α-Gal Syndrome Research Articles

Diagnosis and Management of Patients with the α-Gal Syndrome

The galactose-α-1,3-galactose (α-Gal) syndrome has many novel features that are relevant to diagnosis and management. In most cases, the diagnosis can be made on a history of delayed allergic reactions to mammalian meat and the blood test for IgE to the oligosaccharide α-Gal. In general, the diagnosis also dictates the primary treatment, that is, avoiding mammalian meat and also dairy in some cases. In the United States, the lone star tick is the primary cause of this disease, but different ticks are responsible in other countries. Blood levels of IgE to α-Gal often drop in patients who avoid recurrent tick bites, but the rate of decline is variable. Similarly, the delay before reactions is variable and the severity of the allergic reactions is not predicted by the delay or the titer of specific IgE. Some mammalian-derived products such as heart valves, gelatin-based plasma expanders, and pancreatic enzymes are relevant to only select patient groups. A minority of cases may benefit from avoiding a wide range of products that are prepared with mammalian-derived constituents, such as gelatin. This review focuses on the nature of the syndrome, common challenges in diagnosis and management, and also gaps in our current knowledge that would benefit from additional investigation.

Delayed hypersensitivity reaction to mammalian galactose-α-1,3-galactose (α-Gal) after repeated tick bites in a patient from France

The α-Gal syndrome is a tick-associated and emerging IgE-mediated hypersensitivity reaction directed against the carbohydrate Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal) epitope after red meat intake. Herein, we describe a clinical case of a 44-year-old French patient who suffered from recurrent anaphylactic reactions after mammalian meat consumption for five years before the final diagnosis of the α-Gal syndrome was established in 2018. The patient also reported multiple tick bites prior to symptom onset. This unique type of allergy has increasingly been reported across the world, but it is still unknown in many European countries. Therefore, the present clinical case should increase awareness among primary care practitioners and further improve the early diagnosis of the α-Gal syndrome in affected individuals.

Environmental and Molecular Drivers of the α-Gal Syndrome.

The α-Gal syndrome (AGS) is a type of allergy characterized by an IgE antibody (Ab) response against the carbohydrate Galα1-3Galβ1-4GlcNAc-R (α-Gal), which is present in glycoproteins from tick saliva and tissues of non-catarrhine mammals. Recurrent tick bites induce high levels of anti-α-Gal IgE Abs that mediate delayed hypersensitivity to consumed red meat products in humans. This was the first evidence that tick glycoproteins play a major role in allergy development with the potential to cause fatal delayed anaphylaxis to α-Gal-containing foods and drugs and immediate anaphylaxis to tick bites. Initially, it was thought that the origin of tick-derived α-Gal was either residual blood meal mammalian glycoproteins containing α-Gal or tick gut bacteria producing this glycan. However, recently tick galactosyltransferases were shown to be involved in α-Gal synthesis with a role in tick and tick-borne pathogen life cycles. The tick-borne pathogen Anaplasma phagocytophilum increases the level of tick α-Gal, which potentially increases the risk of developing AGS after a bite by a pathogen-infected tick. Two mechanisms might explain the production of anti-α-Gal IgE Abs after tick bites. The first mechanism proposes that the α-Gal antigen on tick salivary proteins is presented to antigen-presenting cells and B-lymphocytes in the context of Th2 cell-mediated immunity induced by tick saliva. The second mechanism is based on the possibility that tick salivary prostaglandin E2 triggers Immunoglobulin class switching to anti-α-Gal IgE-producing B cells from preexisting mature B cells clones producing anti-α-Gal IgM and/or IgG. Importantly, blood group antigens influence the capacity of the immune system to produce anti-α-Gal Abs which in turn impacts individual susceptibility to AGS. The presence of blood type B reduces the capacity of the immune system to produce anti-α-Gal Abs, presumably due to tolerance to α-Gal, which is very similar in structure to blood group B antigen. Therefore, individuals with blood group B and reduced levels of anti-α-Gal Abs have lower risk to develop AGS. Specific immunity to tick α-Gal is linked to host immunity to tick bites. Basophil activation and release of histamine have been implicated in IgE-mediated acquired protective immunity to tick infestations and chronic itch. Basophil reactivity was also found to be higher in patients with AGS when compared to asymptomatic α-Gal sensitized individuals. In addition, host resistance to tick infestation is associated with resistance to tick-borne pathogen infection. Anti-α-Gal IgM and IgG Abs protect humans against vector-borne pathogens and blood group B individuals seem to be more susceptible to vector-borne diseases. The link between blood groups and anti-α-Gal immunity which in turn affects resistance to vector-borne pathogens and susceptibility to AGS, suggests a trade-off between susceptibility to AGS and protection to some infectious diseases. The understanding of the environmental and molecular drivers of the immune mechanisms involved in AGS is essential to developing tools for the diagnosis, control, and prevention of this growing health problem.

Investigation into the α-Gal Syndrome: Characteristics of 261 Children and Adults Reporting Red Meat Allergy

Red meat allergy has historically been understood as a rare disease of atopic children, but the discovery of the "α-Gal syndrome," which relates to IgE to the oligosaccharide galactose-α-1,3-galactose (α-Gal), has challenged that notion. To describe the clinical and immunologic characteristics of a large group of subjects with self-reported allergy to mammalian meat. This was an observational study of 261 children and adults (range, 5-82 years) who presented for evaluation for allergic reactions to mammalian meat. Results were based on serum assays and a detailed questionnaire. α-Gal specific IgE ≥ 0.35 IU/mL was detected in 245 subjects and symptom onset occurred ≥2 hours after eating mammalian meat in 211 (81%). Component testing supported a diagnosis of α-Gal syndrome in 95%, pork-cat syndrome in 1.9%, and primary beef allergy in 1.1%. Urticaria was reported by 93%, anaphylaxis by 60%, and gastrointestinal symptoms by 64%. Levels of IgE and IgG specific to α-Gal were similar in subjects who reported early- or delayed-onset symptoms, and in those with and without anaphylaxis. Levels of α-Gal specific IgE and severity of reactions were similar among those with and without traditional atopy, and among children (n= 35) and adults (n= 226). Blood group B trended toward being under-represented among α-Gal-sensitized subjects; however, α-Gal specific IgE titers were high in symptomatic cases with B-antigen. The α-Gal syndrome is a regionally common form of food allergy that has a characteristic but not universal delay in symptom onset, includes gastrointestinal symptoms, can develop at any time in life, and is equally common in otherwise nonatopic individuals.

Investigation into the α-Gal syndrome: Characteristics of a large cohort sensitized to galactose-α-1,3-galactose (α-Gal)

Investigation into the α-Gal syndrome: Characteristics of a large cohort sensitized to galactose-α-1,3-galactose (α-Gal)

Drugs of porcine origin—A risk for patients with α-gal syndrome?

Drugs of porcine origin—A risk for patients with α-gal syndrome?

GALACTOSE-A-1,3-GALACTOSE SENSITIZATION AND THE A-GAL SYNDROME: CHARACTERISTICS OF SUBJECTS SEEKING EMERGENCY CARE

Introduction Galactose -α-1,3- galactose (α-Gal) is an oligosaccharide of non-primate mammals and the culprit allergen in a syndrome of delayed anaphylaxis to mammalian meat (ie, α-Gal syndrome). We sought to describe the clinical presentations of a large cohort of subjects from Central Virginia, with or without IgE to α-Gal, who presented for emergent care for allergic reactions. Methods A detailed questionnaire regarding clinical reactions was completed by patients who received care at a Virginia allergy clinic and who reported a history of anaphylaxis or urticaria. Many, but not all, related their reactions to mammalian meat. Serum was obtained and total IgE and α-Gal specific IgE (sIgE) were measured by ImmunoCAP. Results Of 408 patients who completed the survey, 224 had sought urgent care (195 of which were in the emergency department) for allergic reactions. Of these, 191 were α-Gal sIgE positive, of whom 82% perceived an association between consumption of mammalian meat and allergic symptoms. When compared to non-sensitized subjects, α-Gal sensitized subjects were more commonly male (45% vs. 18%, p2 hours after a perceived trigger (82% vs. 25%, p Conclusions The α-Gal syndrome is commonly adult-onset, has a characteristic delay of onset >2 hours following mammalian meat ingestion, and frequently results in presentation for emergent medical care.

Tick galactosyltransferases are involved in \u03b1-Gal synthesis and play a role during Anaplasma phagocytophilum infection and Ixodes scapularis tick vector development

The carbohydrate Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal) is produced in all mammals except for humans, apes and old world monkeys that lost the ability to synthetize this carbohydrate. Therefore, humans can produce high antibody titers against α-Gal. Anti-α-Gal IgE antibodies have been associated with tick-induced allergy (i.e. α-Gal syndrome) and anti-α-Gal IgG/IgM antibodies may be involved in protection against malaria, leishmaniasis and Chagas disease. The α-Gal on tick salivary proteins plays an important role in the etiology of the α-Gal syndrome. However, whether ticks are able to produce endogenous α-Gal remains currently unknown. In this study, the Ixodes scapularis genome was searched for galactosyltransferases and three genes were identified as potentially involved in the synthesis of α-Gal. Heterologous gene expression in α-Gal-negative cells and gene knockdown in ticks confirmed that these genes were involved in α-Gal synthesis and are essential for tick feeding. Furthermore, these genes were shown to play an important role in tick-pathogen interactions. Results suggested that tick cells increased α-Gal levels in response to Anaplasma phagocytophilum infection to control bacterial infection. These results provided the molecular basis of endogenous α-Gal production in ticks and suggested that tick galactosyltransferases are involved in vector development, tick-pathogen interactions and possibly the etiology of α-Gal syndrome in humans.

The Oligosaccharide Galactose-α-1,3-Galactose and the α-Gal Syndrome: Insights from an Epitope that is Causal in Immunoglobulin E-Mediated Immediate and Delayed Anaphylaxis

Galactose-α-1,3-galactose (α-Gal) is an oligosaccharide that was first described as a cause of immunoglobulin E-mediated anaphylaxis in cases of first-in-man reactions to the monoclonal antibody cetuximab. Soon thereafter, immunoglobulin E antibodies to this epitope were linked with anaphylactic episodes to mammalian meat, which had a characteristic delay of ~3-6 hours. The ‘α-Gal syndrome’ is now recognised globally as a significant form of food allergy, albeit with regional variation, which reflects that sensitisation relates to bites from certain species of hard tick. The α-Gal epitope is present in organs and muscles from most mammals (with the exception of humans, apes, and Old World monkeys) as a glycan conjugated to both proteins and lipids. There are a number of unusual features that distinguish α-Gal from other traditional food allergies, including the fact that the oligosaccharide can be causal in both immediate and delayed allergic responses, and that co-factors, such as alcohol or exercise, often relate to the instigation and/or severity of clinical reactions. In this narrative review, the authors focus on the novelty of α-Gal’s intrinsic lipid form; consider aspects of glycolipid digestion, absorption, and processing; and explain how this ‘glycolipid hypothesis’ may explain several of the clinical features of α-Gal syndrome. This review draws on pioneering studies of the biochemistry of α-Gal, contemporary understanding of lipid metabolism, and comparisons to other clinically important oligosaccharides.

Meat allergy and allergens

IgE-mediated hypersensitivity to ingested animal products, including both mammalian and avian sources, is increasingly appreciated as an important form of food allergy. Traditionally described largely in children, it is now clear that allergy to meat (and animal viscera) impacts both children and adults and represents a heterogeneous group of allergic disorders with multiple distinct syndromes. The recognition of entities such as pork-cat syndrome and delayed anaphylaxis to red meat, i.e- the α-Gal syndrome, have shed light on fundamental, and in some cases newly appreciated, features of allergic disease. These include insights into routes of exposure and mechanisms of sensitization, as well as the realization that IgE-mediated reactions can be delayed by several hours. Here we review mammalian and avian meat allergy with an emphasis on the molecular allergens and pathways that contribute to disease, as well as the role of in vitro IgE testing in diagnosis and management.

Galactose-α-1,3-galactose syndrome: an Italian survey.

Background. The term of α-Gal syndrome, which includes the delayed allergy to red meat and the allergic reactions following the administration of cetuximab, is associated to the presence of specific IgE to α-Gal. In Italy, only anecdotal cases were reported so far. The Association of Italian Allergists (AAITO) carried out a survey with the aim of evaluating presence, characteristics, clinical features, and distribution of the syndrome in Italy. Methods. A web structured questionnaire was made available on the website of AAIITO from July 2016 to January 2017. It included 31 multiple-choice questions concerning different items, including the site of physicians, the number of patients diagnosed as having cetuximab allergy and/or delayed red meat allergy, recall of tick bites, symptoms, time to reactions, elicitor foods, reactions with foods other than meat, and in-vivo and in-vitro tests used for the diagnosis. Results. Seventy-nine physicians completed the questionnaire. Nine cases of allergy to cetuximab and 40 cases of delayed red meat allergy were recorded across Italy. 22.5% of patients with cetuximab allergy and 62.5% of those with delayed red meat allergy recalled a tick bite. 75% of patients with delayed red meat allergy experienced symptoms after eating beef (butcher's cut in 72.5%). Urticaria was the most frequent clinical manifestation (65% of cases). In 60.6% of cases symptoms appeared 2 - 4 hours after meat ingestion, while in 7.9% symptoms appeared after > 4 hours. The most used diagnostic methods were the intradermal test for cetuximab allergy (88.9%) and the detection of IgE to α-Gal (55.5%) for red meat allergy. Most case reports came from Northern Italy. Conclusions. α-Gal syndrome is present in Italy and beef is the most frequent offending food. In most cases symptoms were not severe.

Alpha-Gal Syndrome: Clinical Presentation, New Concepts, and Unmet Needs

For decades, carbohydrate determinants were seen as cross-reactive structures without clinical impact. The discovery of specific IgE to the carbohydrate galactose-α-1,3-galactose, called α-gal, changed our perspective on the allergenic potential of carbohydrate determinants. α-Gal is present in tissues of non-primate mammals and, upon ingestion, can provoke a delayed form of allergic reaction in sensitized patients. We are faced with a new and unique entity of allergy with high clinical relevance in food allergy and anaphylaxis to drugs derived from mammalian products. Tick bites are assumed to constitute the primary sensitization source to α-gal. To address the complexity of this disease, the term α-gal syndrome has been suggested.

Particular features in the diagnosis and management of α-Gal syndrome

Particular features in the diagnosis and management of α-Gal syndrome