Thomas Platts-Mills, MD, a professor of medicine and microbiology and division head for the Department of Medicine’s Division of Allergy and Clinical Immunology, was awarded a $3.1 million R37 MERIT award for his research on the allergic and non-allergic effects of IgE antibodies to the oligosaccharide galactose alpha-1,3-galactose (alpha-gal), work that has been funded consistently by the NIH since 2008. This year Dr. Platts-Mills received approval for the second half of his merit award R37 AI-20565-39. His work on this novel form of allergic disease started with the investigation of the causes of severe, immediate reactions to infusions of the monoclonal antibody Cetuximab. Those studies established that the reactions occurred in patients who had specific IgE antibodies prior to the first infusion (NEJMed 2008). In addition, his lab established that those IgE antibodies were specific for alpha-gal, which was known to be the primary glycosylation on the FAB section of the MAb. In turn, measuring IgE antibodies to alpha-gal identified a novel form of delayed anaphylaxis occurring 3 to 6 hours after eating red meat. Subsequently, they identified that bites from Lone Star Ticks were strongly associated with the production of IgE ab to alpha-gal, and that the syndrome is largely restricted to areas where bites of the tick are common. Further, the nature of the oligosaccharide provides a good explanation for the specificity of the reactions to products from non-primate mammals.
By the time Dr. Platts-Mills’ group applied for renewal of his grant in 2018, the basic features of the IgE response to the clinical syndrome had been confirmed in many other parts of the world. In particular, the specificity of the IgE response was confirmed in Amsterdam and Stockholm; the relevance of tick bites was confirmed in Australia, Sweden, Belgium, France, Germany, and Japan. Cases of the syndrome have now been reported on all continents except for Antarctica!
In addition to the allergic features that can follow several hours after eating red meat, abdominal symptoms are also an important part of the syndrome, and in some cases are the dominant feature. The UVA group has collaborated with outside gastroenterologists Dr. Bob Richards (Lynchburg, VA) and Dr. Sarah McGill (UNC Chapel Hill) to study the GI cases. There have also been several observations that suggest an association between IgE to alpha-gal and coronary artery disease (CAD). The first observations included allergic reactions at the time that porcine or bovine valves were implanted in humans, and a clinical impression that too many of the IgE positive patients were having heart attacks. Direct evidence of the relevance of IgE to alpha-gal and CAD came from a collaboration with their UVA cardiology colleagues Angela Taylor, MD and Colleen McNamara, MD. That study documented increased severity of plaques in the coronary arteries in patients with sIgE to alpha-gal. The association was further confirmed by a cardiology group in Sydney, and they included evidence about STEMI. However; both in Charlottesville and in Sydney, most of the IgE positive patients had not reported allergic symptoms. In a fascinating twist to the story, Hendrik Jan Ankersmit, MD in Vienna has recently reported a possible role of IgG3 antibodies to alpha-gal, including evidence that these antibodies increase after bio-valve transplantation.
The current studies of his group include: 1) Using alpha-gal knock out pork as a placebo to challenge individuals who report abdominal pain after eating meat; 2) investigating the mechanism of the delay in reactions following eating beef steak that include glyco-lipids entering the circulation on chylomicrons of 400 nm and the question about whether foreign glyco-lipids are still present on LDL of 20 nm which could penetrate arterial walls; 3) investigation of IgG3 antibodies to alpha-gal in collaboration with Phadia/Thermo Fisher. This includes studies on the role of bio-valves acting as a foreign body, as well as the role of chronic dietary exposure to alpha-gal.