Galactose-α-1,3-Galactose: Atypical Food Allergen or Model IgE Hypersensitivity?

Abstract

Purpose of review: Galactose-α-1,3-galactose (α-gal) is a carbohydrate allergen with several unique characteristics. In this article, we discuss some recent advances in our understanding of the 'alpha-gal syndrome,' highlight data supporting the role of ticks in pathogenesis, and speculate on immune mechanisms that lead to sensitization.

Recent findings: First described as the target of IgE in individuals suffering immediate hypersensitivity reactions to the novel anti-EGF monoclonal antibody cetuximab, it is now clear that α-gal sensitization is associated with mammalian meat allergy as well as reactions to other mammalian products. Unlike traditional IgE-mediated food allergies, reactions to α-gal often do not manifest until several hours following an exposure, although co-factors can influence the presentation. Multiple pieces of evidence, including recent work with a mouse model, point to the fact that sensitization is mediated by exposure to certain hard ticks and increasingly we are aware of its globally widespread impact. The oligosaccharide α-gal represents a novel allergen with several unusual clinical features. It has been recognized now on multiple continents and its clinical presentation can be quite variable. Moreover, efforts to delineate the mechanisms leading to α-gal sensitization may have ramifications for our broader understanding of type 2 immunity.

Keywords: Alpha-gal (α-gal); Food allergy; Red meat allergy; Th2; Type 2 immunity.

Fig. 1

Serum IgE in a patient pre and post natural tick exposure. The subject was bitten in 2013 by about 30 nymphs, presumably A. americanum, and total and α-gal-specific IgE were followed. Interestingly, while the α-gal IgE titers rose over tenfold to a peak in about 1 month, they also decreased over a period of months in the absence of ongoing exposure

Fig. 2

Analysis of skin lesion from site of tick bite at 48 h in an α-gal naïve individual. a H&E staining reveals inflammatory infiltrate, b with pronounced neutrophils evident on further magnification. c Immunohistochemistry demonstrates T and B cell clusters. Legend: for a TP = tick ‘parts,’ C = tick ‘cement’; for c blue = DAPI (nuclei stain), red = anti-CD3 (T cells), green = anti-CD20 (B cells)

Fig. 3

Proposed mechanisms by which A. americanum and other hard ticks could promote α-gal sensitization. Our working assumption is that α-gal in the form of glycoprotein or glycolipid is present at the site of the tick lesion. There is also local damage to the epithelia and/or recognition of tick-related PAMPs. Cytokines such as IL-25, IL-33, and TSLP are released and signal to immune cells including mast cells, ILC2, and dendritic cells. Collectively, these innate cells promote differentiation of Th2 cells and/or T follicular helper 2 cells (Tfh2) and favor B cell class switch to IgE, though B cell activation independent of T cell help is also possible. Factors in tick saliva such as prostaglandin E2, phospholipase A2, lipocalins, or adenosine are putative immunomodulators that favor Th2 responses. Lastly, α-gal itself may be recognized as a PAMP by carbohydrate-binding lectin receptors and thus directly stimulate signaling pathways culminating in IgE