Tick bites, IgE to galactose-alpha-1,3-galactose and urticarial or anaphylactic reactions to mammalian meat: The alpha-gal syndrome

Abstract

The recent recognition of a syndrome of tick-acquired mammalian meat allergy has transformed the previously held view that mammalian meat is an uncommon allergen. The syndrome, mediated by IgE antibodies against the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal), can also involve reactions to visceral organs, dairy, gelatin and other products, including medications sourced from non-primate mammals. Thus, fittingly, this allergic disorder is now called the alpha-gal syndrome (AGS). The syndrome is strikingly regional, reflecting the important role of tick bites in sensitization, and is more common in demographic groups at risk of tick exposure. Reactions in AGS are delayed, often by 2-6 h after ingestion of mammalian meat. In addition to classic allergic symptomatology such as urticaria and anaphylaxis, AGS is increasingly recognized as a cause of isolated gastrointestinal morbidity and alpha-gal sensitization has also been linked with cardiovascular disease. The unusual link with tick bites may be explained by the fact that allergic cells and mediators are mobilized to the site of tick bites and play a role in resistance against ticks and tick-borne infections. IgE directed to alpha-gal is likely an incidental consequence of what is otherwise an adaptive immune strategy for host defense against endo- and ectoparasites, including ticks.

Keywords: IgE; alpha‐gal; anaphylaxis; mammalian meat allergy; ticks.

FIGURE 1

Structure of alpha-gal in relation to human ABO-blood group antigens. Representative alpha-gal glycolipids detected by mass spectrometry on rabbit red blood cells (acknowledgement to Parastoo Azadi and Stephanie Archer-Hartmann at the University of Georgia Complex Carbohydrate Center).

FIGURE 2

Map of countries with reported alpha-gal syndrome (AGS) cases (or alpha-Gal IgE sensitization) and relevant species of ticks that have been linked with sensitization in various regions.

FIGURE 3

Clinical spectrum of alpha-gal syndrome symptoms. Delay of up to 5 h in onset of symptoms does not preclude rapid development of severe symptoms at that time. Severe anaphylaxis in AGS can include major increases in serum tryptase.

FIGURE 4

The ‘glycolipid hypothesis’ posits that the 3–6 h delay in symptom onset after ingestion of mammalian meat—which is unusual for an IgE-mediated food allergy but is characteristic of AGS—is explained by glycolipid forms of alpha-gal. This premise is based on the known kinetics of lipid digestion, absorption, packaging and circulation. Lipids are packaged into chylomicrons in the intestine, transit via the thoracic duct and first emerge into the systemic circulation about 2–3 h after a fatty meal. In turn, over the next few hours, lipids progressively transition to smaller lipoprotein particles such as low-density lipoproteins (LDL) that are sufficiently small to pass through endothelial walls and enter interstitial tissues where mast cells reside. Of note, experimental evidence for this hypothesis is incomplete and alternative explanations involving glycoprotein forms of alpha-gal cannot be excluded. For example, it is possible that alpha-gal expression on highly stable proteins such as collagen and laminin contribute to delayed digestion and absorption kinetics in vivo.

FIGURE 5

IgM, IgG and IgA antibodies specific for alpha-gal develop in all humans as a consequence of exposure to alpha-gal expressed by gut commensals. IgE antibodies specific for alpha-gal develop as a consequence of tick bites. The mechanisms that drive this response remain incompletely understood but are hypothesized to involve innate and adaptive immune pathways that promote type 2 immunity and IgE class switch.