Receptors on the outside of mast cells (pictured here) expose antibodies and release inflammation-causing histamines.
Image credit: Priyanka Pundir/University of Alberta
The researchers, who worked with colleagues at the University of Alberta in Canada, say their findings could be used to develop drugs that enable people with conditions such as prostate cancer, diabetes and HIV to experience better treatment.
Their results are published in the journal Nature.
Drug allergies are a result of the immune system producing antibodies called IgE against a medication. In these cases, the IgE instructs white blood cells to make histamines, which in turn cause allergy symptoms.
However, drug allergies can also occur without the body producing IgE, in which case the body produces other types of antibodies or has reactions that do not produce antibodies at all.
Xinzhong Dong - associate professor of neuroscience at Johns Hopkins - and colleagues say that previous studies have traced symptoms of allergic reactions at injection sites of many drugs to mast cells, which are part of the immune system.
Disabling gene for receptor eradicated allergy symptoms in mice
The team explains that specialized receptors on the outside of mast cells expose antibodies, which act as warning signals, and these receptors then release histamines and other substances that call immune cells into the area and generate inflammation.
- Common symptoms include hives, itchy skin or rash, swelling or wheezing
- Anaphylaxis can include abdominal pain, dizziness, difficulty breathing, rapid pulse or diarrhea
- Though skin testing can diagnose allergies to penicillin, there are no reliable skin or blood tests to diagnose other drug allergies.
But Dong notes that "although many of these injection site reactions look like an allergic response, the strange thing about them is that no antibodies are produced."
In order to determine the cause of these reactions, the researchers - including Benjamin McNeil, a postdoctoral fellow in Dong's lab - aimed to discover which mast cell receptors responded in this way to drugs in mice.
Though previous studies identified a human receptor that was a likely culprit in the allergic reactions, McNeil found a similar receptor in mice that is also only found in mast cells.
As such, he tested the receptor by putting it into lab-grown cells, and results showed that they reacted to drugs that provoke responses in mast cells. Additionally, he found similar results for the previously identified human receptor.
Next, to determine whether getting rid of the receptor would also get rid of the allergic reactions, the researchers disabled the gene for that specific receptor in mice and found that these mice did not display any of the drug allergy symptoms.
Receptor is 'an attractive drug target'
Identifying an individual receptor means the researchers' future work can be much more streamlined. McNeil adds:
"It's fortunate that all of the drugs turn out to trigger a single receptor - it makes that receptor an attractive drug target."
Now, the team is working on finding compounds to block the human form of the receptor - MRGPRX2 - which would prevent reactions triggered by the receptor but not true antibody-producing allergic reactions.
The researchers say medications that trigger this receptor include cancer drugs cetrorelix, leuprolide and octeotide; the HIV drug sermorelin; fluoroquinolone antibiotics; and neuromuscular blocking drugs.
McNeil says their work could help lessen drug side effects for many patients, and they are also looking into whether MRGPRX2 is behind immune conditions that do not come from medication use, including rosacea and psoriasis.
The researchers conclude their study by noting that their "discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects."