It kind of makes you think how can someone, who has a complement inhibitor treatment that blocks their C5 from being chopped by the C5 convertase to start a Membrane Attack Complex ( MAC) response by their complement , still have enough free newly created C5 to continually have some MAC formation at the same time?
Should this be a concern?
Particularly those aHUS patients with no genetic mutations in their alternative pathway components to hinder normal complement control whether they have complement treatment or not.
Is it not enough complement inhibitor or just too low a drug trough level?
Or maybe a time lag in C5 being acted on by complement inhibitor?
Or is it something else? A different syndrome?
There are two C5 convertases*. These are a combination of complement components which when they attach to C5 cleave it , i.e. chop it in two, to start off the MAC**, which is quite normal but only when unregulated and causes self damage and brings on a TMA..
The best known convertase, the one most associated with aHUS, or what is increasingly called complement mediated TMA, comes from the alternative pathway. It is described as C3bBbC3b.
The other begins in the Classic Pathway of complement and is described as C4b2b3b.
Both these convertases have a short life , between 3 and 30 minutes but in that time they will chop up as many C5 components as they can and start the MAC , described as C5b-9.
A complement version of protein S can bind to new MAC formation to prevent it from inserting into cell membranes. This is called sC5b-9 and is an “inactive” MAC and will disappear eventually.
The reason it exists is to protect other cells in the blood that could be destroyed by active MAC. It is normal in the general population but levels are low, maybe zero.
Elevated levels of sC5b-9 suggest there is complement activity. Continuous elevated levels suggest a continuous trigger and insufficient control or blockade. Also what is happening with active C5b-9?
Complement ticks over for all, even the “NORMAL” people. Parts are created, they do something, then they disappear.
But would any MAC, active or inactive be formed when the means for its creation is stopped altogether by a drug or by natural unmutated complement control components.
But it is estimated to be so in 30% or so of aHUS patients.
Would intense complement activation mean that both of the C5 convertases get to the newly made C5 before a complement inhibitor like eculizumab can act?
Is there a continuous competition to get to the C5 first?
But that could happen to all aHUS patients and what would be the perpetual trigger to raise the intense state?
Any competition would be won by the C5 convertases if there was not enough eculizumab, or with trough levels being too low.
Something can be done about these, just adjust dosing.
Even if the inactive MAC is all there is, it is still indicative that not all C5 is blocked but to be excessive it needs something to stimulate it.
Is it the classical pathway that does it for some, particularly those with no known alternative pathway genetic mutations. New biomarkers are turning more attention to Classical Pathway. Can it act independently of the alternative pathway not just along side it?
It seems to be the case. Even when the alternative pathway is blocked. In high load overwhelming volumes it can win the competition to get to C5 first.
This is not primary aHUS , but would this be something different.
Is this the way Lupus/SLE, APS, Scleroderma and other secondary autoimmune antibodies are getting to create a TMA and trigger MAC on a continuous basis ?
Or plausibly it is another syndrome or different sub type of complement mediated TMA.
Needing a tailored therapy perhaps.
Article No. 768
* C4b2aoxy3b and CVFBb also are C5 convertases
**sometimes called the TCC – Terminal C5b-9 Complement Complex
