MASP-2 for C1r and C1s in Figure 4).
What is C4b2a? What is the its job and significance?
C4b2a is an active C3 convertase, capable of cleaving C3 into C3b and C3a.
This is a major point of amplification of the pathways, since one C3 convertase can cleave up to 1000 molecules of C3.
C4b2a is a C3 convertase, capable of cleaving C3 into C3b and C3a.
Describe C3b.
C3b covalently bound to the antigenic surface, acts as a powerful opsonin and enhances the uptake of antigenic particle by phagocytes.
What will MASP-2 do?
does same thing as C1s.
cleaves C4 to C4a and C4b
(C4b then binds C2)
MASP-2 cleaves C2 to C2a and C2b forming the C4b2a complex
Describe C4b2a3b. What does it do?
C4b2a3b complex, also called C5 convertase, cleaves C5 into C5a, which is a soluble
inflammatory mediator, and C5b, which is capable of complexing with additional complement components. The generation of C5b initiates the final phase of complement activation, which is the formation of the Membrane Attack Complex (MAC). See
Figure 8.
The MAC is identical for all pathways of complement activation. C3a and C5a remain
soluble and produce local inflammatory effects.
p9
What does activation of the alternative complement pathway depend on?
The alternative pathway depends upon the slow hydrolysis of C3, which spontaneously occurs in plasma.
