Content Reviewers:Rishi Desai, MD, MPH
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. Think of them like a little militia that “complement” the work of antibodies.
There are actually three complement pathways: The classical pathway - called that because it was discovered first, the alternative pathway which was found second and is always at work, and the Lectin binding pathway - which was found third and when folks got more descriptive with their naming.
So let’s start with the proteins that make up the classical pathway - C1, C2, C3, C4, C5, C6, C7, C8, and C9. Pretty easy right?
Now these were numbered, in the order they were discovered, but not the order in which they function.
Generally speaking, each complement protein is normally inactive, and it becomes activated when it’s cleaved - in other words when some part of it breaks free. A bit like how a fire extinguisher isn’t “active” until a pin is pulled out.
Now in the classical pathway things start out with C1.
C1 has three component C1q, C1r, and C1s.
It has six C1q subunits, which are able to bind to the Fc portion of an antibody when it is bound to antigen.
Each C1q can bind to 1 antibody-antigen complex, so technically each C1 molecule can bind 6 antibodies.
Both the C1r and C1s subunits are both enzymes called serine proteases.
C1q has zero enzymatic activity and typically the serine proteases C1s and C1r are hidden so they cannot perform their enzymatic activity.
This is all tied together in a calcium bow, so when there is a lack of calcium, C1 is also lacking.
When 2 or more of the C1q portions bind to the Fc receptors of 2 or more antibodies that are bound to antigen it causes a conformational change of the C1 molecule which twists, exposing the C1s and C1r serine protease sites. A bit like taking the safety cover off of a pair of scissors.
This allows C1r to to cleave C1s activating the C1 molecule.
The activated C1 cleaves C4 into C4a and C4b.
C4a floats away, but C4b binds to the surface of the pathogen.
C1 also cleaves C2 into C2a and C2b.
This time, C2a floats away and C2b joins C4b on the surface of the pathogen forming a protein complex called C4b2b or C3 convertase.
C3 convertase cleaves C3 into C3a and C3b.
Now this is the step that really amplifies things. That’s because a single C1 can generate maybe 10 C3 convertases, but a single C3 convertase can cleave over a 1000 C3 proteins per second, and this enzyme stays active for about 2 minutes, so you’ll get a lot of C3b very quickly.
C3b is also called opsonin, and in general opsonins are terrific because they 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 faster too. In this case, C3b is serving as that fork!
Once there’s a certain amount of C3b made, some of the C3b proteins come and bind really close to the C4b2b or C3 convertase, and turn it into a C4b2b3b protein complex which is called C5 convertase.
The C5 convertase cleaves C5 into C5a and C5b.
C5b binds to C6, C7, and C8 and together 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 thru the membrane the pathogen.