Scientists at the Garvan Institute of Medical Research in Australia have gained mechanistic insights on a life-threatening mammalian meat allergy brought on by tick bites that could pave the way for therapeutics to treat the rare anaphylactic response.

The study takes a close look at how human antibodies interact with a sugar molecule called alpha-gal that is found on gut bacteria, malarial parasites, the cancer drug cetuximab, and tick proteins, but not in humans, old world monkeys, and other great apes.

The findings were published on July 4, 2022, in an article in the Proceedings of the National Academy of Sciences (PNAS) titled, “Genetic and structural basis of the human anti-alpha-galactosyl antibody response.” The study confirms the role of alpha-gal as the key molecule underlying this unique allergy and may lead to strategies toward antibody therapeutics for alpha-gal syndrome in mammalian meat allergy, malaria, and xenotransplantation.

Northern Sydney has the highest prevalence of tick-induced mammalian-meat allergy, with more than 1800 cases reported. The Sunshine Coast hinterland around Maleny in Queensland is another hot spot. Sheryl van Nunen, MBBS, MM, FRACP, an allergy specialist at Sydney’s Northern Beaches Hospital, and a co-author on the paper, was the first clinician to link tick bites with mammalian-meat allergy. “Not a week goes by that I don’t see two people with this allergy,” she said.

“Our findings outline common binding modes and germline usage underpinning the alpha-gal response, providing molecular insights and guidance for drug development efforts,” the authors noted. The study is led by Daniel Christ, PhD, professor and head of antibody therapeutics and director of the Centre for Targeted Therapy at Garvan, and Joanne Reed, PhD, an associate professor at the Westmead Institute.

Human serum contains high levels (nearly 1%) of antibodies against alpha-gal. Therefore, when humans are exposed to alpha-gal—such as, through bites of the paralysis-inducing tick Ixodes holocyclus that is endemic to Eastern Australia—the human immune system mounts a massive anaphylactic response.

In the current study, the researchers investigated the basis of anti-alpha gal antibody gene restriction to the germline. They analyzed the structural and genetic mechanisms of alpha-gal recognition by solving the crystal structure of the mouse immunoglobulin M (M86) bound to alpha-gal. They also characterized the affinity and structures of human anti-alpha-gal antibodies in alpha-gal binding B cells isolated from healthy individuals and patients of mammalian meat allergy.

Analyzing blood from patients with tick bite-induced mammalian-meat allergy, the researchers frequently found the antibody type IGHV3-7 in response to alpha-gal. Molecular analysis showed that alpha-gal fits snugly into a pocket in this antibody. “We have more than 70 types of antibodies and this one is significantly overrepresented with alpha-gal recognition. We seem to be genetically predisposed to being sensitive to this sugar,” Christ said.

Alpha-gal is not found in humans and higher primates because a gene for the enzyme that adds the final galactose in alpha-gal was inactivated in the hominid lineage some 20 to 30 million years ago. This inactivation potentially occurred as a survival mechanism when pathogens with alpha-gal emerged. The high level of alpha-gal antibody levels in humans is likely driven by the constant exposure to resident gut bacteria that also express alpha-gal on their surfaces. The current study points to the evolutionary benefit of having an antibody response against alpha-gal.

“Humans lost the capacity to produce α-gal throughout evolution, but we don’t know why,” said Reed. “The suspicion is that it has to do with protection against infectious disease.”

Christ noted a rapid immune response to alpha-gal could destroy the malarial parasite Plasmodium that bears alpha-gal on its coat, protecting a person from malaria.

The reason why some people develop anaphylaxis and others don’t, remains unknown. It could be related to the number of tick bites, the amount of saliva injected during a tick bite or genetic sensitivity, says van Nunen. About a third of the population with sensitivity to alpha-gal exhibit symptoms of an allergy to mammalian meat. A second tick bite can more than double this allergic response.

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