And then there were 3.
3 pathways to rule them all – destroying microbes, clearance of cellular debris/apoptotic cells and promote inflammation.
The classical, lectin and alternative pathways.
Each pathway is activated by a different mechanism. The major goal of all three cascades is the deposition of large quantities of C3b on a target (opsonization), which marks it for elimination. Engagement of each pathway also leads to the release of proinflammatory anaphylatoxins (C3a and C5a) and assembly of the membrane attack complex (MAC).
But I mean, let’s face it. What we really want to know is how to interpret the tests and what they mean right?
So let’s make it simple.
Classical pathway is represented by C3 and C4 levels.
Low C3/C4 or Low C3 only can represent:
- Antiphospholipid syndrome
- Mixed cryoglobulinemia
- Sjögren’s syndrome
- Any causes of circulating immune complexes – IE, hepatitis, mononucleosis, shunt nephritis
Low C4 but normal C3
- Hereditary angioedema
- Acquired C1 inhibitor deficiency
- Genetic partial deficiency of C4
But sometimes SLE too as C3 is 6x higher in concentration than C4 and while it falls, the level might still remain in the ‘normal limit’ whereas C4 levels will have dropped below the lab limit.
Things to note : The complement system is designed to work onthe biological membrane. In diseases like angioedema, C3 convertase works poorly in the plasma (fluid) phase, hence C3 levels appear normal (but they are also consumed) as they are not broken down whereas C4 levels are low.
But in syndromes involving excessive soluble immune complexes, such as mixed cryoglobulinemia, SLE, and MPGN can also lead to ‘normal’ C3 but low C4. Hence, screen for all the above if complement is low!
Alternative pathway activation is indicated by low levels of factor B, low C3 with normal C4 and is a pathway that is constantly working at a low level behind the scenes (like how your heart beats all the time!)
Now, sometimes I feel certain things are easier to be explained using layman terms. Too much medical jargon makes one’s head go round and round.
Especially explaining things that are just LETTERS. I mean H, I, B … they are just that. Alphabets.
So I’m going to say there are accelerators and brakes in the alternative pathway system.
Complement Factor H (CFH), Factor I (CFI) and Membrane cofactor protein (MCP) are all BRAKES.
Complement Factor B (CFB) and D (CFD) are ACCELERATORS.
So something comes along and activates our dear old alternative pathway. C3 generates C3b which binds indiscriminately to pathogens and host cells. On a foreign surface, such as a bacterium, C3b binds CFB, which is then cleaved by Factor D to form the C3 convertase C3bBb. This amplifies the C3 convertase loop leading to formation of the MAC that kills of the bacteria.
Now if this continues to go into overdrive (i.e. the accelerators are being stepped on all the time) pretty soon we will be attacking all cell surfaces which leads to all sorts of problems. Our brakes CFH, CFI and MCP are there to police this. Competition between CFH (which is the main player) binding to C3b limits the binding of CFB instead hence reducing C3 convertases and reducing MAC formation.
In summary (but not exclusively)