Regulation of mast cells by IgE and stem cell factor (SCF)

Mast cells are regulated by two dominant mechanisms. The first is the allergic response via the high affinity IgE receptor. This receptor is called FcεRI. When an IgE molecule binds to this receptor, it triggers the release of calcium in pockets inside the cells, causes the cells to take up more calcium from outside the cell, and changes the cell membrane so that it can degranulate and secrete mediators. There are a number of other things that can affect the strength of the response triggered by FcεRI.

The second mechanism is the survival and activation response when stem cell factor (SCF) binds to the CKIT receptor (also called KIT). SCF is the primary growth and survival factor in non-neoplastic mast cells. In the absence of mast cell disease, it is absolutely required for survival. SCF also attracts mast cells and enhances degranulation from the FcεRI (IgE) receptor, production of cytokines and movement of mast cells from one place to another.

When SCF is increased in tissues, it increases the amount of mast cells there, how long they live and what roles they play. It also increases mast cell responsiveness. In some instances, SCF can directly cause degranulation with IgE involvement.

Despite understanding the importance of SCF, it is not well understood what happens after SCF binds to the CKIT receptor. We know that it increases survival and proliferation, but it’s not clear how. It is possible that the concentration of SCF or CKIT may play a role.

In tissues, mast cells often exist as a part of a membrane, and SCF is important in mast cell adhesion to other cells. When SCF is part of that membrane, it can increase histamine and eotaxin production in mast cells.

Monomeric IgE is IgE that is not bound to an allergen. In the presence of SCF, monomeric IgE can directly cause release of histamine, LTC4 and IL-8. It also makes mast cells more reactive.   When monomeric IgE binds to the FcεRI (IgE) receptor without SCF present, it causes production of IL-6 but not degranulation. However, IL-6 promotes mast cell survival.

References:

Cruse, G., Bradding, P. Mast cells in airway dieases and institial lung disease. Eur J Pharmacol (2015).

River, K., Gilfillian, A.M. Molecular regulation of mast cell activation. J Allergy Clin Immunol 2006, 117, 1214-1225.

Gilfillian, A.M., Beaven, M.A. Regulation of mast cell responses in health and disease. Crit Rev Immunol 2011, 31, 475-529.