Life and death of mast cells

Mast cells are often referred to as being “long-lived.”  While the studies on the duration of mast cell life span produced conflicting data, it is generally believed that mature mast cells live for months in human tissues.  Numbers are kept relatively constant by controlled proliferation and apoptosis.  This means that the amount of new mast cells made and old mast cells killed in regulated.  Mast cell numbers are known to increase in inflammatory conditions, like asthma, RA and tumors.  In some diseases, including mastocytosis, mast cell number correlates with disease severity.

Mature mast cells depend on a molecule called Stem Cell Factor (SCF) for survival.  Decreasing the amount of SCF available reduces the number of mast cells.  SCF binds to the CKIT receptor on the outside of the mast cell.  Once it is bound to CKIT, SCF controls mast cell survival by sending a signal to change a protein inside the mast cell, which then degrades another protein, called Bim. The Bim protein is pro-apoptotic.  That means that it signals to the cell that it is time to die.  So SCF prevents Bim from telling the cell to die, thereby keeping the cell alive. 

When an IgE (antibody) molecule binds to the receptor on the surface of the mast cell, this is called “cross linking.”  Cross linking can cause degranulation, when the mast cell releases chemicals like histamine.  Mast cells can survive degranulation, an unusual quality.  This has been proven many times, but exactly how this survival is mediated is unclear.  The most convincing report I found showed that weak or moderate cross linking led to increased cell survival, while stronger cross linking caused more degranulation but less survival. 

How each cell responds to IgE crosslinking is very specific to exactly what kind of mast cell it is (what tissue they live in, etc) as well as what kind of IgE it is.  This is because IgE cross linking actually regulates proteins inside the cell that tell the cell to die, as well as different proteins that tell the cell not to die.  This is an extremely complicated process, and very specific to the IgE and mast cell subtype.

Most people with systemic mastocytosis, as well as other types of mastocytosis, have a mutation in the CKIT gene called the D816V mutation.  This change causes the CKIT receptor.  Normally, in order to send a signal into the cell to suppress cell death, SCF must bind the CKIT receptor.  However, the D816V mutation allows the receptor to send this signal into the cell without SCF binding to it.  It can do it all by itself, a phenomenon known as “autoactivation.” 

In regular mast cells, when appropriate, SCF binds to the CKIT receptor, signaling to keep levels of pro-apoptotic proteins low.  These are the proteins that tell the cell to die.  How often SCF binds to CKIT is regulated carefully by lots of signals from the surrounding cells in the tissue. 

In neoplastic mast cells, like in mastocytosis, pro-apoptotic proteins are found in very low levels, regardless of SCF activity.  This causes the cells to proliferate, or make more cells.  There has been some success with activating this pro-apoptotic protein using medications, thereby inhibiting proliferation.