The alpha-gal story: lessons learned from connecting the dots

Abstract

Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal, and therefore establishing its cause is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal). IgE to alpha-gal has been associated with 2 distinct forms of anaphylaxis: (1) immediate-onset anaphylaxis during first exposure to intravenous cetuximab and (2) delayed-onset anaphylaxis 3 to 6 hours after ingestion of mammalian food products (eg, beef and pork). Results of our studies and those of others strongly suggest that tick bites are a cause, if not the only significant cause, of IgE antibody responses to alpha-gal in the southern, eastern, and central United States; Europe; Australia; and parts of Asia. Typical immune responses to carbohydrates are considered to be T-cell independent, whereas IgE antibody production is thought to involve sequential class-switching that requires input from T cells. Therefore, establishing the mechanism of the specific IgE antibody response to alpha-gal will be an important aspect to address as this area of research continues.

Keywords: Anaphylaxis; delayed reaction to red meat; galactose-alpha-1,3-galactose.

Figure 1. Major carbohydrate structures on Fab portion of cetuximab

Carbohydrate structure of N-linked glycans on the Fab portion of cetuximab as determined by mass spectrometry. Alpha-gal (red), manose (blue), N-acetylglucosamine (green), N-glycolyl neuraminic acid (black). The percentages represent the proportion of the indicated structures found on the Fab region of cetuximab. Adpated from Qian et al .

Figure 2. Relationship of IgE to alpha-gal with IgE to Amblyomma americanum (Lone Star tick)

Specific IgE to alpha-gal and Amblyomma americanum was measured using ImmunoCAP and the correlation between the two was determined using Spearman’s correlation r_s=0.66: p<0.001.

Figure 3. Summary of alpha-gal sensitization leading to clinical symptoms of red meat allergy

The southeastern section of the US is where most of the reactions to red meat have been reported. This region overlaps with the distribution of the Lone Star tick. The current hypothesis is that people are bitten by Lone Star ticks carried by deer into rural and urban areas. Following a period of time, IgE to alpha-gal develops. Once IgE to alpha-gal reaches sufficient levels, ingestion of red meat can trigger reactions.