Hypersensitivity in the allergic setting refers to immune reactions, stimulated by soluble antigens that can be rapidly progressing and, in the case of anaphylaxis, are occasionally fatal. As the number of known exposures associated with anaphylaxis is limited, identification of novel causative agents is important in facilitating both education and other allergen-specific approaches that are crucial to long-term risk management. Within the last 10 years several seemingly separate observations were recognized to be related, all of which resulted from the development of antibodies to a carbohydrate moiety on proteins where exposure differed from airborne allergens but which were nevertheless capable of producing anaphylactic and hypersensitivity reactions. Our recent work has identified these responses as being due to a novel IgE antibody directed against a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal). This review will present the history and biology of alpha-gal and discuss our current approach to management of the mammalian meat allergy and delayed anaphylaxis.
IgE; alpha-gal; food allergy; mammalian meat
Galactose-alpha-1,3-Galactose (alpha-gal); perioperative anaphylaxis; porcine valve replacement; bovine valve replacement; heparin
In 2009, we reported a novel form of delayed anaphylaxis to red meat related to serum IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Although patients were remarkably consistent in their description of a 3- to 6-hour delay between eating mammalian meat and the appearance of symptoms, this delay has not been demonstrated under observed studies.
We sought to formally document the time course of clinical symptoms after the ingestion of mammalian meat in subjects with IgE to alpha-gal and to monitor ex vivo for the appearance of markers of an allergic reaction.
Open food challenges were performed with mammalian meat in 12 subjects with a history of severe urticarial reactions 3 to 6 hours after eating beef, pork, or lamb, as well as in 13 control subjects. Blood samples were taken hourly during each challenge.
Ten of 12 subjects with IgE to alpha-gal had clinical evidence of a reaction during the food challenge (vs none of the control subjects, P < .001). The reactions occurred 3 to 7 hours after the initial ingestion of mammalian meat and ranged from urticaria to anaphylaxis. Tryptase levels were positive in 3 challenges. Basophil activation, as measured by increased expression of CD63, correlated with the appearance of clinical symptoms.
The results presented provide clear evidence of an IgE-mediated food allergy that occurs several hours after ingestion of the inciting allergen. Moreover, here we report that in vivo basophil activation during a food challenge occurs in the same time frame as clinical symptoms and likely reflects the appearance of the antigen in the bloodstream. (J Allergy Clin Immunol 2014;)
Anaphylaxis; alpha-gal; basophil; mammalian meat; food allergy
IgE-mediated hypersensitivity refers to immune reactions that can be rapidly progressing and, in the case of anaphylaxis, are occasionally fatal. To that end, identification of the associated allergen is important for facilitating both education and allergen avoidance that are essential to long-term risk reduction. As the number of known exposures associated with anaphylaxis is limited, discovery of novel causative agents is crucial to evaluation and management of patients with idiopathic anaphylaxis. Within the last 10 years several apparently separate observations were recognized to be related, all of which resulted from the development of antibodies to a carbohydrate moiety on proteins. Interestingly, the exposure differed from airborne allergens but was nevertheless capable of producing anaphylactic and hypersensitivity reactions. Our recent work has identified these responses as being due to a novel IgE antibody directed against a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (“alpha-gal”). This review will present the historical summary of the identification of cetuximab hypersensitivity due to alpha-gal IgE and discuss the non-primate mammalian meat food allergy as well as current goals and directions of our research programs.
Alpha-gal; Delayed anaphylaxis; Glycan; IgE; Red meat allergy
Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal; thus, establishing the etiology of anaphylaxis 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 two distinct forms of anaphylaxis: i) immediate onset anaphylaxis during first exposure to intravenous cetuximab, and ii) delayed onset anaphylaxis 3–6 hours after ingestion of mammalian food products (e.g., 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, while 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.
anaphylaxis; delayed reaction to red meat; galactose-alpha-1; 3-galactose
Purpose of review
A novel form of anaphylaxis has been described that is due to IgE antibody (Ab) directed against a mammalian oligosaccharide epitope, galactose-alpha-1, 3-galactose (alpha-gal). Ongoing work regarding the cause and distribution of this IgE response is reviewed.
Our recent work has identified a novel IgE Ab response that has been associated with two distinct forms of anaphylaxis: immediate-onset anaphylaxis during first exposure to intravenous cetuximab and delayed-onset anaphylaxis 3–6 h after ingestion of mammalian food products (e.g. beef and pork). Further studies strongly suggested that tick bites were a cause, if not the only significant cause, of IgE Ab responses to alpha-gal in the United States and internationally.
Large numbers of patients with IgE Ab to alpha-gal continue to be identified in the USA and globally. Clinicians should be aware of this IgE response as the reactions often appear to be idiopathic because of the significant delay between eating mammalian meat and the appearance of symptoms.
alpha-gal; anaphylaxis; food allergy; IgE; mammalian meat; tick bites
BACKGROUND AND OBJECTIVE:
Despite a thorough history and comprehensive testing, many children who present with recurrent symptoms consistent with allergic reactions elude diagnosis. Recent research has identified a novel cause for “idiopathic” allergic reactions; immunoglobulin E (IgE) antibody specific for the carbohydrate galactose-α-1,3-galactose (α-Gal) has been associated with delayed urticaria and anaphylaxis that occurs 3 to 6 hours after eating beef, pork, or lamb. We sought to determine whether IgE antibody to α-Gal was present in sera of pediatric patients who reported idiopathic anaphylaxis or urticaria.
Patients aged 4 to 17 were enrolled in an institutional review board–approved protocol at the University of Virginia and private practice allergy offices in Lynchburg, VA. Sera was obtained and analyzed by ImmunoCAP for total IgE and specific IgE to α-Gal, beef, pork, cat epithelium and dander, Fel d 1, dog dander, and milk.
Forty-five pediatric patients were identified who had both clinical histories supporting delayed anaphylaxis or urticaria to mammalian meat and IgE antibody specific for α-Gal. In addition, most of these cases had a history of tick bites within the past year, which itched and persisted.
A novel form of anaphylaxis and urticaria that occurs 3 to 6 hours after eating mammalian meat is not uncommon among children in our area. Identification of these cases may not be straightforward and diagnosis is best confirmed by specific testing, which should certainly be considered for children living in the area where the Lone Star tick is common.
α-Gal; galactose-α-1,3-galactose; delayed anaphylaxis; pediatric urticaria
cat serum albumin; food allergy; pork
Anaphylaxis is traditionally recognized as a rapidly developing combination of symptoms often including hives and hypotension or respiratory symptoms. Furthermore, when a specific cause is identified, exposure to this cause is usually noted to have occurred within minutes to 2 hours before the onset of symptoms. This case is of a 79 year-old female who developed a severe episode of anaphylaxis 3 hours after eating pork. Prior to 2012, she had not experienced any symptoms after ingestion of meat products. Delayed anaphylaxis to mammalian meat has many contrasting features to immediate food-induced anaphylaxis. The relevant IgE antibody is specific for the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal), a blood group substance of non-primate mammals. Evidence from Australia, Sweden, and the U.S. demonstrates that the primary cause of this IgE antibody response is tick bites. These bites characteristically itch for ten days or more. Diagnosis can be made by the presence of specific IgE to beef, pork, lamb, and milk and lack of IgE to chicken, turkey, and fish. Prick skin tests (but not intradermal tests) are generally negative. Management of these cases, now common across the southeastern U.S., consists of education combined with avoidance of both red meat and further tick bites.
Anaphylaxis; delayed reaction to red meat; galactose-alpha-1,3-galactose
New allergic diseases can “emerge” because of exposure to a novel antigen, because the immune responsiveness of the subject changes, or because of a change in the behavior of the population. Novel antigens have entered the environment as new pests in the home (e.g., Asian lady beetle or stink bugs), in the diet (e.g., prebiotics or wheat isolates), or because of the spread of a biting arthropod (e.g., ticks). Over the last few years, a significant new disease has been identified, which has changed the paradigm for food allergy. Bites of the tick, Amblyomma americanum, are capable of inducing IgE antibodies to galactose-alpha-1,3-galactose, which is associated with two novel forms of anaphylaxis. In a large area of the southeastern United States, the disease of delayed anaphylaxis to mammalian meat is now common. This disease challenges many previous rules about food allergy and provides a striking model of an emerging allergic disease.
Anaphylaxis is a severe allergic reaction that can be rapidly progressing and occasionally fatal. In instances where the triggering allergen is not obvious, establishing the etiology of anaphylaxis is pivotal to long-term management. Assigning etiology is limited, however, by the number of known exposures associated with anaphylaxis. Therefore, identification of novel causative agents can provide an important step forward in facilitating new, allergen specific approaches to management. In contrast to the view that carbohydrate-directed IgE has minimal, if any, clinical significance, recent data suggests that IgE antibodies to carbohydrate epitopes can be an important factor in anaphylaxis that may otherwise appear to be idiopathic. Specifically, IgE antibodies to the carbohydrate galactose-α-1,3-galactose (alpha-gal) were found to be capable of eliciting serious, even fatal, reactions to the monoclonal antibody (ab) cetuximab.1 Moreover, alpha-gal has recently been identified as a novel food allergen.2 Patients who have IgE to alpha-gal report delayed anaphylaxis or urticaria occurring 3-6 hours after eating beef, pork or lamb. Here, we review the evidence relating to carbohydrates in food allergy and anaphylaxis and discuss the implications of a new mammalian cross-reactive carbohydrate determinant (CCD).
anaphylaxis; cross-reactive carbohydrate determinant (CCD); alpha-gal; glycosylation
Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal. In instances where the triggering allergen is not known, establishing the etiology of anaphylaxis is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody (Ab) response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal), that has been associated with two distinct forms of anaphylaxis: (1) immediate onset anaphylaxis during first exposure to intravenous cetuximab, and (2) delayed onset anaphylaxis 3–6 h after ingestion of mammalian food products (e.g., beef and pork). The results of our studies strongly suggest that tick bites are a cause, if not the only significant cause, of IgE Ab responses to alpha-gal in the southern, eastern and central United States. Patients with IgE Ab to alpha-gal continue to emerge and, increasingly, these cases involve children. This IgE Ab response cross-reacts with cat and dog but does not appear to pose a risk for asthma; however, it may impair diagnostic testing in some situations.
Anaphylaxis; Delayedanaphylaxis; Alpha-gal; Galactose; Food allergy; IgE; Mammalian meat; Tick bites; Asthma; Red meat
In recent years, a newly recognized allergic disease has been uncovered, and seemingly idiopathic causes of anaphylaxis now have an explanation. Individuals bitten by the lone star tick may develop IgE antibodies to the carbohydrate galactose-α-1,3-galactose (alpha-gal). Upon exposure of sensitized subjects to mammalian meat containing alpha-gal on glycoproteins or glycolipids, delayed anaphylaxis may ensue, often three to six hours after ingestion.1 Many of these individuals have negative allergy skin prick tests to meat, further obscuring the diagnosis. With the recent development of IgE alpha-gal tests, the clinical diagnosis can be confirmed in the laboratory.
allergy; anaphylaxis; immunology; tick; meat
IgE antibodies to gal-α-1,3-gal-β-1,4-GlcNAc (α-gal) can mediate a novel form of delayed anaphylaxis to red meat. Although IgG antibodies to α-gal (anti-α-gal or anti-Gal) are widely expressed in humans, IgE anti-α-gal is not. We explored the relationship between the IgG and IgE responses to both α-gal and the related blood group B antigen. Contradicting previous reports, antibodies to α-gal were found to be significantly less abundant in individuals with blood group B or AB. Importantly, we established a connection between IgE and IgG responses to α-gal: elevated titers of IgG anti-α-gal were found in IgE-positive subjects. In particular, proportionally more IgG1 anti-α-gal was found in IgE-positive subjects against a background of IgG2 production specific for α-gal. Thus, two types of immune response to α-gal epitopes can be distinguished: a ‘typical’ IgG2 response, presumably in response to gut bacteria, and an ‘atypical’, Th2-like response leading to IgG1 and IgE in addition to IgG2. These results suggest that IgE to a carbohydrate antigen can be formed (probably as part of a glycoprotein or glycolipid) even against a background of bacterial immune stimulation with essentially the same antigen.
Rationale: IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose (α-gal) are common in the southeastern United States. These antibodies, which are induced by ectoparasitic ticks, can give rise to positive skin tests or serum assays with cat extract.
Objectives: To evaluate the relationship between IgE antibodies to α-gal and asthma, and compare this with the relationship between asthma and IgE antibodies to Fel d 1 and other protein allergens.
Methods: Patients being investigated for recurrent anaphylaxis, angioedema, or acute urticaria underwent spirometry, exhaled nitric oxide, questionnaires, and serum IgE antibody assays. The results were compared with control subjects and cohorts from the emergency department in Virginia (n = 130), northern Sweden (n = 963), and rural Kenya (n = 131).
Measurements and Main Results: Patients in Virginia with high-titer IgE antibodies to α-gal had normal lung function, low levels of exhaled nitric oxide, and low prevalence of asthma symptoms. Among patients in the emergency department and children in Kenya, there was no association between IgE antibodies to α-gal and asthma (odds ratios, 1.04 and 0.75, respectively). In Sweden, IgE antibodies to cat were closely correlated with IgE antibodies to Fel d 1 (r = 0.83) and to asthma (P < 0.001).
Conclusions: These results provide a model of an ectoparasite-induced specific IgE response that can increase total serum IgE without creating a risk for asthma, and further evidence that the main allergens that are causally related to asthma are those that are inhaled.
α-gal; red meat allergy; ticks; total serum IgE; ectoparasite
Carbohydrate moieties are frequently encountered in food and can elicit IgE responses, the clinical significance of which has been unclear. Recent work, however, has shown that IgE antibodies to galactose-α-1,3-galactose (α-gal), a carbohydrate commonly expressed on nonprimate mammalian proteins, are capable of eliciting serious, even fatal, reactions.
We sought to determine whether IgE antibodies to α-gal are present in sera from patients who report anaphylaxis or urticaria after eating beef, pork, or lamb.
Detailed histories were taken from patients presenting to the University of Virginia Allergy Clinic. Skin prick tests (SPTs), intradermal skin tests, and serum IgE antibody analysis were performed for common indoor, outdoor, and food allergens.
Twenty-four patients with IgE antibodies to α-gal were identified. These patients described a similar history of anaphylaxis or urticaria 3 to 6 hours after the ingestion of meat and reported fewer or no episodes when following an avoidance diet. SPTs to mammalian meat produced wheals of usually less than 4 mm, whereas intradermal or fresh-food SPTs provided larger and more consistent wheal responses. CAP-RAST testing revealed specific IgE antibodies to beef, pork, lamb, cow’s milk, cat, and dog but not turkey, chicken, or fish. Absorption experiments indicated that this pattern of sensitivity was explained by an IgE antibody specific for α-gal.
We report a novel and severe food allergy related to IgE antibodies to the carbohydrate epitope α-gal. These patients experience delayed symptoms of anaphylaxis, angioedema, or urticaria associated with eating beef, pork, or lamb.
Anaphylaxis; urticaria; food allergy; galactose-α-1; 3-galactose; cross-reactive carbohydrate determinant
In 2009, we reported a novel form of delayed anaphylaxis to red meat, which is related to serum IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Most of these patients had tolerated meat for many years previously. The implication is that some exposure in adult life had stimulated the production of these IgE antibodies.
To investigate possible causes of this IgE antibody response, focusing on evidence related to tick bites, which are common in the region where these reactions occur.
Serum assays were carried out using biotinylated proteins and extracts bound to a streptavidin ImmunoCAP.
Prospective studies on IgE antibodies in three subjects following tick bites showed an increase in IgE to alpha-gal of twenty-fold or greater. Other evidence included i) a strong correlation between histories of tick bites and IgE to alpha-gal (χ2=26.8, p<0.001), ii) evidence that these IgE antibodies are common in areas where the tick Amblyomma americanum is common, and iii) a significant correlation between IgE antibodies to alpha-gal and IgE antibodies to proteins derived from A. americanum (rs=0.75, p<0.001).
The results presented here provide evidence that tick bites are a cause, or possibly the only cause, of IgE specific for alpha-gal in this area of the United States. Both the number of subjects becoming sensitized and the titer of IgE antibodies to alpha-gal are striking. Here we report the first example of a response to an ectoparasite giving rise to an important form of food allergy.
ticks; anaphylaxis; oligosaccharide; alpha-gal; IgE antibody to CCD
The IgE response to pollen allergens often includes IgE antibodies specific for glycosylation motifs on the pollen proteins. These oligosaccharides are present on many different species and are known as cross-reactive carbohydrate determinants. However, IgE antibodies to plant-derived cross-reactive carbohydrate determinants seem to have only minor clinical significance and have not been related to anaphylaxis. Recently, two novel forms of anaphylaxis have become apparent in the southeastern United States: 1) reactions during the first infusion of the monoclonal antibody cetuximab and 2) adult-onset delayed anaphylaxis to red meat. Detailed investigation of serum antibodies established that in both cases, the patients had IgE antibodies specific for the mammalian oligosaccharide galactose alpha-1, 3-galactose. Identification of these cases is helpful in avoiding infusion reactions to cetuximab or recommending specific avoidance of meat derived from mammals. However, the current evidence does not fully resolve why these IgE antibodies are so common in the Southeast or why the anaphylactic or urticarial reactions to red meat are delayed.
Anaphylaxis; Oligosaccharides; Cross-reactive Carbohydrate Determinants; Red Meat; IgE to Alpha-Gal