Complement System

Question 1

What is the complement system?

Answer 1

The complement system refers to a group of plasma proteins called the complement proteins which are produced in the liver and act collectively to help destroy pathogens.

Question 2

How many complement pathways are there, name them

Answer 2

There are three complement pathways

The classical pathway
The alternative pathway
The lectin binding pathway

Question 3

What are the proteins that make up the classical pathway?

Answer 3

C1
C1
C3
C4
C5
C6
C7
C8
C9

Note: They are numbered in the order they were discovered and not in the other they function.

Question 4

What is the normal state of the complement proteins, active or inactive?

Answer 4

generally each complement protein is normally in active and it becomes activated when it’s cleaved, in other words, when some part of it breaks free.

Question 5

What activates the complement proteins?

Answer 5

Cleavage

Question 6

What protein does the classical pathway start with?

Answer 6

C1

Question 7

What are the component of the C1 protein?

Answer 7

C1q

C1r

C1s

Question 8

How many subunits does the c1q component of the c1 complement protein have and what is the function of the c1q?

Answer 8

C1q has 6 subunits which are able to bind to the FC portion of an antibody when the antibody is bound to an antigen.

Question 9

How many immune complexes can one C1 bind to?

Answer 9

The C1 complement protein binds to antigen-antibody complexes using its c1q component which has 6 subunits, and each c1q can bind to one antibody-antigen complex. So technically, a C1 molecule can bind to 6 antibodies.

Question 10

What are the C1r and C1s Subunits, their name, and their function?

Answer 10

The C1r and C1s sub units are both enzymes called serine proteases. C1q has zero enzymatic activity and typically the serine proteases C1s and C1r are hidden, so they can’t perform their enzymatic activity, and this is all tied together in a calcium bow. So when there’s a lack of calcium, C1 is also lacking.

Question 11

How does the C1 get activated?

Answer 11

When two or more of the C1q portions bind to the Fc receptors of two or more antibodies that are bound to antigen, it causes a conformational change of the C1 molecule, which then twists, exposing the C1s and C1r serine protease sites.

This allows C1r to cleave C1s, activating the C1 molecule.

Question 12

Whst does the activated C1 do once activated?

Answer 12

The activated C1 cleaves C4 into C4 a and C4 b.

C4 a floats away, but C4 b binds to the surface of the pathogen.

C1 also cleaves C2 into C2 a and C2 b, but this time C2 b floats away and C2a joins C4 b on the surface of the pathogen, forming a protein complex called C4b2a or C3 convertase.

Question 13

Activated C1 in the classical pathway will cleave other C proteins to create an enzyme called C4bC2a. What is another name of this enzyme, what is its function and why is this step important.

Answer 13

C3 convertase.

C3 convertase cleaves C3 into C3 a and C3 b.

This is the step that really amplifies things, because a single C1 can generate maybe 10 C3 convertases, but a single C3 convertase can cleave over a thousand C3 proteins per second, and this enzyme stays active for about two minutes, so you’ll end up with a lot of C3 b really quickly.

Question 14

What are C3b called? what is their function? Explain.

Answer 14

C3 b is also called opsonin, and in general opsonins help phagocytes get a firm grip on bacteria.

Normally bacteria have an antiphagocytic capsule, which makes them slippery and hard to grab. Opsonization is the process by which pathogens are coated with molecules so that they can be more easily picked up by phagocytes.

Imagine trying to pick up a slippery meatball with your fingers versus stabbing it with a fork, and then just having to pick up the fork.

Opsonization also makes it easier to eat meatballs (microbes) faster too, in this case C3 b is serving as that fork.

So 2 functions.

Question 15

What happens when enough C3b are made?

Answer 15

Once there’s a certain amount of C3 b made, some of the C3 b proteins come and bind really close to the C4b2a or C3 convertase, and turn it into C4b2a3b protein complex, which is called C5 convertase.

Question 16

What is the function of C5 convertase?

Answer 16

C5 convertase (C4b2a3b) cleaved C5 to C5a and C5b

Question 17

Which portion of C5 is important to the Classical pathway? What’s is function? Conclude the classical pathway from this point.

Answer 17

C5b.

C5b binds to C6, C7 and C8, and together with these four proteins begin to penetrate through the pathogen’s cell membrane. They’re joined by small groups of C9 proteins, which help form a channel straight through the membrane of the pathogen.

So this cluster of C5b, C6, C7, C8 and C9 proteins form the membrane attack complex (MAC), which is what creates a hole in a bacterial cell membrane.

Question 18

Explain the lectin binding pathway.

Answer 18

This pathway has one key difference from the classical pathway, instead of being triggered by an antigen-antibody complex and C1, the lectin binding pathway uses a protein called mannose binding lectin protein, which is the protein that binds mannose, a sugar found on the surface of many bacterial surfaces.

Mannose binding lectin protein is similarly shaped to C1, and can cleave C4 and C2, helping to establish C4b2a (C3 convertase). From that point on things are the same as the classical pathway.

Question 19

How does the alternative pathway start?

Answer 19

Although C3 gets cleaved into C3 a and C3 b by C3 convertase, this also happens in the absence of the enzyme at a very slow rate. That means that there’s always small amounts of C3 b floating around and binding to any bacterial surfaces that it might encounter.

There are proteins called factor B and factor D that are also in the blood.

Factor B will bind to C3 b on the bacterial surface, and when it does, it allows factor b to be cleaved by factor D, which is always active.

So factor B becomes Ba and Bb.

Question 20

What happens to the post cleavage portions of factor B in the alternative pathway? What does the relevant portion do? Complete the pathway from this point.

Answer 20

The Ba will float off, but Bb will stay associated with C3 b.

The C3 b Bb complex has its own cleaving abilities, it’s a C3 convertase, so it will cleave C3 into C3 a and C3 b, thus acting as an amplification step.

At this point, the pathway will follow the classical and lectin binding pathways, building the MAC.

Question 21

What is C1 inhibitor? What does it do? When does it act?

Answer 21

But because C3 can spontaneously get cleaved and trigger this alternative pathway, it has to be carefully regulated, and that’s where C1 inhibitor comes in.

C1 inhibitor will dissociate factor Bb from C3 b, thus shutting down the alternative C3 convertase.

So C1 inhibitor is a regulator of the of the alternative pathway.

Question 22

What is another regulatory mechanism for the alternative pathway?

Answer 22

Factor H also acts as a cofactor for another factor called factor 1, which breaks C3 b into inactive C3 b (i C3 b).

i C3 b is still a potent opsonin, but it has no enzymatic activity and cannot propagate the alternative complement pathway.

Question 23

So what is the main objective of the complement system?

Answer 23

All three pathways start out a bit differently, but they all end the same way, with a membrane attack complex, and this again is a protein complex that creates a hole in a bacterial cell membrane, which effectively destroys mainly gram negative bacteria.

Question 24

What are the functions of the C5a and C3a fragments?

Answer 24

• In addition to C3 b serving as opsonins, other fragments like . C5 a and C3 a also act as chemotaxins, which recruit neutrophils, eosinophils, monocytes, and macrophages to the site of inflammation.
  
  • C5 a and C3 a are also anaphylatoxins, which means that they help basophils and mast cells degranulate, releasing proinflammatory molecules like histamine and heparin into the area. This can cause contraction of the smooth muscles as well as bronchial constriction and increased vascular permeability.

Question 25

What happens in C1, C2, C3 and C4 deficiency,?

Answer 25

because C1, C2, C3 and C4 are all involved in removing antigen-antibody complexes, individuals that lack any of these proteins can experience a lupus-like illness, as well as chronic renal disease and repeated infections.

Question 26

What happens in C5, C6, C7 or C8 deficiency?

Answer 26

Individuals who are deficient in C5, C6, C7 or C8 suffer from repeated Neisseria infections and are at higher risk for developing gonorrhea or meningitis.

Question 27

What happens in C9 deficiency?

Answer 27

Interestingly, individuals who are deficient in C9 seem to have no problems, because C5, C6, C7 and C8 can lyse a bacterium all on their own, with C9 being icing on the cake.