Food Allergy and Anaphylaxis Research (29)Allergic Rhinitis and Sensitization (17)Mast cells and histamine (11)Asthma and respiratory diseases (8)Contact Dermatitis and Allergies (7)
Current opinion in allergy and clinical immunology •
Alpha-gal syndrome (AGS) is a unique allergy to the carbohydrate galactose-alpha-1,3-galactose, which is found in mammalian products, excluding humans and Old World primates. As its prevalence increases, we are learning that AGS has broader geographical range and wider medical impact than initially recognized. Time to diagnosis has improved in recent years, but AGS still presents challenges for diagnosis and management, AGS may be found in a larger geographic distribution than originally supposed, and new potential arthropod triggers have been identified. Recent research demonstrates some of the immunologic changes that occur after arthropod bites that can lead to the production of alpha-gal IgE, but we still do not understand why certain individuals become allergic while others are only sensitized. Presentation can vary widely, and reactions may be inconsistent. The list of foods and medical products recognized to have potential for causing reactions continues to expand, which has implications for management of other conditions in patients with AGS. With the growing prevalence of AGS, it is increasingly important for clinicians to recognize the syndrome and understand its management.
Wang Y, Zhang Y, Dudley C, Fitzgerald K, Carson AS, et al.
The Journal of allergy and clinical immunology •
In alpha-gal syndrome (AGS), IgE antibodies form against the glycan galactose-α-1,3-galactose (alpha-gal) in mammal products rather than food proteins. Alpha-gal glycolipids and glycoproteins activate human basophils sensitized with AGS plasma in an IgE-dependent fashion. However, it is unknown whether alpha-gal specific IgE (sIgE), independent of other blood proteins, is sufficient for mediating basophil and mast cell activation. We sought to determine whether alpha-gal antigens could activate passively sensitized rat basophilic leukemia (RBL) SX-38 cells, which express human IgE receptors and are commonly used to model allergen/IgE-mediated mast cell activation in food protein allergy. Using the clustered regularly interspaced short palindromic repeats technology, we created a novel, alpha-gal-deficient RBL cell line, alpha-gal knockout RBL SX-38, passively sensitizing cells with sera from AGS donors or with novel alpha-gal sIgE clones, and then stimulated with alpha-gal glycoproteins. To assess effector cell activation, we measured cell surface expression of activation marker CD63 by flow cytometry and mediator release through β-hexosaminidase release assays. After alpha-gal antigen stimulation, the percentage of CD63 alpha-gal knockout RBL SX-38 cells sensitized with AGS sera increased 3-fold compared with cells sensitized with control serum. Select human AGS IgE clones facilitated alpha-gal antigen-dependent and antigen-independent CD63 upregulation. Cells sensitized with pooled AGS sera released β-hexosaminidase in an alpha-gal-independent fashion. We saw no β-hexosaminidase release above background in cells sensitized with alpha-gal sIgE clones. Certain alpha-gal-specific human IgE clones may partially activate allergic effector cells independent of antigen, potentially lowering thresholds for subsequent alpha-gal-induced or antigen-independent allergic effector cell degranulation. This may affect duration and severity of allergic symptoms in patients with AGS.
Kepley CL, Wang Y, Yelton A, Siebert ER, Iweala OI
Current allergy and asthma reports •
Alpha-gal syndrome (AGS) is a novel allergic disease characterized by hypersensitivity responses following exposure to the glycan galactose-alpha-1,3-galactose (alpha-gal or α-Gal) attached to mammalian proteins and fats in food, supplements, and medications. Bites from hard-bodied ticks, including Amblyomma americanum (Aa or lone star tick) in the United States, have been identified as drivers of allergic sensitization to alpha-gal. Here, we review clinical presentation, epidemiology, diagnosis, and current understanding of the mechanistic drivers of AGS, with particular focus on the roles of allergic effector cells - mast cells (MCs) and basophils. We explore unique clinical characteristics of AGS through the lens of alpha-gal-specific IgE and MC activation in AGS. We propose potential explanations for delayed symptom onset, inconsistent symptom development, and persistence of allergic symptoms in some AGS patients despite removing all mammal products from the diet. Current evidence implicate bites from hard-bodied ticks as the primary sensitizing agent in AGS. However, there is emerging evidence that other ecto- and endoparasites may also induce alpha-gal-specific IgE. Multiparameter flow and mass cytometry and RNA sequencing have demonstrated an enrichment of unique populations of T, B, invariant natural killer T (iNKT), natural killer B (NKB) and MC progenitor cells in human volunteers with AGS. Recently developed mouse models of AGS will support future studies to identify which cells are critical for the development of AGS. In vitro models of the allergic effector phase of AGS using human sera and novel human alpha-gal-specific IgE monoclonal antibodies in humanized rat allergic effector cell lines, human basophils, human MC lines, and primary human MC cultures, confirm alpha-gal-induced allergic effector cell activation. They also provide a system to study potential alpha-gal-antigen-independent drivers of MC activation in AGS. Efforts are ongoing to understand the epidemiology and immune mechanisms of AGS. Novel reagents (e.g. alpha-gal-specific monoclonal antibodies) and murine AGS models will facilitate deeper investigation of tick-driven, alpha-gal-specific IgE and allergic effector cell-induced pathology in AGS.
An estimated 7.6% of children and 10.8% of adults have IgE-mediated food-protein allergies in the US. IgE-mediated food allergies may cause anaphylaxis and death. A delayed, IgE-mediated allergic response to the food-carbohydrate galactose-α-1,3-galactose (alpha-gal) in mammalian meat affects an estimated 96 000 to 450 000 individuals in the US and is currently a leading cause of food-related anaphylaxis in adults. In the US, 9 foods account for more than 90% of IgE-mediated food allergies-crustacean shellfish, dairy, peanut, tree nuts, fin fish, egg, wheat, soy, and sesame. Peanut is the leading food-related cause of fatal and near-fatal anaphylaxis in the US, followed by tree nuts and shellfish. The fatality rate from anaphylaxis due to food in the US is estimated to be 0.04 per million per year. Alpha-gal syndrome, which is associated with tick bites, is a rising cause of IgE-mediated food anaphylaxis. The seroprevalence of sensitization to alpha-gal ranges from 20% to 31% in the southeastern US. Self-injectable epinephrine is the first-line treatment for food-related anaphylaxis. The cornerstone of IgE-food allergy management is avoidance of the culprit food allergen. There are emerging immunotherapies to desensitize to one or more foods, with one current US Food and Drug Administration-approved oral immunotherapy product for treatment of peanut allergy. IgE-mediated food allergies, including delayed IgE-mediated allergic responses to red meat in alpha-gal syndrome, are common in the US, and may cause anaphylaxis and rarely, death. IgE-mediated anaphylaxis to food requires prompt treatment with epinephrine injection. Both food-protein allergy and alpha-gal syndrome management require avoiding allergenic foods, whereas alpha-gal syndrome also requires avoiding tick bites.
-Gal syndrome, also known as red or mammalian meat allergy, results from immunoglobulin E-mediated hypersensitivity responses to the carbohydrate galactose--1,3-galactose (-gal). Patients with -gal syndrome experience immediate onset of allergic symptoms following the injection of pharmaceutical products containing -gal. However, it typically takes 2 hours or more after dietary -gal ingestion before patients with -gal syndrome experience immunoglobulin E-mediated hypersensitivity responses. The case report by Heffes-Doon and colleagues highlights the lack of official guidelines on when and how to reintroduce mammalian meat products into the diet when there is clear laboratory evidence of declining -gal immunoglobulin E levels.
Alpha-gal syndrome (AGS) describes a collection of symptoms associated with IgE-mediated hypersensitivity responses to the glycan galactose-alpha-1,3-galactose (alpha-gal). Individuals with AGS develop delayed hypersensitivity reactions, with symptoms occurring >2 h after consuming mammalian ("red") meat and other mammal-derived food products. The mechanisms of pathogenesis driving this paradigm-breaking food allergy are not fully understood. We review the role of tick bites in the development of alpha-gal-specific IgE and highlight innate and adaptive immune cells possibly involved in alpha-gal sensitization. We discuss the impact of alpha-gal glycosylation on digestion and metabolism of alpha-gal glycolipids and glycoproteins, and the implications for basophil and mast cell activation and mediator release that generate allergic symptoms in AGS.
Alpha-gal syndrome is an unconventional food allergy, characterized by IgE-mediated hypersensitivity responses to the glycan galactose-alpha-1,3-galactose (alpha-gal) and not to a food-protein. In this review, we discuss how alpha-gal syndrome reframes our current conception of the mechanisms of pathogenesis of food allergy. The development of alpha-gal IgE is associated with tick bites though the possibility of other parasites promoting sensitization to alpha-gal remains. We review the immune cell populations involved in the sensitization and effector phases of alpha-gal syndrome and describe the current understanding of why allergic responses to ingested alpha-gal can be delayed by several hours. We review the foundation of management in alpha-gal syndrome, namely avoidance, but also discuss the use of antihistamines, mast cell stabilizers, and the emerging role of complementary and alternative therapies, biological products, and oral immunotherapy in the management of this condition. Alpha-gal syndrome influences the safety and tolerability of medications and medical devices containing or derived from mammalian products and impacts quality of life well beyond food choices.
Alpha-gal syndrome (AGS) is characterized by delayed hypersensitivity to non-primate mammalian meat in people having specific immunoglobulin E (sIgE) to the oligosaccharide galactose-alpha-1,3-galactose. AGS has been linked to tick bites from Amblyomma americanum (Aa) in the U.S. A small animal model of meat allergy is needed to study the mechanism of alpha-gal sensitization, the effector phase leading to delayed allergic responses and potential therapeutics to treat AGS. Eight- to ten-weeks old mice with a targeted inactivation of alpha-1,3-galactosyltransferase (AGKO) were injected intradermally with 50 μg of Aa tick salivary gland extract (TSGE) on days 0, 7, 21, 28, 42, and 49. Total IgE and alpha-gal sIgE were quantitated on Day 56 by enzyme-linked immunosorbent assay. Mice were challenged orally with 400 mg of cooked pork kidney homogenate or pork fat. Reaction severity was assessed by measuring a drop in core body temperature and scoring allergic signs. Compared to control animals, mice treated with TSGE had 190-fold higher total IgE on Day 56 (0.60 ± 0.12 ng/ml vs. 113.2 ± 24.77 ng/ml; p < 0.001). Alpha-gal sIgE was also produced in AGKO mice following TSGE sensitization (undetected vs. 158.4 ± 72.43 pg/ml). Further, sensitized mice displayed moderate clinical allergic signs along with a drop in core body temperature of ≥2°C as an objective measure of a systemic allergic reaction. Interestingly, female mice had higher total IgE responses to TSGE treatment but male mice had larger declines in mean body temperature. TSGE-sensitized AGKO mice generate sIgE to alpha-gal and demonstrate characteristic allergic responses to pork fat and pork kidney. In keeping with the AGS responses documented in humans, mice reacted more rapidly to organ meat than to high fat pork challenge. This mouse model establishes the central role of tick bites in the development of AGS and provides a small animal model to mechanistically study mammalian meat allergy.