The Oligosaccharide Galactose-α-1,3-Galactose and the α-Gal Syndrome: Insights from an Epitope that is Causal in Immunoglobulin E-Mediated Immediate and Delayed Anaphylaxis

Galactose-α-1,3-galactose (α-Gal) is an oligosaccharide that was first described as a cause of immunoglobulin E-mediated anaphylaxis in cases of first-in-man reactions to the monoclonal antibody cetuximab. Soon thereafter, immunoglobulin E antibodies to this epitope were linked with anaphylactic episodes to mammalian meat, which had a characteristic delay of ~3-6 hours. The ‘α-Gal syndrome’ is now recognised globally as a significant form of food allergy, albeit with regional variation, which reflects that sensitisation relates to bites from certain species of hard tick. The α-Gal epitope is present in organs and muscles from most mammals (with the exception of humans, apes, and Old World monkeys) as a glycan conjugated to both proteins and lipids. There are a number of unusual features that distinguish α-Gal from other traditional food allergies, including the fact that the oligosaccharide can be causal in both immediate and delayed allergic responses, and that co-factors, such as alcohol or exercise, often relate to the instigation and/or severity of clinical reactions. In this narrative review, the authors focus on the novelty of α-Gal’s intrinsic lipid form; consider aspects of glycolipid digestion, absorption, and processing; and explain how this ‘glycolipid hypothesis’ may explain several of the clinical features of α-Gal syndrome. This review draws on pioneering studies of the biochemistry of α-Gal, contemporary understanding of lipid metabolism, and comparisons to other clinically important oligosaccharides.