Lisa
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Hi Peter,
I'm confused. I didn't say that the constant IgE activation damages the MCs as in that's what's behind mastocytosis. It's not this at all.
In mastocytosis there is a genetic defect on all of the MCs. In fact, they have proven that there is more than one genetic defect. This defect is on the membrane which lies around the cell itself. This make is very vulnerable and easily triggered. The MC doesn't need to be triggered through IgE and often IgE isn't even involved, so in that sense what you are saying about constant IgE activation has nothing to do with this. In fact, what you have said about "constant IgE activation" is nothing more than someone with chronic true allergies. There are loads of people who live with true allergies but they never go on to get tumors or sarcoma ou even mastocytosis due to the constant IgE activation.
You see, Peter, when the mast cell is activated by IgE it's compelely destroyed - it can't regenerate and then the dead cell ends up being filtered out of the blood along with many other dead blood cells. This is normal body function.
Mastocytosis is a disease where the cell itself is formed with the genetic defect from the time it develops from the progenitor cell. Again, depending upon the defect, if it has the one which has been found with SM, then the MCs will aggregate and form small "tumors" as you said. Yet, these are not cancerous and they do not form into a sarcoma. Sarcomas are made up of other cells I believe and not mast cells. The only real MC tumor is called a mastocytoma.
As to the accumulation of the MCs going into the bone marrow, it's also not quite like this.
MCs are called to go into tissues where they go to help support blood vessel growth and health, they go into tissues like the mucus membranes in the nose, throat, intestines, etc, wherever there is tissue which is exposed to the outside world in some form. They remain there and when they have the SM defect on those cells, they then will accumulate one after another and invade the tissues through proliferation of these very same cells. They end up crowding out other cells. It's NOT like a true cancer where the cells divide themselves. Instead it's more like a party where you go people who crash the party and invade adding more partygoers to the original list. They are uninvited and end up forming a crowd.
This is why mastocytosis is not really considered a cancer - the cells don't divide and multiply and mestastize. They are born in a normal blood process only the defective ones just don't die off and they end up forming clumps which then eventually crowd out the other cells.
They end up migrating to the bone marrow because some are formed there and they don't exactly migrate there but they end up not leaving there, I believe. So they stay in the marrow where they should not be and thus they begin to crowd out the other cells which should be there. It's like filling a sausage case with the meat, it eventually takes over depending upon the form of masto you have.
As to the second part of your comment, Peter, this too isn't quite like this.
According to the research, and I've been talking with Dr. Escribano about some of this, they honestly can't seem to find MC aggregates in the non-clonal masto patient. This is why they call them "non-clonal". However, they know that there is some kind of clonality going on in that you have patients who have damaged MCs and that those damaged MCs are activating without clumping together. In finding more than one genetic defect on the MCs, they have found that this explains the activation and the fact that those cells don't aggregate. So, if you have a patient with MCAS who does not have the activation defect, you can't say that their MCs are entering into the bone marrow. In fact, they really don't understand yet how it is that the MCAS patients can be as reactive and even more so than the SM patients. And they can't explain why there are patients who have ASM - aggressive masto, and that they are not as reactive at times as those patients who have the non-clonal form!!! They can't explain it yet, they just don't know! So, you can't say that they hypersensitivity begins upon the MCs entering the bone marrow. Why? Because there are plenty of us who have undergone BMBs and almost no MCs can be found in the marrow and zero aggregates!
It's still a big mystery still Peter and a really hard nut to crack!!!!
I hope this helps you to understand!
Lisa
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