Disclaimer- The posts in this series are intended to improve awareness of this important and potentially deadly disease. I am not an Allergist or Immunologist and I am not offering any medical advice. Please consult with your own physician or health care provider for that. An educated patient and their family are the best advocates for their health care.

The Alpha-gal syndrome (AGS) or as it was initially called “the red meat allergy” has been recognized for nearly 20 years. It is not just an allergy to red meat but is most commonly the result of ingestion of any mammalian tissue or organ. Unlike other food allergies the onset of symptoms does not occur for about 2-6 hours after ingestion making it more difficult for patients to associate their symptoms with a meal. Many food products and additives, as well as inactive ingredients in medications, may be derived from non-primate mammals. As a result symptoms in sensitized individuals can be triggered by orally ingested food or medications, intravenous medications and in rarer cases products applied to the skin. In 2011 the allergy was found to result from the bite/s of a tick. In the United States the tick most often associated with the syndrome is the Lone Star star tick. The delineation of the syndrome, the development of a test to diagnose it, and the discovery of a tick bite as the sensitizing event were largely the work of one laboratory, that of Dr. Thomas Platts-Mills at the University of Virginia School of Medicine. Dr. Platts-Mills and his group, along with collaborators, were able to synthesize clinical and research insights to define and diagnose the syndrome, determine its cause and develop a strategy for patients to avoid its symptoms. Much work still needs to be done but remarkable progress has been made in a short period. This is the story of how these investigators connected the dots along their journey.

The first dot– In 2004 a new monoclonal antibody manufactured by Bristol Myers Squibb, cetuximab, was FDA approved for use in the United States for the treatment of stage 4 colon cancer and head and neck cancer. As the drug began to be administered to patients with no previous exposure to it, a subset developed severe allergic reactions (death, anaphylaxis, angioedema, and urticaria/hives) with their first intravenous infusion. The dilemma for oncologists was how could someone be allergic to something that they had never been exposed to before? In addition, the reaction was only occurring in clinics in the southeast (North Carolina, Virginia, Tennessee, Missouri and Arkansas) but not in Boston, New York or Chicago. Dr. Roger Cohen an Oncologist at the University of Virginia (UVA) turned to his colleague, Dr. Thomas Platts-Mills at UVA for help. Dr. Platts-Mills laboratory had expertise in developing assays to detect novel antigens. In 2005, Dr. Tina Merrit, a fellow in his lab, identified a specific antibody (IgE- immunoglobulin E) to cetuximab in the blood of affected patients provided by Dr. Cohen.

They tested additional samples from Vanderbilt and Bristol Myers Squibb and verified that patients with severe allergic reactions to cetuximab had in their circulation a preformed antibody, an IgE, to the cetuximab molecule. They next conducted a series of experiments to determine which part (epitope) of the cetuximab molecule the patients were reacting to. An important clue was that cetuximab can be made in two different cell lines, one from mice and the other from hamsters, but the affected-patients’ antibodies bound only to cetuximab made in the mouse cell line. This suggested that the antibodies were reacting to a sugar molecule on the drug and not the protein itself. Further studies revealed that the sugar molecule was galactose alpha-1,3 galactose (alpha-gal). The glycosylation site where alpha-gal is bound is shown in the image below.

The alpha-gal antigen is shown below. It is structurally similar to the type B major blood group antigen.

The second dot– In 2007-2009 Dr. Platts-Mills’ group reported at meetings and subsequently published data from patients that suddenly developed severe allergic reactions to beef and pork after tolerating it well for years. Interestingly, these patients tested positive for IgE to alpha-gal, the exact same molecule the cetuximab patients reacted to (Delayed Anaphylaxis, Angioedema, or Urticaria, After Consumption of Red Meat in Patients with IgE Antibodies Specific for Galactose-Alpha-1,3-Galactose. Commins SP et al Journal of Allergy and Clinical Immunology 123: 426-433, 2009 link).

The third dot– Jake Hosen in the Platts-Mills lab was asked to search Google for a map of patients with a disease that was comparable to the areas where patients had developed severe allergic reactions to cetuximab infusion. The only map he could find was a CDC map of cases of Rocky Mountain Spotted Fever. Rocky Mountain Spotted Fever is caused by the bacteria Rickettsia rickettsii transmitted to humans by the bite of a tick. A milder infection caused by Rickettsia amblyommatis is much more common in Virginia and is transmitted by the tick Amblyomma americanum (the Lone Star tick). The group then began collecting data on tick bites in their red meat allergy patients. Almost all had a known history of one or more tick bites as reported by Scott Commins who was then at UVA (The Relevance of Tick Bites to the Production of IgE Antibodies to the Mammalian Oligosaccharide Galactose-α-1,3 galactose. Commins SP et al Journal of Allergy and Clinical Immunology 127:1286-1293, 2011 link).

Subsequent studies have confirmed the causal relationship between tick bites and AGS, evidence shown below.

The dots are connected and AGS in Virginia is defined– AGS results from the bite/s of adult, nymphal or larval Lone Star ticks. This is followed over weeks to months by a rise in IgE specific for alpha-gal and allergic reactions to meats or organs, from non-primate mammals, which begins 2-6 hours after ingestion. A subset of patients may also react to other substances in foods or medications derived from non-primate mammals. If these medications are infused intravenously the effect is immediate (we’ll discuss why this occurs in a subsequent post). In different parts of the world other tick species have been implicated.

Next- Alpha-gal Syndrome- An Overview