Hi GA (Global Action) tell me something new about complement.
Hi again. The Complosome.
The “COM PLO SOAM” what is that?
It’s the intracellular complement system.
“Intracellular” is that something to do with what goes on inside cells?
Yes that is it, it is just the complement system you know about but inside the body’s cells.
Wait what, the complement system can fit into a cell and inside all body cells?
Yes but not all types of cells.
But cells are very small how can the complement system fit into such small spaces.
Cells are small, many, many, times smaller than the point of a pin but the components of complement are many times smaller than them. You probably have seen images of the complement system in articles or conference presentations alongside the surface of capillaries, but they are not to scale. Complement components look bigger because they have to have identifying labels in them like C3 or CFH using small fonts. Complement components are much smaller and can’t really be easily seen even with the highest resolution equipment available today.
So how do we know they are there?
Thirteen years ago, a researcher called Professor Claudia Kemper, then of King’s College London, was looking at some highly magnified immune cells and spotted some C3 within them. It was just a small dot, but it was there.
So that was the first time this new complement system was identified.
Yes. The complement system you know about has been known for about for nearly 125 years (found by Jules Bordet who called it Alexine). In that time much has been learned about it. In particular its role in aHUS disease. Now much needs to be learned about the complosome and researchers have barely scratched the surface in the past 13 years but have found out some stuff about it.
Like what?
Well unlike complement outside cells complement inside is important for the health of each cell. It is important for getting rid of material the cell no longer needs to keep the cell alive and healthy. It help keeps the shape of the cell. It keeps it normal.
But is it not the same as outside complement?
External complement does not do that. The complosome is independent of external complement or “circulating” in the blood complement. Intracellular complement components are produced by each cell. Not mostly produced by the liver as for circulating complement. The DNA instruction is in the cell’s nucleus. Its uses the same DNA instructions as liver produced circulating complement.
Hang on does that mean…?
Yes if the circulating complement DNA has mutations/ variants which can cause disease, the complosome has them too.
Does that mean that complosome can become uncontrolled just like the outside complement?
It is not known yet. Some can lack CFH. Further research is needed to understand.
And can a complement inhibitor stop the intracellular complement activation too?
No there is no evidence yet that the currently used complement inhibitors affect the complosome.
So, what happens then?
It is not known; it is yet to be found out. It could be that any over activation spontaneously stops, or it continues but cannot affect what goes on outside the cell. But it can interact with the immune system.
Whoa!
Yes “whoa” because one the functions of complement in cells is to create an interaction with the immune cells to create inflammation. It is an active part of something called the “lysosome”. This can break down excess or worn-out material but can also destroy viruses. But it can regulate how the cell uses its energy. This helps the cell to produce inflammatory molecules that can interact with other parts of the immune system outside of the cell.
You said earlier that Prof. Kemper discovered intracellular complement inside an immune cell. So that makes it an immune system inside a part of another immune system, doesn’t it?
Yes in the T Cells but it is now known it is in other types of immune cells too. It is helps these other parts of what is known the adaptive immune system do their job.
The adaptive immune system? Is that something that creates antibodies to destroy virus etc in the blood and reacts to vaccinations too.
Yes and it is known that intracellular complement helps them do it.
You could say it is like a bridge between the two systems.
Indeed.
You mentioned earlier that only some cells have a complosome. You have mentioned immune cells but which nonimmune cells have it too.
There are different types of cells in other organs like the liver, lung, intestines, brain, pancreas, eyes…
The kidneys?
Yes not least the kidneys and the different cells that make up that very delicate organ. Particularly the epithelial and endothelial cells which are important in complement kidney diseases like aHUS. These cells have the same DNA as liver produced complement with the same genetic mutations. The endothelial cells in the kidneys of some aHUS patients lack Factor H.
Is a complement TMA in the kidney worsened by the complosome in cells more than in any other organ? Would that explain why the disease is mostly associated with the kidney?
From what is known so far there is no answer to that or the way in which it could do that.
OK time may tell. Thinking of time which came first the complosome which has only recently been discovered or the circulating complement which has been known about for longer.
Well, both are ancient in evolutionary terms but the answer to that is not known. Single cell organisms preceded multi cell creatures in evolution so who knows? But for now, more research is needed to map out the components in the complosome and what different things they do before any thought of developing specific therapeutic interventions on intracellular complement. Current knowledge of it is too new.
OK so as I see it, the complosome is important for proper functioning of some cells, a sort of “ housekeeping” role, and forms a link between two of the body’s immune systems and can stir things up, and also may be implicated in kidney disease. And there is still more to be discovered, research has barely scratched the surface.
Yes but as far as aHUS is concerned knowing it would not necessarily mean any changes to any present treatment of uncontrolled external complement.
Acknowledgement: aHUS alliance Global Action would like to thank Prof. Lubka Roumenina for talking to us about the complosome which became the basis of this article
According to Researchgate : Lubka, Deputy Director of the Centre de Recherche des Cordeliers (CRC), Paris , studies the role of complement proteins in cellular homeostasis and aims to decipher the mechanisms by which complement contributes to pathological conditions ranging from vascular damage to tumour progression. Understanding the action of complement in different microenvironments fosters the development of innovative therapeutic strategies. Lubka is interested in atypical hemolytic uremic syndrome, sickle cell disease, rhabdomyolysis-associated acute kidney injury and clear cell renal cell carcinoma.
Article No. 701
Parul Singh, Claudia Kemper Complement, complosome, and complotype: A perspective First published: 30 April 2023 https://doi.org/10.1002/eji.202250042
West, E.E., Kemper, C. Complosome — the intracellular complement system. Nat Rev Nephrol 19, 426–439 (2023). https://doi.org/10.1038/s41581-023-00704-1
