van Hage M

IgE And IgG Antibody Responses to α-Gal and Association With Carotid Stenosis in Swedish Patients.

Increasing prevalence of galactose-α-1,3-galactose sensitization in the Danish general adult population.

Alpha-gal syndrome is a novel food allergy to the oligosaccharide galactose-α-1,3-galactose (alpha-gal) present in mammalian meat. Tick bites are considered an important route of sensitization to alpha-gal. Data on alpha-gal sensitization in the general population is scant. We utilized a unique data source of repeated population-based health examination studies to assess prevalence, time trends, risk factors, and characteristics of alpha-gal sensitization. Alpha-gal sensitization was assessed in >11.000 adults from four health examination studies of randomly invited residents in the Copenhagen region conducted in 1990-1991, 2011-2012, 2012-2015, and 2016-2017. Alpha-gal sensitization was defined as serum specific IgE (sIgE) to alpha-gal ≥0.1 kU/L; ≥0.35 kU/L; ≥0.7 kU/L; ≥3.5 kU/L. The population was characterized according to genetically determined ABO blood group, aeroallergen sensitization, and pets at home. The prevalence of sIgE to alpha-gal ≥0.1 kUA/L was 1.3% in 1990-1991, 3.7% in 2012-2015 and 3.2% in 2016-2017. Of those sensitized to alpha-gal >97% reported to consume red meat at least once a week, even for sIgE to alpha-gal ≥3.5 kU/L. Male sex, older age, aeroallergen sensitization, cat at home, and blood group A were associated with increased odds of alpha-gal sensitization. The known protective effect of blood group B was confirmed. In this general adult population, the prevalence of alpha-gal sensitization had doubled from 1990-1991 to 2016-2017. This could potentially be due to increased tick exposure and an increased atopic predisposition.

Allergenic potency of various foods of mammalian origin in patients with α-Gal syndrome.

The α-Gal syndrome (AGS) is an emerging allergy to mammalian food caused by IgE-mediated reactions to the carbohydrate galactose-α-1,3-galactose (α-Gal). Mammalian food sources contain α-Gal, but the amount differs. The objective of this study was to investigate the allergenic potency of various foods of mammalian origin among AGS patients. Twenty-six AGS patients were included. Food extracts from innards, lean meats, processed meat products, milk, and whey were analyzed. Immunoblot, ELISA, immunofluorescence, and basophil activation test were used to determine the α-Gal content, characterize IgE binding, and assess foods' allergenicity. The determined amount of α-Gal, IgE reactivity to food extracts, and food extract potencies to activate patients' basophils correlated well with each other. Pork and beef kidney showed the highest allergenicity. Beef liver and bacon showed allergenicity comparable to that of lean meats. Game meat seemed to have a higher allergenic potency than meats from farm-raised animals. The processed meat products liver pâté and black pudding, despite lower α-Gal content, demonstrated moderate allergenicity. Milk showed the lowest allergenicity. IgE reactivity to food extracts was highly similar for all patients and strongly dominated by the α-Gal epitope. The allergenic potency of mammalian meat depends on the origin of the meat, the different cuts, and type of processing, with innards posing the greatest risk to AGS patients. Even processed mammalian meat constitutes a risk. Dairy products show the lowest risk. This study highlights the importance of analyzing even more foods to improve the management of AGS.

Living close to the forest is a risk factor for galactose-α-1,3-galactose sensitization.

The α-gal syndrome is a food allergy to galactose-α-1,3-galactose present in mammalian meat; it usually develops after tick bites. Despite being considered an emerging health problem, little is known about the geographic risk factors and patterns of α-gal sensitization. The aim of this study was to assess geographic clusters of α-gal sensitization and determine whether distance from home address to the forest and tick abundance are risk factors for α-gal sensitization in a Danish adult population. We utilized 3 population-based health examination studies that were conducted in 2011-2017 and covered a total of 8742 participants living in a suburban area. All participants were screened for a level of serum-specific IgE to α-gal of 0.1 kU/L or higher. Their home addresses were linked with CORINE Land Cover data and a tick prediction model. The associations of (1) distance to the forest and (2) tick abundance with α-gal sensitization were assessed by using multivariable logistic regression. There were 344 cases of galactose-α-1,3-galactose-specific IgE level being 0.1 kU/L; we identified 1 geographic cluster of cases. For every 1 km closer a participant lived to the forest, the odds ratio of α-gal sensitization was 1.09 (95% CI = 1.05-1.13). There were no associations between predicted tick nymph abundance and α-gal sensitization. In a general, individuals residing in a suburban area had 9% higher odds of being sensitized to α-gal the closer they lived to a forest, thus supporting exposure to ticks as a risk factor for sensitization to α-gal.

A case of alpha-gal syndrome: Recall urticaria and 10 years of measurements of IgE to galactose-α-1,3-galactose.

Alpha-gal IgE level can change rapidly. Reassessment of a patient's alpha-gal IgE level may be helpful in the patient's clinical follow-up. Pruritus related to the site of a previous tick bite strengthens the diagnosis of alpha-gal syndrome.

The α-Gal epitope - the cause of a global allergic disease.

The galactose-α-1,3-galactose (α-Gal) epitope is the cause of a global allergic disease, the α-Gal syndrome (AGS). It is a severe form of allergy to food and products of mammalian origin where IgE against the mammalian carbohydrate, α-Gal, is the cause of the allergic reactions. Allergic reactions triggered by parenterally administered α-Gal sources appear immediately, but those triggered via the oral route appear with a latency of several hours. The α-Gal epitope is highly immunogenic to humans, apes and old-world monkeys, all of which produce anti-α-Gal antibodies of the IgM, IgA and IgG subclasses. Strong evidence suggests that in susceptible individuals, class switch to IgE occurs after several tick bites. In this review, we discuss the strong immunogenic role of the α-Gal epitope and its structural resemblance to the blood type B antigen. We emphasize the broad abundance of α-Gal in different foods and pharmaceuticals and the allergenicity of various α-Gal containing molecules. We give an overview of the association of tick bites with the development of AGS and describe innate and adaptive immune response to tick saliva that possibly leads to sensitization to α-Gal. We further discuss a currently favored hypothesis explaining the mechanisms of the delayed effector phase of the allergic reaction to α-Gal. We highlight AGS from a clinical point of view. We review the different clinical manifestations of the disease and the prevalence of sensitization to α-Gal and AGS. The usefulness of various diagnostic tests is discussed. Finally, we provide different aspects of the management of AGS. With climate change and global warming, the tick density is increasing, and their geographic range is expanding. Thus, more people will be affected by AGS which requires more knowledge of the disease.

Th2-skewed T cells correlate with B cell response to α-Gal and tick antigens in α-Gal syndrome.

Tick bites have been shown to transmit a novel form of severe food allergy, the galactose-α-1,3-galactose (α-Gal) syndrome (AGS). Cellular responses to α-Gal in patients with AGS have, to date, not been thoroughly scrutinized. Therefore, we investigated T and B cell proliferation, activation, and cytokine profiles in response to tick protein extract (TE) and α-Gal-free TE in patients with AGS and in healthy controls. T and B cells from both patients and controls proliferated in response to TE, but significantly more in patients with AGS. B cell proliferation, but not T cell proliferation, in patients with AGS was reduced by removing α-Gal from the TE. In addition, TE induced a clear Th2 cytokine profile in patients with AGS. Expression of CD23 by B cells correlated only to T cell proliferation. However, both B cell proliferation and CD23 expression were reduced when CD40L and IL-4 were blocked. A large portion of the IgG1 and IgE antibodies binding TE in patients with AGS were directed against the α-Gal epitope. We have, for what we believe to be the first time, investigated T and B cell responses to α-Gal carrying tick proteins in patients with AGS, which will be essential for the understanding of the immune response against an allergenic carbohydrate transmitted by ticks.

Cross-reactivity between tick and wasp venom can contribute to frequent wasp sensitization in patients with the α-Gal syndrome.

α-Gal syndrome (AGS) is a food allergy with severe delayed allergic reactions, mediated by IgE-reactivity to galactose-α1,3-galactose (α-Gal). AGS is strongly associated with tick bites. An increased incidence of venom sensitization has been found in AGS patients. Here, we evaluated the frequency of wasp sensitization in Swedish AGS patients and the possible cross-reactivity between wasp venom and tick proteins. Sera from 136 Swedish AGS patients and 29 wasp-positive non-AGS control sera were analyzed for IgE-reactivity against wasp venom ( spp.), the European tick (Streptavidin ImmunoCAP), α-Gal and total IgE by ImmunoCAP. The presence of α-Gal on wasp venom proteins () was investigated by western blot (WB), and possible cross-reactivity between wasp venom and tick proteins by enzyme-linked immunosorbent assay and WB. Involvement of cross-reactive carbohydrate domains (CCDs) was also assessed. Wasp sensitization was present in 54% of AGS patients, although the IgE levels were low. Wasp sensitized patients had higher IgE levels to α-Gal and total IgE levels compared to non-wasp sensitized AGS patients. α-Gal was not detected in wasp venom, but cross-reactivity between wasp and tick proteins was demonstrated which was not dependent on CCDs. The same cross-reactivity was also observed in the control sera. Furthermore, 17 putative cross-reactive peptides were identified using an approach. For the first time, cross-reactivity between wasp venom and tick proteins has been described. This may be a reason why the majority of Swedish AGS patients, who have all been tick bitten, are also sensitized against wasp.

Alpha-gal sensitization among young adults is associated with male sex and polysensitization.

Course of IgE to α-Gal in a Swedish population of α-Gal syndrome patients.

Bovine γ-globulin, lactoferrin, and lactoperoxidase are relevant bovine milk allergens in patients with α-Gal syndrome.

Mammalian meat is the most common trigger of the allergic reactions in patients with α-Gal syndrome (AGS). Milk and dairy, although less often, also cause a significant number of allergic manifestations. The aim of this study was to identify α-Gal-containing bovine milk proteins with allergenic properties among AGS patients. Thirty-eight AGS patients with IgE to milk were included in the study. Milk proteins were analyzed for the presence of α-Gal and for binding by patients' IgE using immunoblot, ImmunoCAP, and inhibition ELISA. Allergenicity of milk and milk proteins was assessed by basophil activation test. More than half of the AGS patients reported allergic reactions to milk or dairy products. Bovine γ-globulin (BGG), lactoferrin (LF), and lactoperoxidase (LPO) were identified as α-Gal carrying proteins which were recognized by AGS patients' IgE. Whey mirrored the anti-α-Gal and IgE reactivity of BGG, LF, and LPO. Eighty-nine percent of the patients displayed IgE to BGG, 91% to LF, and 57% to LPO. Inhibition of α-Gal-specific IgE binding was achieved by BGG, LF, LPO, and whey. These proteins also activated AGS patients' basophils. Interestingly, at lower concentrations, LF was the most potent inhibitor of IgE binding, and the most potent activator of basophils. BGG, LF, and LPO were all found to be relevant milk α-Gal-containing glycoproteins that bound AGS patients' IgE antibodies and activated their basophils. These proteins are probably involved in the allergic reactions to milk in AGS patients. LPO was for the first time shown to be an allergen.

Carbohydrate epitopes currently recognized as targets for IgE antibodies.

Until recently, glycan epitopes have not been documented by the WHO/IUIS Allergen Nomenclature Sub-Committee. This was in part due to scarce or incomplete information on these oligosaccharides, but also due to the widely held opinion that IgE to these epitopes had little or no relevance to allergic symptoms. Most IgE-binding glycans recognized up to 2008 were considered to be "classical" cross-reactive carbohydrate determinants (CCD) that occur in insects, some helminths and throughout the plant kingdom. Since 2008, the prevailing opinion on lack of clinical relevance of IgE-binding glycans has been subject to a reevaluation. This was because IgE specific for the mammalian disaccharide galactose-alpha-1,3-galactose (alpha-gal) was identified as a cause of delayed anaphylaxis to mammalian meat in the United States, an observation that has been confirmed by allergists in many parts of the world. Several experimental studies have shown that oligosaccharides with one or more terminal alpha-gal epitopes can be attached as a hapten to many different mammalian proteins or lipids. The classical CCDs also behave like haptens since they can be expressed on proteins from multiple species. This is the explanation for extensive in vitro cross-reactivity related to CCDs. Because of these developments, the Allergen Nomenclature Sub-Committee recently decided to include glycans as potentially allergenic epitopes in an adjunct section of its website (www.allergen.org). In this article, the features of the main glycan groups known to be involved in IgE recognition are revisited, and their characteristic structural, functional, and clinical features are discussed.