Prevalence and Seroconversion of IgE to the Mammalian Oligosaccharide Galactose-Alpha-1,3-Galactose and Relationship to Comorbid Disease in Military Personnel

It has been 10 years since the initial recognition that a specific immune response to a sugar present in nonprimate mammals could contribute to severe, and in some cases, life-threatening allergic reactions. The sugar is called galactose-alpha-1,3-galactose (more commonly referred to as alpha-gal) and the specific type of immune response relates to antibodies of the immunoglobulin E (IgE) isotype. Individuals who generate IgE antibodies to alpha-gal are at risk for having allergic reactions to an array of products that are derived from non-primate mammals. Although most commonly understood as a form of food allergy to 'red' meat, reactions can also relate to dairy, as well as certain medications and vaccines that are manufactured with cells or tissues derived from non-primate mammals, and thus the hypersensitivity is now commonly called the alpha-gal syndrome. There are several additional features that distinguish the alpha-gal syndrome from more traditional food allergies. For example, unlike allergic reactions to peanut, egg, or shellfish, in which the symptom onset (such as hives, itching, swelling, or shortness of breath) occurs rapidly after ingestion of the relevant food, the reactions to alpha-gal often do not manifest until at least 3 to 6 hours after ingestion of red meat. An important consequence of this characteristic delay is that patients and providers often fail to recognize that the allergic symptoms could be attributed to red meat. Another unusual feature of the alpha-gal syndrome is that disease onset is caused by tick bites. The culprit tick in the United States is the lone star tick (Amblyomma americanum) and thus the prevalence of alpha-gal syndrome cases is most pronounced in areas of the Southeast and coastal Atlantic where the lone star tick is endemic. An additional feature of alpha-gal syndrome is that there are many reasons to believe that symptoms are not restricted to allergic manifestations such as hives or anaphylaxis. We have hypothesized that alpha-gal is an unrecognized cause of gastrointestinal problems and, as supported by one of our recent publications in an American Heart Association journal, cardiovascular disease as well. Our understanding of the alpha-gal syndrome has advanced significantly since its initial recognition in 2008, but there are still many unresolved questions and the syndrome has been little investigated in the military population.

Because alpha-gal syndrome is a tick-mediated disease, we hypothesize that active duty military personnel are at high risk for the syndrome. The focus of the current research proposal is to investigate the prevalence of the alpha-gal IgE blood marker in serum that was banked in 3,000 military personnel at the time of enlistment and at a subsequent blood draw from 3 to 4 years later. The investigation will include subjects who joined the military from 2002 to 2004 and were stationed at installations in the Southeast and coastal Atlantic in areas where the lone star is known or thought to be common. We will then correlate the results of the IgE blood tests with the clinical record of the service members over a 15-year time window to determine whether the alpha-gal test is associated with reported allergic, gastrointestinal, or cardiovascular symptoms or disease. An additional element in the proposal seeks to understand whether the risk of getting alpha-gal syndrome, despite being tick-mediated, is higher in subjects with traditional allergic disease or certain blood groups. Taken together, there are multiple short- and long-term benefits to this work. Recognition of alpha-gal syndrome in the military could lead to improvement in diagnosis of symptoms and diseases that may currently be considered idiopathic. This is especially true as there is already a clinically available blood test to facilitate diagnosis. In the short-term, alpha-gal syndrome could be managed by avoidance of food or medication triggers. Perhaps more importantly, recognition of alpha-gal as a problem would open up several areas of possible long-term intervention, ranging from greater efforts at prevention (for example, tick-avoidance) to the development of specific immunotherapy that could 'reprogram' the immune response. Despite the fact that it is currently little recognized in the military, there are many reasons to think that alpha-gal syndrome could significantly contribute to health problems and comorbidities in military personnel. The proposed research will not only shed valuable insight into the magnitude of the problem that alpha-gal represents in the active duty military population, but will also represents a unique opportunity to investigate potential novel associations between IgE to alpha-gal and inflammatory diseases not usually associated with allergic disease. Evidence supporting a link between alpha-gal and gastrointestinal or cardiovascular disease could represent an important finding for all Americans.