alpha-Gal

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Code: o215
Source material: Bovine thyroglobulin
Common names: alpha-Gal

ImmunoCAP allergen component:

Allergen: Galactose-alpha-1,3-galactose

Biological function: alpha-Gal is a carbohydrate present on glycoproteins in non-primate mammals and certain invertebrates, but not in humans, Old World monkeys or apes.  

Clinical Utility

  • alpha-Gal is beneficial in the diagnosis of delayed reactions to red meat.
  • alpha-Gal may be beneficial in the diagnosis of delayed reactions to red-meat-derived gelatin.
  • alpha-Gal may be beneficial in elucidating the allergen responsible in patients initially diagnosed as having ‘idiopathic’ anaphylaxis or urticaria.

Allergen Exposure

See Beef, f27; Pork, f26; Mutton f88

Exposure to galactose-alpha-1,3-galactose occurs upon intake of mammalian, non-primate meats such as beef, pork, mutton, horse, game, tongue as well as offal such as kidney and liver, and gelatin.

Allergen description

alpha-Gal is an oligosaccharide of non-primate mammals, not present in humans, Old World monkeys or apes. (1)

Carbohydrate moieties are frequently encountered in food, and can elicit IgE responses – the clinical significance of which, until recently, has been unclear. However, recent work has shown that IgE antibodies to galactose-alpha-1,3-galactose (alpha-Gal), a carbohydrate commonly expressed on non-primate mammalian proteins, are capable of eliciting serious – even fatal – reactions. (1)

All humans have IgG antibodies specific for the oligosaccharide galactose-alpha-1,3-galactose, which is closely related to substances in the ABO blood group. This oligosaccharide is one of the major barriers to the transplantation of organs from other mammals in humans. Natural exposure to galactose-alpha-1,3-galactose appears to induce the production of IgE antibodies against galactose-alpha-1,3-galactose in some people. The presence of such IgE antibodies before treatment may put patients who receive monoclonal antibodies containing galactose-alpha-1,3-galactose at risk for hypersensitivity reactions. (1)

A naturally-occurring human antibody (anti-Gal), produced as the most abundant antibody (1% of immunoglobulins) throughout the life of all individuals, was described in 1985 and reported to recognize a carbohydrate epitope, Galalpha1-3Galbeta1-4GlcNAc-R (the alpha-Gal epitope). Although an extensive literature developed on discoveries related to the alpha-Gal epitope and the anti-Gal antibody, including the barrier they form in xenotransplantation and their reciprocity in mammalian evolution,(1) the involvement of alpha-Gal in delayed adverse reactions to meat is a recent discovery.

Sensitization may occur through tick bites, (1,2,3) parasitic infestations, (1) or exposure to cetuximab. (3,1)

In the USA, individuals bitten by the Lone Star tick (Amblyomma americanum) may develop IgE antibodies to the carbohydrate galactose-α-1,3-galactose (alpha- Gal).(5) The tick species that appears to be responsible for these responses in France is Ixodes ricinus, while in Australia it is Ixodes holocyclus.(1,2,6) The presence of alpha-Gal in ticks – which potentially explains the relationship between tick exposure and sensitization to alpha-Gal, with development of red meat allergy as a secondary phenomenon – has been described.(7) Serum from Swedish patients with delayed severe reactions to red meat was assessed, and a dose-dependent inhibition of IgE responses to alpha-Gal by the tick Ixodes ricinus demonstrated. The presence of alpha-Gal in the gastrointestinal tract of the tick was shown, with the implication of host exposure to alpha-Gal during a tick bite.(7)

Upon exposure of sensitized subjects to mammalian red meat containing alpha-Gal on glycoproteins or glycolipids, delayed anaphylaxis may ensue, often three to six hours after ingestion.(2) alpha-Gal-specific IgE can be detected commercially using a solid-phase immunoassay.(5)

IgG anti-alpha-Gal has been shown to constitute up to 1% of all circulating IgG antibodies[i] in humans, and is a major obstacle in xenotransplantation.(2)

Potential Cross-Reactivity

Cross-reactivity between alpha-Gal and other foods, plants and pollens has not been determined to date.

Extensive homology of plasma and tissue proteins across mammalian species occurs, e.g. bovine serum albumin, serum gamma globulins, actin, and tropomyosins. Delayed anaphylaxis due to IgE antibodies to alpha-Gal is different in that the IgE antibodies bind to a specific oligosaccharide, which is present on proteins and lipids from a large number of non-primate mammals. Notable among the cross-reactive syndromes, however, is the ‘pork–cat syndrome’. In this uncommon syndrome, patients develop an IgE antibody response specific to cat serum albumin that cross-reacts with porcine albumin and can lead to severe or even fatal allergic reactions when pork is consumed.(2)

Clinical Experience

Beef is the most commonly reported meat allergen, with up to 20% of children with cow’s milk allergy reported as having beef allergy.(2) The dominant beef allergens have been reported in previous studies to include BSA and bovine IgG, and to a lesser extent, muscle-derived proteins such as actin, myosin, or tropomyosin. (2-3) These reactions are typically immediate in onset. Allergic reactions to bovine- and porcine-derived gelatin are less commonly described.(2-3,10)

In contrast, the syndrome of delayed anaphylaxis of several hours (three to six hours) to red meat (beef, pork or lamb) as a result of sensitization to alpha-Gal was first described in 24 cases in 2009.(2) Subsequently, similar reports from the southern and eastern USA (2) and several other countries in Europe, and also from Australia, suggested that this syndrome is widespread.(2-3,6,10) The delayed onset suggested a delayed release due to a possible digestion process.

The syndrome of delayed anaphylaxis due to IgE antibodies to alpha-Gal is different in that the IgE antibodies bind to a specific oligosaccharide, which is present on proteins and lipids from a large number of non-primate mammals.14 However, in the uncommon ‘pork-cat syndrome’ (2-3), patients develop an IgE antibody response specific for cat serum albumin that cross-reacts with porcine albumin and can lead to severe or even fatal allergic reactions when pork is consumed.(2, 22-23) In these patients, reactions to pork are immediate, beginning soon after eating the meat, compared to patients with IgE antibodies to alpha-Gal. (14) In general, patients with pork-cat syndrome neither react to beef nor have serum evidence of sensitization.(14)

Similarly, patients with IgE to alpha-Gal may react upon first exposure to the drug cetuximab, which contains the epitope on the Fab fragment due to the manufacturing process, or following ingestion of red meat.

Patients reporting delayed severe allergic reactions, anaphylaxis, urticaria or angioedema after consumption of red meat (beef, pork or lamb) have been found to be IgE-sensitized to alpha-Gal.(2,6-7,10-11,21)  Most of the patients reported a late-in-life onset of delayed reactions to meat, suggesting a recent development of IgE antibodies to alpha-Gal.7 Sensitization to alpha-Gal does not appear to be a risk for asthma.(14) In some cases, the alpha-Gal IgE responses are very high in titer, and make a large contribution to total serum IgE.(2)

Assessing patient history for delayed reactions to red meat may be misleading, for often, only food that was taken shortly before the reaction is considered. Skin-prick tests are also unreliable, for tests with commercial red meat extracts and with crude red meats are often negative or equivocal.[ii] It is possible that delayed reactions to beef may have inadvertently been labelled idiopathic because the onset of signs and symptoms occurs three to six hours after exposure. (1)

Early studies on patients who presented with delayed anaphylaxis to red meat were skin-prick test-positive for cat, and demonstrated raised serum-specific IgE to cat, but did not experience or report allergic symptoms related to cat exposure. (14) Subsequently, it became clear that the sensitivity to cat extracts could be explained by IgE antibodies binding to alpha-Gal on cat-derived proteins, the best defined of these proteins being cat IgA. It was established that the epitope on cat IgA was alpha-Gal. (14) However, many proteins which are important targets for IgE antibody responses, such as Fel d 1 and cat albumin, are not glycosylated with alpha-Gal. (14) Initially, serum-specific IgE assays for IgE antibodies to cat extract were consistently positive in patients with IgE to alpha-Gal; but recently, the ImmunoCAP assay for IgE to cat was changed to become purely dander, and as a result it may underestimate IgE to cat albumin or alpha-Gal, while being a more effective indicator of Fel d 1. (14) Epithelial extracts include multiple proteins present in the pelt, unlike extracts made from ‘dander’ only.14

Sensitization to alpha-Gal may occur through tick bites,(5-7) parasitic infestations,(8) parasitic infestations or exposure to cetuximab.(3,9) The association between tick bites, red meat allergy and IgE to alpha-Gal has been reported from four continents to date.(3,7)

In Europe, a history of tick bites has been reported in four of five patients with IgE antibodies to alpha-Gal from northern Spain, (26) and similarly, serum from Swedish patients with delayed severe reactions to red meat was found to have IgE antibodies to alpha-Gal.(3,7) The presence of the common European tick Ixodes ricinus in Stockholm has been demonstrated.(30) The Swedish study using serum from five Swedish patients with delayed severe reactions (anaphylaxis or urticaria) to red meat demonstrated raised IgE to alpha-Gal and beef, but no IgE to chicken, due to the absence of alpha-Gal.(7)

In Australia, a relationship was reported between red meat allergy, gelatin allergy, alpha-Gal sensitization and tick exposure, as well as tick-allergic patients with sensitization to red meat and alpha-Gal without necessarily having red meat allergy.(10) Specific IgE for alpha-Gal was raised in 20 of 24 patients with meat allergy, and in 20 of 22 patients with positive gelatin skin-test results. The results of gelatin skin-testing and anti-alpha-Gal IgE measurements were strongly correlated. alpha-Gal was detected in bovine gelatin colloids at concentrations of approximately 0.44 to 0.52 μg/g gelatin. Most patients allergic to red meat were sensitized to gelatin, and a subset was clinically allergic to both. The authors considered that the detection of alpha-Gal in gelatin and correlation between the results of alpha-Gal and gelatin testing raised the possibility that alpha-Gal IgE might be the target of reactivity to gelatin. Unlike other studies that have found a strong correlation between tick bites and alpha-Gal, the authors concluded that in this study, the pathogenic relationship between tick bites and sensitization to red meat, alpha-Gal, and gelatin (with or (without clinical reactivity) remained uncertain, although the detection of a-Gal in gelatin and correlation between the results of a-Gal and gelatin testing raise the possibility that a-Gal IgE might be the target of reactivity to gelatin,(10) although the detection of alpha-Gal in gelatin and the correlation between the results of alpha-Gal and gelatin testing raise the possibility that alpha-Gal IgE might be the target of reactivity to gelatin.(10)

A recent case report concurred with these findings. A 58-year-old hunter was described with a 10-year history of experiencing episodes of anaphylaxis (flush, urticaria, hypotension, diarrhea) during the night after consuming meat and entrails from beef, pork, and game. The most severe reactions started <3 hours after eating entrails. Symptoms started 3 to 8 hours after eating, and were elicited by exercise. Prick-to-prick skin-testing of pork meat, pork kidney, and beef kidney were positive. Total IgE was 595 kUA/L. Specific IgE to pork was 4 kUA/L, to beef 4.3 kUA/L, and to alpha-Gal 29.2 kUA/L. Tryptase was elevated. Oral challenge with cooked pork kidney (12g and 36g, separated by 2 hours) elicited a severe allergic reaction that included diarrhea and urticaria lasting 8 hours, with onset 1.5 hours after the last portion of pork kidney. Consumption of grilled beef (350g) resulted in mild, self-limiting, generalized urticaria occurring 7.5 hours later. In contrast, grilled pork (350 g) resulted in no allergic symptoms. However, provocation tests with grilled pork (350g) in combination with physical exercise 60 minutes after eating elicited urticaria 5 hours later. The patient also complained of recurring dizziness, abdominal pain, and diarrhea with delayed onset after ingestion of sweets (gums containing pork-derived gelatin). Prick-to-prick skin-testing of gelatin-containing gums and bovine gelatin-derived colloid showed neither was reactive. Specific IgE to gelatin was 0.04 kUA/L. An oral challenge test with 250g of gelatin-containing gums (corresponding to about 30g of gelatin), followed by physical exercise 60 minutes later, resulted (about 10 hours after ingestion) in flatulence and abdominal cramps, followed by flushing, tachycardia, and diarrhea. Physical exercise on its own was always tolerated by the patient. The authors conclude that gelatin-containing sweets can elicit type-I allergic symptoms in patients sensitized to alpha-Gal. The authors suggest that minimal amounts of gelatin in food or in medical products – for example, in capsules or pills – are unlikely to cause severe allergic reactions, but further analysis is warranted. The authors point out that in contrast to ingestion as the route of exposure, anaphylaxis will not be delayed but rather will occur within minutes.[iii]

A Japanese study investigated beef proteins that predominantly react with serum IgE, in Japanese patients with beef allergy. Sera collected from 29 patients with beef allergy, who had allergic reactions (urticaria, abdominal pain, vomiting, and anaphylactic shock) after ingestion of beef and pork, found raised IgE against beef and pork. Two IgE-binding proteins (240 kDa and 140 kDa) were detected in beef extract and identified as laminin gamma-1 and the collagen alpha-1 (VI) chain from Bos taurus, respectively. Further analysis demonstrated the presence of alpha-Gal on the 240- and 140-kDa beef proteins. Furthermore, the level of IgE bound to cetuximab was significantly correlated with that to beef in the patients with beef allergy.(29)

In Africa, although IgE to alpha-Gal has been identified in both adults and children, there was no evidence of delayed adverse reactions to mammalian meat.27

Recent evidence indicates that children may also experience anaphylaxis and urticaria occurring 3 to 6 hours after eating mammalian meat.(14) Pediatric patients with IgE antibodies to alpha-Gal and the characteristic delayed reactions to mammalian meat have been diagnosed. Unlike their adult counterparts, who frequently present with anaphylaxis, it has been our experience that the majority of children with this syndrome present with urticaria rather than acute episodes of delayed anaphylaxis.14 Similarly to those of adults, authors have noted, these cases may not be straightforward, and diagnosis is best confirmed by specific testing; and in this particular study, for children living in the area where the Lone Star tick is common.[iv]

alpha-Gal is also found in mammalian milk, as evidenced by positive immunoassay results to cow’s milk and goat’s milk; and therefore, in a patient over the age of 5 who has an apparent new-onset milk allergy, IgE antibodies to alpha-Gal should be considered as an alternative diagnosis to protein-based milk allergy.14

A number of studies are illustrative.

A 51-year-old woman reported two anaphylactic episodes that developed in the middle of the night, and several episodes of urticaria, some preceded by ingestion of red meat 3 to 6 hours before the reactions. Skin tests were negative to beef, pork, and environmental allergens. Serum-specific IgE to beef was 20.7 kUA/L; to pork, 15.5 kUA/L; lamb, 3.08 kUA/L; milk, 2.98 kUA/L; cat, 4.48 kUA/L; dog, 2.75 kUA/L; and shrimp, 1.32 kUA/L. Serum-specific IgE for bovine gelatin was <0.35, and for alpha-Gal, 88 IU/mL. The authors differentiate these delayed reactions from patients who have experienced significant local irritation and even urticaria that can occur soon after handling, preparing, or washing products that have had meat on them (or liquid from the meat).(5)

A 74-year-old woman developed anaphylaxis 5 hours after eating mammalian meat. She experienced delayed anaphylaxis following ingestion of roast beef, 2 months after being bitten by ticks. She also developed anaphylaxis 2 hours after drinking a glass of cow’s milk. Serum-specific IgE against beef was 2.46 kUA/mL, against pork 1.51 kUA/mL, mutton 2.61 kUA/mL, and milk 1.52 kUA/mL. A challenge with 50 g of roast chicken and roast pork resulted in swelling and redness of the face and generalized wheals 5 hours after eating pork, but no symptoms following ingestion of chicken. Allergy was attributed to alpha-Gal. Anaphylaxis after ingestion of milk was also attributed to the presence of alpha-Gal in milk.[v]

A study of 4 patients aged 44, 55, 55, and 67 years – 3 experiencing recurrent, severe, delayed anaphylactic reactions after the ingestion of red meat – described the benefit (because of the low sensitivity of skin-prick tests to meat) of performing skin-prick tests with cetuximab, which carries the alpha-Gal epitope. Skin-prick tests with commercial meat extracts were negative or equivocal. Low titers of specific IgE antibodies to red meat extracts were measured; in contrast, specific-IgE levels to alpha-Gal were 2.1, 4.2, 5.8, and 10.0 kUA/l, respectively. Skin-prick and intradermal tests with cetuximab were clearly positive in 2 of 2 patients.28

See Beef f27 for clinical information and further details on Beef allergy, Pork f26 for Pork allergy, and Mutton f88 for Mutton allergy.

Compiled by Dr Harris Steinman, harris@allergyadvisor.com

References

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  2. Commins SP, Satinover SM, Hosen J, Mozena J, Borish L, Lewis BD, Woodfolk JA, Platts-Mills TA. Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose. J Allergy Clin Immunol 2009;123(2):426-33.
  3. Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, Murphy BA, Satinover SM, Hosen J, Mauro D, Slebos RJ, Zhou Q, Gold D, Hatley T, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med 2008;358(11):1109-17.
  4. Macher BA, Galili U. The Galalpha1,3Galbeta1,4GlcNAc-R (alpha-Gal) epitope: a carbohydrate of unique evolution and clinical relevance. Biochim Biophys Acta 2008;1780(2):75-88.
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As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.