Mechanisms Behind Severe Anaphylaxis Could Lead to New Treatments

Removing proteins from the surface of secretory granules can potentially prevent anaphylactic shock.

Scientists in a recent study have discovered the mechanism behind the release of inflammatory factors associated with severe allergic reactions, which could lead to new treatments for anaphylactic shock.

Mast cells are white blood cells that fight off parasitic infections through the release of histamine and inflammatory factors that are contained in secretory granules. Allergens can also cause this release, and if it happens in cells throughout the body, it can result in a potentially fatal response.

In patients with asthma, inflammatory eosinophils are recruited to cause an asthma attack. Newly discovered resident eosinophils live in healthy lungs, and play a regulatory and protective role in maintaining the balance of the immune system to prevent asthma attacks. However, these good eosinophils may not always prevent anaphylactic responses.

Life-threatening anaphylactic responses can lead to facial swelling, difficulty breathing, low blood pressure, and fainting. The current treatment protocol is to inject the patient with epinephrine devices, such as the highly scrutinized EpiPen.

When allergens bound to immunoglobulin E antibodies activate mast cells, secretory granules travel to the periphery of the cells through microtubules. Once the cells reach the edge of the cell, they fuse to the plasma membrane and release their contents.

Scientists in a study published in The Journal of Cell Biology explored the role of kinesin-1 in the reactions, which is a protein that transports various cargoes along microtubules.

Mice models were created to lack Kif5b, a critical subunit of kinesin-1. Scientists found that these mice were not as sensitive to anaphylaxis when exposed to allergens. The mast cells in these animals had lower levels of secretory granule release, since the granules were not transported to the plasma membrane, according to the study.

They discovered that a signaling pathway involving the phosphatidylinositol 3-kinase enzyme triggers kinesin-1 to link to proteins on secretory granules. Rab27b, a member of the protein complex on the granules, has been known to control mast cell secretion.

The scientists also found that removing Slp3 from the protein complex was also able to elicit a similar response to that of Kif5b, which inhibits secretory granule transport and release. These findings could lead to novel ways to treat anaphylaxis and prevent potential deaths.

“The fact that mice lacking Kif5b in their mast cells exhibited very low levels of passive, systemic anaphylaxis suggests that kinesin-1 could be a valuable new therapeutic target for controlling allergic reactions,” lead researcher Gaël Ménasché, PhD, concluded.