On the cause and consequences of IgE to galactose-α-1,3-galactose: A report from the National Institute of Allergy and Infectious Diseases Workshop on Understanding IgE-Mediated Mammalian Meat Allergy

Abstract

The mammalian meat allergy known as the "α-Gal syndrome" relates to IgE specific for galactose-α-1,3-galactose (α-Gal), an oligosaccharide that is present in cells and tissues of nonprimate mammals. The recognition of delayed reactions to food derived from mammals in patients with IgE to α-Gal and also the association with tick bites have been increasing worldwide. In 2018, the National Institute of Allergy and Infectious Diseases, Division of Allergy, Immunology and Transplantation, sponsored a workshop on this emerging tick-related disease. International experts from the fields of tick biology, allergy, immunology, infectious disease, and dermatology discussed the current state of our understanding of this emerging medical condition. The participants provided suggestions for specific research priorities and for the development of resources to advance our knowledge of the mechanisms, diagnosis, management, and prevention of this allergic disease. This publication is a summary of the workshop and the panel's recommendations are presented herein.

Keywords: IgE; anaphylaxis; glycolipids; mammalian meat allergy; oligosaccharide allergen; ticks; α-Gal.

FIG 1.

Depiction of the structure of the α-Gal epitope and representative α-Gal–bearing glycoproteins and glycolipids. A, The structure of the complete α-Gal trisaccharide epitope (galactose-α−1,3-galactose-β1,4-GIcNAc) in comparison to the blood group B antigen. B, Cetuximab is a chimeric mouse-human monoclonal IgG that expresses α-Gal glycans. Although α-Gal can be present in the Fc domain, the strongest expression of α-Gal, and that which is recognized by IgE antibodies, occurs in the Fab domain. The dominant form of α-Gal that is present in cetuximab is a bi-antennary glycan. C, Lipid forms of α-Gal are less well studied than their glycoprotein counterparts, but it is known that nonprimate erythrocytes are an abundant source of O-linked glycosphingolipids, which can bear α-Gal epitopes.

FIG 2.

A, Time course of self-reported symptom onset of allergic symptoms in 261 patients evaluated for mammalian meat allergy, of which 248 had IgE testing consistent with AGS, from Wilson et al. B, Results of basophil activation as assessed by CD63 expression in PBMCs drawn sequentially following mammalian meat challenges in individuals with known AGS from Commins et al.

FIG 3.

Representative cross-sectional imaging of coronary arteries of a subject without (left) or with (right) IgE to α-Gal. Images obtained by intravascular ultrasound, with central black area representing the lumen of the coronary artery and surrounding colored areas indicative of atherosclerotic lesions with fibrous (dark green), fibrofatty (light green), necrotic (red), and calcified plaques (white) evident. Images courtesy of Angela Taylor, MD, University of Virginia Health System and the National Heart, Lung, and Blood Institute.

FIG 4.

A, Cases of the AGS based on an ongoing survey of allergy practices in the United States (unpublished results, 2018). B, Density of the most abundant tick species in eastern North America based on a sampling of 95 sites, from Diuk-Wasser et al. Of note, there is a striking overlap of α-Gal cases with the presence of A americanum (the lone star tick), but not I scapularis (the black-footed deer tick) or Dermacentor variabilis (the American dog tick).