The alpha gal story: Lessons learned from connecting the dots

Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal; thus, establishing the etiology of anaphylaxis is pivotal to long-term risk management. Recently, Steinke and colleagues have identified a novel IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal) (J Allergy Clin Immunol 2015; 135: 589-596). IgE to alpha-gal has been associated with two distinct forms of anaphylaxis: i) immediate onset anaphylaxis during first exposure to intravenous cetuximab which is a monoclonal antibody specific for the epidermal growth factor receptor (EGFR), and ii) delayed onset anaphylaxis 3-6 hours after ingestion of mammalian food products (e.g., beef and pork). Results from their studies and those of others strongly suggest that tick bites are a cause, if not the only significant cause, of IgE antibody responses to alpha-gal in the southern, eastern and central United States, Europe, Australia and parts of Asia.

In 2004, cetuximab was in clinical trials for the treatment of metastatic colorectal cancer and was causing hypersensitivity reactions, but they were occurring primarily in a group of southern US states. Patients who had reactions to cetuximab also had IgE antibodies specific for this molecule before they started treatment. It was later determined that the antigen was alpha-gal which represents a major transplantation barrier between primates and other mammals. Humans and higher primates cannot produce alpha-gal which makes it possible for these animals to make IgG antibodies directed towards this oligosaccharide. The antibodies causing reactions to cetuximab overlapped the same geographical area where allergic reactions to red meat were occurring. It was later discovered that tick bites represent the most important cause of alpha-gal sensitization and that epidemiological evidence in the USA would suggest that the rise in the deer population has played an important role.

The results described in this review provide evidence that: IgE responses to an oligosaccharide can induce significant or severe allergic symptoms, demonstration of sensitization to this epitope by skin test often requires intradermal as well as prick test, ticks can induce high titer food specific IgE responses in adult life, and also that eating mammalian products carrying this epitope does not give rise to any symptoms during the first hour or more. The delay in onset of symptoms following eating red meat is best explained by delayed arrival of the relevant form of antigen in the circulation, but the question remains as to what form of glycoprotein or more likely glycolipid takes 3 hours or more to appear in the circulation. Finally, the often-rapid production of IgE antibodies to alpha-gal after tick bites provides a striking model of a parasite induced IgE response; however, it remains a challenge to identify why the response is so strong and why it is directed so consistently against the alpha-gal carbohydrate residue.