Causes of Alpha-gal Allergy

Meat is an important part of the Western diet but anaphylaxis is rare. This is explained by the fact that most proteins in human and animal meat are homologous, preventing the emergence of IgE antibodies. Many instances of cross-reactivity have been found, of which a few are clinically important. One of the most striking of these is the pork-cat syndrome, which is often mistaken for alpha-gal allergy.

Pork-cat Allergy vs Alpha-gal Allergy

An individual who is sensitized to cat serum albumin may develop a cross-reaction with pork albumin, which can even prove fatal in some cases. In most cases the allergy develops in those who have a close association with cats and show evidence on skin tests of allergy to both cat proteins or to pork. They show immediate reactions on the ingestion of pork, though not uniformly. However, these patients never have a reaction to beef. Thus the pork-cat syndrome does not appear to be anything other than a typical IgE-mediated food allergy which develops in response to cat protein sensitization over a period of time, with immediate manifestations (even during the meal, or within 30-45 minutes of it) following exposure to pork proteins.

Alpha-gal allergy, on the other hand, is a distinct type of allergy which is the result of the absorption of antigens in meat, which are carbohydrates rather than proteins. Secondly, unlike known food allergies, the time delay between exposure and reaction is measured in hours rather than minutes, with an average of 3-8 hours elapsing in most cases before the symptoms start.

The typical delay from eating to the appearance of symptoms is approximately 3-6 hours.

Factors Which Affect the Type and Severity of Reaction

In alpha-gal allergy, the strength of the reaction depends upon many factors such as:

• The dose of meat: In many patients, a small amount of animal meat does not bring about a hypersensitivity reaction. However, larger doses precipitate allergy, and full helpings such as a plate of barbecued pork often cause a multi-system anaphylactic reaction.
• The time of exposure in relation to the tick bite: The timing with regard to the duration since the tick bite suggests the IgE antibody production naturally fades with time but reactivates with repeated bites. Thus patients may not suffer any reaction to meat for several months but then suddenly suffer a severe anaphylactic reaction following a recent tick bite.
• The type of meat ingested as well as the fat content: Meats with a higher fat content also bring on severe reactions often requiring emergency treatment, even when the same patient had eaten the same type of meat lean a few days earlier.

Mechanism of Allergy

Alpha-gal allergy is an allergy to meat products which manifests several hours after eating meat. It is caused by an IgE-mediated antibody response to an oligosaccharide called galactose-alpha 1,3 galactose, which is found on animal proteins from a variety of species. Allergic reactions to this oligosaccharide epitope can occur in an immediate or delayed fashion.

Immediate reactions occur upon the administration of a monoclonal antibody cetuximab. This is an anticancer drug which is directed against the epidermal growth factor receptor. This drug was found to evoke rapid and often severe reactions, occurring within 20 minutes of intravenous administration. Infrequently, the drug caused fatal reactions. These reactions are confined to areas of the world where tick bites are common, and thus the possibility of a link between the exposure to ticks and the development of hypersensitivity to the drug was strong. The patients who developed allergy to the drug were found to have preexisting IgE antibodies to cetuximab (before the start of treatment). These IgE molecules recognized alpha-gal residues on the heavy chain on the Fab portion of the cetuximab molecule. The gene which encodes the enzyme directing the synthesis of this oligosaccharide is non-functional in humans and other primates, but functional in all other mammalian species. Cetuximab was produced in murine cell lines which would therefore glycosylate it with alpha-gal, rendering it allergenic to individuals with IgE antibodies to this oligosaccharide.

Later another type of hypersensitivity was manifested, in the form of urticaria, repeated episodes of anaphylaxis and angioedema, mostly in people who spent much time outdoors. They had eaten meat several hours earlier. Intradermal allergy testing for meat was strongly positive, and IgE for meat was found to be high. The IgE is directed against alpha-gal residues on the meat. This was therefore designated red meat allergy.

The areas from which red meat allergy was being reported overlapped the geographical distribution of cetuximab distribution and of tick bites. Researchers tested for the presence of IgE to alpha-gal in these patients, and it was found to be positive. In addition, there was a strong history of tick bite weeks or months before the onset of allergy. Following the bite, the level of IgE rose 4-10 times. The more itching the bite caused, the more likely it was to precipitate red meat allergy.

Tick Bites and Alpha-al Allergy

The relation of the tick bite to the causation of allergy to alpha-gal has been postulated to be due to one of the following ways:

• An unknown component in the tick saliva
• Partially digested mammalian non-primate glycosylated proteins or lipids in the tick’s stomach which are ejected into the next bite wound
• The presence of commensal organisms on the ticks which are responsible for the allergic reaction

The sensitization of the patient to the alpha-gal antigen site on the mammalian protein takes from 3-5 hours to manifest due to the delay in absorption of this oligosaccharide into the blood from the gut. Organ meats, especially pork kidneys, cause both more severe and more rapid onset of anaphylaxis.

References

• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545071/
• https://www.med.unc.edu/tarc/research/jerath-team/jerath-research
• http://news.vanderbilt.edu/2016/03/asthma-sinus-allergy-alpha-gal-syndrome/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600073/