The Immunology of Alpha-Gal Syndrome: History, Tick Bites, IgE, and Delayed Anaphylaxis to Mammalian Meat

Abstract

The primary features of the alpha-gal syndrome (AGS) are (i) The IgE ab that are causally related to anaphylaxis with infusions of Cetuximab are specific for galactose alpha-1,3-galactose. (ii) In the USA, this IgE ab is induced by bites of the tick Amblyomma americanum. (iii) The anaphylactic reactions to food derived from non-primate mammals are delayed in onset by three to five hours. A further important fact is that all humans make a "natural" response to alpha-gal which includes IgM, IgG, and IgA, but not IgE. The clinical features of AGS are recognized in many parts of the world, but different species of ticks are involved. The immune response to tick bites includes T cells specific for tick protein, while IgE producing B cells appear to be derived from B cells specific for IgM or IgG. With repeated tick bites, the T cells develop a strong Th2 signal with IL-4 and IL-13 This obviously relates to IgE production, but may also be relevant to itching after tick bites which can last for weeks. The current hypothesis about the cause of the delayed reactions is based on the time that it takes to digest glycolipids from meat to LDL. The management of AGS symptoms is based on the avoidance of food derived from mammals; however, the only thing that can allow IgE to decrease is avoidance of tick bites.

Keywords: alpha‐gal knock‐out animals; anaphylaxis to meat; galactose alpha‐1,3‐galactose; glycolipids; tick bites.

FIGURE 1

The alpha 1–3 galactosyltransferase that establishes the alpha‐gal linkage is different from the alpha 1–3 galactosyltransferase that can make a very similar linkages to a substituted galactose on blood group B. The alpha‐gal hapten as well as the A and B blood group oligosaccharides can be linked either to asparagine or O‐linked to the sphingolipid ceramide.

FIGURE 2

Alpha‐gal syndrome involves a human with a pre‐existing natural antibody response to the oligosaccharide galactose alpha‐1‐3‐galactose (alpha‐gal), receiving tick bites which induce an IgE antibody response to the same epitope. Over the next few weeks or months, IgE antibodies may increase. After that time, eating meat or organs can induce an allergic reaction which does not start for 3–5 h.

FIGURE 3

Basophils are primarily present in the circulation and only accumulate in tissues at the site of an inflammatory reaction. Basophils can be triggered in the circulation to activate CD‐63 as they release histamine. Release of mediators from mast cells requires a protein with multiple epitopes, or a particle carrying multiple epitopes of the same antigen, which enters the tissues.

FIGURE 4

Confocal microscopy of ventral side of an adult female Lone Star tick: The barbs on the hypostome, stained here in blue, make ticks difficult to remove. Pigment bleached with peroxide, cuticle stained with Congo Red and Calcofluor White imaged on Zeiss LSM at 100× magnification. Image courtesy of Igor Siwanowicz Janelia Research Campus of the Howard Hughes Medical Institute, Ashburn, Virginia, USA.

FIGURE 5

South Eastern USA, showing the area where A. americanum was established prior to 2015, and also the expansion of fire ants following their introduction in Mobile, AL (71, 72). The red bars represent the number of AGS cases reported by allergy clinics while the dashed bars indicate responses related to fire ant anaphylaxis (FAA), in the same clinics. The data for fire ant quarantine dates is curtesy of the USDA (www.aphis.usda.gov).

FIGURE 6

Alpha‐gal IgE prevalence by state. States in light green without annotation did not have any subjects with positive alpha‐gal specific IgE. In 2024 we published a study on serum assays for IgE antibodies to alpha‐gal among 3000 recruits to the armed services whose county and state of origin was known. The results for the states are presented as a % of individuals with positive assays for IgE antibodies to alpha‐gal and that varied from 39% in Arkansas and 35% in Oklahoma, to 2% in Arizona and 0% in New Mexico.

FIGURE 7

Basophil activation test results from 2 subjects with α‐gal syndrome and one non‐allergic control. Basophils were exposed, ex vivo, to bovine thyroglobulin (BTG; serially diluted 1:10 from 100 to 0.01 μg/mL), or to the antivenom biologics Anavip (diluted 1:5 from 1000 to 0.32 μg/mL) or CroFab (diluted 1:5 from 10,000 to 1.6 μg/mL). Flow cytometry was used to detect the percentage of CD63‐positive basophils (a measure of basophil activation). The % CD63 positive data were normalized based on the anti‐FcεRI positive control (100%) and baseline negative control (stimulation buffer; 0%).

FIGURE 8

Time course of the digestion of glycolipids after eating mammalian meat or organs. Over the first hour, glycolipids but not glycoproteins can pass through the intestinal wall and be formed into the chylomicrons in the lacteals, which lead to the thoracic duct. Chylomicrons are large (i.e., 300–1000 nm) and are largely made of fat, so they float on the top of serum. Over the next 2–6 h they are transformed into VLDL and finally to LDL, which are 12–25 nm in diameter, and can pass through endothelial walls. In the tissues of an allergic subject, the LDL, with alpha‐gal on them, could cause release of mediators such as histamine, leukotrienes, and tryptase from mast cells.