A tick bite can leave some people unable to safely eat beef, pork, or other mammalian products, but scientists may have found a way to interfere with the unusual allergy at its source.
Researchers from the National Institutes of Health and collaborating institutions have identified the first suite of human antibodies that specifically target alpha-gal, the sugar molecule responsible for alpha-gal syndrome. Two of the antibodies blocked important steps in the immune reaction in laboratory experiments, including the activation of cells involved in allergic reactions.
The discovery was actually made while researchers were looking for something else.
The Search Started with Malaria
The team was studying antibodies that recognise alpha-gal on Plasmodium falciparum, the parasite responsible for the most dangerous form of malaria.
They isolated 42 alpha-gal-specific antibodies from B cells, which are immune cells that make antibodies, obtained from people exposed to malaria.
The antibodies did not bind strongly enough to the malaria parasite to become useful for that purpose. But some behaved differently when the researchers tested them against alpha-gal on other substances.
That unexpected reaction sent the researchers in a new direction.
They tested the antibodies against several alpha-gal-containing allergens, including proteins from mammalian tissues and cetuximab, a cancer drug known to contain alpha-gal. Thirteen antibodies were able to bind to these allergy triggers.
The researchers then wanted to know whether binding to alpha-gal could actually interfere with the allergic response.
The Antibodies Got in the Way of the Allergy Signal
Alpha-gal syndrome is unusual because the allergy typically begins with a tick bite.
Alpha-gal is a sugar found in most mammals but not normally found in humans. After certain tick bites, the immune system can become sensitised to it and produce IgE antibodies against the molecule.
IgE is an antibody involved in allergic reactions. When it encounters alpha-gal, it can activate immune cells such as basophils and mast cells, which then release substances that produce allergy symptoms.
Those symptoms can include hives, stomach pain, vomiting, and, in severe cases, anaphylaxis.
The reaction can also take several hours to appear after eating mammalian meat, making it surprisingly easy for people to miss the connection between the meal and their symptoms.
The new antibodies appeared to interfere with this process.
Two, called AG028 and AG050, prevented IgE from binding to some alpha-gal-containing allergens in laboratory tests. AG028 went a step further. Its IgA2 and IgM forms reduced the activation of basophils that had been exposed to blood serum from people with alpha-gal syndrome.
That result is what makes the discovery potentially useful beyond simply understanding the allergy.
The Idea Is to Stop the Reaction Before It Starts
People with alpha-gal syndrome currently have to avoid foods and other products that contain the molecule. That can be difficult because alpha-gal is found in more than red meat. Some medications and medical products made with mammalian ingredients can also contain it.
The newly identified antibodies offer a different approach.
Rather than waiting for an allergic reaction and treating its symptoms, researchers could potentially use an antibody-based drug to interfere with alpha-gal before allergy-causing IgE can trigger immune cells.
That is still a possibility, not an available treatment.
The experiments were performed in laboratory systems, and the antibodies have not yet been shown to prevent alpha-gal reactions in people. Researchers would also need to determine how long the antibodies remain active, how they should be given and whether blocking alpha-gal in this way is safe.
There is another reason the discovery is intriguing. The antibodies came from human B cells rather than being designed entirely from scratch, giving researchers naturally occurring molecules that already know how to recognise alpha-gal.
For people with alpha-gal syndrome, the long-term hope is straightforward: instead of having to constantly avoid a growing list of mammalian products, they could one day have a treatment that prevents the immune system from recognising alpha-gal as a threat in the first place.
