α-Gal Syndrome Research Articles

Longitudinal Follow-up Reveals Peripheral Immunological Changes Upon Tick Bite in α-Gal–Sensitized Individuals

Background: α-Gal syndrome is characterized by specific IgE (sIgE) antibodies to the carbohydrate galactose-α-1,3-galactose (α-Gal) and delayed onset of allergic symptoms after ingestion of mammalian meat. While tick bites are assumed to mediate sensitization, the immune response to tick bites has not yet been investigated. Objective: To investigate the peripheral immune response to tick bites in humans over time. Methods: In a longitudinal cohort study, immunological reactions associated with tick bites (Ixodes species) were analyzed within 1 day (V1), 2 weeks (V2), 1 month (V3), and 3 months (V4) after the occurrence of a bite. sIgE, sIgG, and sIgG subclass levels, as well as 10 cytokines, were quantified. Deep immune phenotyping was performed using mass cytometry. Results: A total of 4 controls and 10 patients were bitten by a tick and followed up over 3 months. None of the controls developed sIgE to α-Gal, and sIgE increased in all patients from V1 until V2/V3, as did IL-8 levels. We noted a significant increase in CD19+ B cells and B-cell subpopulations, as well as a decrease in γδ CD56+ T cells in patients between V0 and V1. At V1, frequencies of plasmacytoid dendritic cells (pDCs) and γδ CD56+ T cells were lower in patients than in controls. Conclusion: Our study provides evidence of significant changes in several immune cell populations in α-Gal–sensitized patients, along with increased levels of IL-8 and sIgE. This is the first exploratory study to investigate longitudinal peripheral immune profiles in patients and controls bitten by ticks.

Recurrent tick bites induce high IgG1 antibody responses to α-Gal in sensitized and non-sensitized forestry employees in Luxembourg.

The α-Gal syndrome (AGS) is characterized by the presence of specific IgE-antibodies to the carbohydrate galactose-α-1,3-galactose (α-Gal). Sensitization to α-Gal has been associated with tick bites and individuals exposed to ticks have an elevated risk of sensitization. The aim of this study was to analyze IgG and IgE antibody responses to α-Gal in a high-risk cohort of forestry employees (FE) in Luxembourg. Questionnaires and serum samples of FE from Luxembourg (n=219) were retrospectively analyzed. α-Gal specific IgE was quantified by ImmunoCAP, α-Gal specific IgG and subclasses IgG1-4 were determined by ELISA. Additionally, sera from population-based controls (n=150) and two groups of food-allergic patients, patients with AGS (n=45) and fish-allergic patients (n=22) were assessed for IgG antibody responses to α-Gal and cod extract. Twenty-one percent of FE was sensitized to α-Gal (sIgE≥0.1kUA/L). Both sensitized and non-sensitized FE exhibited high levels of α-Gal specific IgG, IgG1 and IgG3 compared with controls, indicating a stimulation of IgG responses by recurrent tick bites, independent of the sensitization status. AGS patients had the highest levels of IgG1 and IgG2 antibodies, whereas the profile of fish-allergic patients was similar to the profile of the controls for which anti-α-Gal responses were dominated by IgG2 antibodies. α-Gal sIgG4 levels were either very low or undetectable in all groups. Our study provides evidence for a continuous stimulation of α-Gal related immune responses by repeated tick bites, translating into highly elevated levels of IgG1 antibodies directed against α-Gal.

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.

Tick salivary proteome and lipidome with low glycan content correlate with allergic type reactions in the zebrafish model

Ticks, as hematophagous ectoparasites, can manipulate host immune and metabolic processes, causing tick-borne allergies such as α-Gal syndrome (AGS). Glycolipids with bound galactose-alpha-1–3-galactose (α-Gal) are potential allergenic molecules associated with AGS. Nevertheless, proteins and lipids lacking α-Gal modifications may contribute to tick salivary allergies and be linked to AGS. In this study, we characterized the effect of deglycosylated tick salivary proteins without lipids on treated zebrafish fed with dog food formulated with mammalian (beef, lamb, pork) meat by quantitative proteomics analysis of intestinal samples. The characterization and functional annotations of tick salivary lipids with low representation of glycolipids was conducted using a lipidomics approach. Results showed a significant effect of treatment with saliva and saliva deglycosylated protein fraction on zebrafish abnormal or no feeding (p < 0.005). Treatment with this fraction affected multiple metabolic pathways, defense responses to pathogens and protein metabolism, which correlated with abnormal or no feeding. Lipidomics analysis identified 23 lipid classes with low representation of glycolipids (0.70% of identified lipids). The lipid class with highest representation was phosphatidylcholine (PC; 26.66%) and for glycolipids it corresponded to diacylglycerol (DG; 0.48%). Qualitative analysis of PC antibodies revealed that individuals bitten by ticks were more likely to produce PC-IgG antibodies (p < 0.001). DG levels were significantly higher in tick salivary glands (p < 0.05) compared with tick saliva and salivary fractions. The α-Gal content was higher in tick saliva than in deglycosylated saliva and lipid fractions. These results support a possible role for tick salivary proteins and lipids without α-Gal modifications in AGS.

Alpha-Gal Syndrome: An Underrated Serious Disease and a Potential Future Challenge.

Over the past decades, red meat allergy, also known as mammalian meat allergy, which manifests differently from classic food allergies, has been reported in different countries and regions, including China. The allergen of this disease is not a protein but an oligosaccharide: galactose-α-1,3-galactose, i.e., alpha-gal or α-gal. Therefore, this clinical syndrome is also called α-gal syndrome (AGS). It clinically manifests as delayed anaphylaxis, i.e., patients generally develop allergic symptoms 2-6 h after ingesting red meat. This clinical manifestation is believed to be related to sensitization to α-gal after tick bites. Sensitized individuals may also develop anaphylaxis after ingesting food and medicine or being exposed to medical equipment containing α-gal, such as cetuximab and gelatin. Here, the literature on AGS is reviewed for a better understanding of its pathogenesis, clinical diagnosis, and treatment.

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.

Tick-Borne Disease Infections and Chronic Musculoskeletal Pain

Tick-borne diseases (TBDs) other than Lyme disease, such as spotted fever group rickettsiosis, ehrlichiosis, and galactose-α-1,3-galactose (α-gal) syndrome, are an emerging public health issue. Long-term sequelae secondary to Ehrlichia or Rickettsia infection are uncommon; however, musculoskeletal symptoms are often attributed to prior tick exposure. To evaluate the potential associations between prior exposure to TBDs and musculoskeletal symptoms, including radiographic osteoarthritis. This cross-sectional study analyzed serum samples from the fourth visit (2017-2018) of the Johnston County Osteoarthritis (JoCo OA) project, an ongoing longitudinal, population-based study in Johnston County, North Carolina. Biospecimen testing and analysis were performed between May 2022 and November 2023. Participants in the JoCo OA project are noninstitutionalized White and Black Johnston County residents 45 years or older. The primary outcome was seropositivity with Ehrlichia IgG, Rickettsia IgG, and/or α-gal IgE and musculoskeletal symptoms. Secondary outcomes included risk factors associated with elevated α-gal IgE and weighted population point prevalence rates. Participants completed questionnaires, underwent physical assessments, and provided biospecimens for serological testing. Multivariable models were used to estimate associations of interest. Of the 605 participants who completed the fourth visit of the JoCo OA project, 488 (80.7%) had serum samples available for testing. The 488 participants had a median (IQR) age of 72 (68-78) years and included 336 females (68.9%) and 161 Black (33.0%) and 327 White (67.0%) individuals. The overall weighted point prevalence was 8.6% (95% CI, 5.9%-11.3%) for Ehrlichia IgG, 17.1% (95% CI, 12.6%-21.5%) for Rickettsia IgG, and 19.6% (95% CI, 15.3%-23.8%) for α-gal IgE level greater than 0.1 IU/mL. Only α-gal IgE was associated with knee pain, aching or stiffness (mean ratio, 1.30; 95% CI, 1.09-1.56). Antibodies to Rickettsia, Ehrlichia, and α-gal were not associated with symptomatic radiographic knee osteoarthritis. Male sex (odds ratio [OR], 2.63; 95% CI, 1.55-4.47), current smoker status (OR, 3.55; 95% CI, 1.38-9.18), and an attached tick bite in the past 5 years (OR, 3.99; 95% CI, 2.22-7.15) were all risk factors that were associated with α-gal IgE level greater than 0.1 IU/mL. Despite only 84 individuals (17.2%) recalling a tick bite in the past 5 years, 178 (36.5%) had evidence of prior tick-borne exposure, suggesting frequent human-tick interactions. Results of this cross-sectional study indicate no association between Ehrlichia or Rickettsia seropositivity and chronic musculoskeletal symptoms or osteoarthritis. Further investigation is needed into the pathogenesis of α-gal syndrome and interventions to reduce human-tick interactions.

TWO CASES OF α-GAL SYNDROME CAUSED BY INGESTION OF WILD BOAR MEAT

α-Gal syndrome (AGS) is an allergic reaction to galactose-α-1,3-galactose (α-gal) found in the salivary glands of ticks, mammalian meat excluding primates, and some antibody preparations, such as cetuximab. We report two cases of AGS diagnosed after ingestion of wild boar meat. Patient 1, a male in his 70s, developed anaphylactic shock about 3 h after eating wild boar meat. He was transported to our acute and critical care center in Nagasaki University Hospital because he had difficulty in moving. Patient 2, a female in her 60s, developed a skin rash about 2.5 h after ingesting wild boar meat. After visiting our department to investigate the cause of the disease, the sera of both patients were found to be positive for α-gal specific IgE antibody and were diagnosed with AGS caused by ingestion of wild boar meat. Reports of AGS diagnosed after ingestion of wild boar meat are rare in Japan. Compared with other prefectures, the consumption of wild boar meat in Nagasaki is relatively high in Japan. In the past 10 years, four cases of AGS were diagnosed at our department, half of which were caused by the ingestion of wild boar meat, the ratio is possibly higher than that in other prefectures in Japan.

Multiple Allergen Simultaneous Test for Food Allergens Cannot Screen Wheat-Dependent, Exercise-Induced Anaphylaxis and α-Gal Syndrome

Multiple Allergen Simultaneous Test for Food Allergens Cannot Screen Wheat-Dependent, Exercise-Induced Anaphylaxis and α-Gal Syndrome

Tick-borne red meat allergy (α-gal syndrome).

Tick-borne red meat allergy (α-gal syndrome).

A retrospective review of α-gal syndrome complicating the management of suspected pancreatic exocrine insufficiency in one gastroenterology clinic in central Virginia

The galactose-α-1,3-galactose (α-gal) mammalian meat allergy, α-gal syndrome, often includes diarrhea, abdominal pain, and other gastrointestinal (GI) symptoms. Pancreatic exocrine insufficiency causes similar symptoms. The pancreatic replacement enzymes, referred to here as pancreatic enzymes, used to treat pancreatic insufficiency are porcine products and contain α-gal. Patients with pancreatic insufficiency who also have α-gal syndrome may be intolerant of mammalian products in their diet and of α-gal in pancreatic enzymes. In this article, we describe 40 patients from one GI clinic in central Virginia with suspected pancreatic insufficiency and increased α-gal immunoglobulin E (IgE) levels. Over 50% of these patients had some clinical improvement when mammalian products were removed from the diet. Most patients could tolerate pancreatic enzymes; 10% could not tolerate them due to suspected allergy symptoms, but none developed anaphylaxis. Understanding that α-gal syndrome can be superimposed on pancreatic exocrine insufficiency and exacerbate symptoms, and that treatment with pancreatic enzymes may increase GI and/or allergy symptoms in this group, will lead to improved medical management of this complex patient population.

α-Gal Syndrome: Busting Paradigms in Food Allergy

α-Gal Syndrome: Busting Paradigms in Food Allergy

α-Gal Syndrome: A Case Report of Diagnosis and Meat Reintroduction

We report a patient case of a 52-year-old man, with known tick bites, presenting with multiple episodes of generalized urticaria and angioedema that woke him from sleep 8 hours after eating beef. This history, combined with positive galactose-α-1,3-galactose (α-gal serology), led to the diagnosis of α-gal syndrome. Over a 5-year period, he abstained from mammalian meat, avoided further tick bites, and α-gal levels decreased. He was successfully challenged in an allergist's office with meat with no adverse reactions. This case details the process by which our team reviewed available evidence to risk-stratify meat reintroduction in the absence of official guidelines.

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 AGS patients 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 AGS patients and healthy controls. T and B cells from both patients and controls proliferated in response to TE, but significantly more in the patients. B cell proliferation, but not T cell proliferation, in AGS patients was reduced by removing α-Gal from the TE. In addition, TE induced a clear Th2 cytokine profile in AGS patients. 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 proportion of the IgG1 and IgE antibodies binding TE in AGS patients were directed against the α-Gal epitope. We have for the first time investigated T and B cell responses to α-Gal carrying tick proteins in AGS patients, which will be essential for the understanding of the immune response against an allergenic carbohydrate transmitted by ticks.

The advances of allergen component detection in IgE-mediated food allergy

There are many types in food allergy, and the most common is mediated by IgE. Currently, the diagnosis of food allergy mainly relied on skin prick test and serum specific IgE of allergen extract, which can not identify cross-sensitization. Component-resolved diagnosis (CRD) can identify the major allergen components and cross-components of food allergens, which plays an important role in dietary guidance, prognosis monitoring and diagnosis of special types of IgE-mediated food allergy. This article enumerates clinical characteristics of the IgE-mediated common food allergies, such as milk, egg and seafood allergy, and special type of food allergy, such as cat pork syndrome, oral allergy syndrome, α-gal syndrome and food-dependent exercise-induced anaphylaxis, summarizes the advances of CRD in these types of IgE-mediated food allergy, in order to provide an evidence for the diagnosis, treatment and prevention of IgE-mediated food allergy.

The Two-Sided Experimental Model of ImmunoCAP Inhibition Test as a Useful Tool for the Examination of Allergens Cross-Reactivity on the Example of α-Gal and Mammalian Meat Sensitization-A Preliminary Study.

Cross-reactivity of allergens is the cause of various, sometimes unexpected, clinical reactions. There are no standard methods to investigate cross-reactivity. We present an experimental model of a two-sided inhibition test (IT) on ImmunoCAP membranes (CAP). We constructed the described model based on the known cross-allergy syndrome to red meat developing in people bitten by ticks (α-Gal syndrome; AGS). Some individuals who are bitten by ticks develop IgE antibodies specific to the carbohydrate determinant, galactose-α-1,3-galactose (α-Gal), present in the tick's saliva. These antibodies can cross-react with α-Gal molecules expressed on mammalian meat proteins. The well-known property of anti-α-Gal IgE antibodies binding by various sources of this allergen was used by us in the proposed model of the two-sided inhibition test on ImmunoCAP membranes. We expected that anti-α-Gal IgE antibodies bind allergens from mammalian meat and blocking them abolishes this reactivity, and the two-sided inhibition test model we proposed on ImmunoCAP membranes allowed us to observe such a relationship. We conducted the experiment three times on biological material from people with different clinical manifestations of allergy to α-Gal, each time obtaining similar results. In conclusion, the model of bilateral inhibition on ImmunoCAP membranes proposed by us seems to be an attractive, simple tool for direct testing of allergic cross-reactivity.

S68 Alpha-Gal Syndrome Complicating the Management of Suspected Pancreatic Exocrine Insufficiency

Introduction: IgE antibodies to the oligosaccharide galactose-α-1,3-galactose (α-gal) are an important cause of allergic reactions to mammalian meat and other mammal-derived products. The symptoms of α-gal syndrome (AGS) can involve urticaria or anaphylaxis, but increasingly we are aware that GI tract symptoms, including diarrhea, are also a major feature of AGS. Pancreatic exocrine insufficiency (PEI) is a common cause of diarrhea and treatment involves the use of pancreatic replacement enzymes (PRE). PRE are porcine derived and contain α-gal. Patients receiving PRE who are α-gal IgE positive are at risk for allergic reactions and GI symptoms due to α-gal sensitivity. Here we reviewed patients with suspected PEI and concomitant α-gal IgE sensitization in the practice of one gastroenterologist in Virginia. Methods: Retrospective chart review was carried out using inclusion criteria of i) diarrhea, ii) low fecal elastase (< 200 μg/g feces), and iii) α-gal IgE sensitization ( >0.10 kU/L). Results: 15 patients were identified with mean fecal elastase of 123 and median IgE α-gal level 0.96 (Table). 9 improved off of mammalian-containing food products and 3 of these did not require PRE. 11 patients received PRE. Of 5 patients with pre-existing systemic allergy symptoms to mammalian meat, 1 improved off of mammalian products and did not require PRE, 1 had increased diarrhea with Creon and was lost to follow up, 1 tolerated Creon with pruritus, 1 experienced hives from Creon but successfully underwent office-based desensitization, and 1 patient avoided PRE due to the severity of allergy symptoms. 6 patients without the classic cutaneous allergy symptoms of AGS tolerated PRE, though 1 developed some urticaria. Conclusion: In this series of 15 patients with suspected PEI who had concomitant α-gal IgE >0.1 kU/L, 60% improved with removal of α-gal containing products from the diet and 20% did not require PRE. Of the 11 patients who were treated with ongoing PRE, 3 experienced urticaria and 1 had increased diarrhea, but none had severe allergic symptoms. In our experience, patients who are sensitized to α-gal can usually tolerate PRE. Practitioners should also be aware that worsening diarrhea during PRE treatment could be a consequence of α-gal-related hypersensitivity, rather than medication non-compliance. Recognition of AGS superimposed upon PEI will allow improve management in this complex patient population. Table 1. - Clinical data from 15 patients with suspected pancreatic exocrine insufficiency diagnosed with concomitant α-gal syndrome Characteristics Total Cohort (n=15) Age, mean years (range) 59.5 (19-80) Sex, female, n (%) 9 (60%) Race, Caucasian, n (%) 15 (100%) Fecal Elastase, mean μg/g fecal material (range) 123 (49-183) IgE to α-gal, median kU/L (range) 0.96 (0.41-26.1) Diarrhea Severity recorded, n (%) 13 (87%) Mild, 0-4 stools per day, n (%) 4 (31%) Moderate, 5-8 stools per day, n (%) 6 (46%) Severe, >8 stools per day, n (%) 3 (23%) Improvement with mammalian avoidance, n (%) 9 (60%) Treated with PRE, n (%) 11 (73%) Creon, n (%) 10 (91%) Zenpep, n (%) 1 (9%) Allergy Symptoms attributed to PRE, n (%) 4 (36%) Urticaria, n (%) 3 (27%) Diarrhea, n (%) 1 (9%)

Analysis of Dynamics in Beef-Specific IgE Levels and Clinical Prognosis in 13 Patients with α-Gal Syndrome

Analysis of Dynamics in Beef-Specific IgE Levels and Clinical Prognosis in 13 Patients with α-Gal Syndrome

Cohort study of subclinical sensitization against galactose-α-1,3-galactose in Japan: Prevalence and regional variations.

Sensitization to galactose-α-1,3-galactose (α-Gal) leads to the development of α-Gal syndrome, which includes red meat allergy and cetuximab-induced anaphylaxis. Since tick bites represent the main cause of α-Gal sensitization, it was speculated that sensitization to α-Gal occurs throughout Japan. However, few cohort studies have investigated α-Gal sensitization in Japan. Therefore, we aimed to elucidate the subclinical sensitization rate to α-Gal in Japan. Sera were obtained from 300 participants without food or cetuximab allergy at Shimane University Hospital (Shimane prefecture), Tokyo Medical and Dental University Hospital (Tokyo metropolis), and Tohoku University Hospital (Miyagi prefecture). ImmunoCAP-bovine thyroglobulin (BTG), ImmunoCAP-beef, and IgE immunoblotting with cetuximab were performed to detect α-Gal-specific IgE. Clinical information was collected from participants using a questionnaire. The overall positivity rate of ImmunoCAP-BTG was 4.0% without significant inter-institute differences, whereas that for ImmunoCAP-beef was 9.7% with a significant inter-institute difference. Tokyo Medical and Dental University Hospital (19.0%) had the highest positivity rate. The positivity rate based on cetuximab IgE immunoblotting was 2.7%, without any significant inter-institute differences. The overall positivity rate for both ImmunoCAP-BTG and cetuximab immunoblotting was 2.0%, with a significant inter-institute difference; 5.0% of Shimane University Hospital was the highest. Two cases showed sensitization against the non-α-Gal epitope of cetuximab. The overall positivity rate for both ImmunoCAP-beef and cetuximab immunoblotting was 1.3%, without significant inter-institute differences. Male sex was associated with positive beef-specific IgE. The prevalence of subclinical sensitization to α-Gal is estimated at 2.0%-4.0% in Japan and may be higher in rural areas, supporting an association between tick bites and α-Gal sensitization. In contrast, the prevalence of subclinical sensitization to beef is 9.7% in Japan and is highest in Tokyo Metropolis, suggesting the presence of another IgE-binding epitope apart from α-Gal and another sensitization route in the sensitization to beef IgE.

Current and Future Strategies for the Diagnosis and Treatment of the Alpha-Gal Syndrome (AGS).

The α-Gal syndrome (AGS) is a pathognomonic immunoglobulin E (IgE)-mediated delayed anaphylaxis in foods containing the oligosaccharide galactose-α-1,3-galactose (α-Gal) such as mammalian meat or dairy products. Clinical presentation of AGS can also comprise immediate hypersensitivity due to anticancer therapy, gelatin-containing vaccines or mammalian serum-based antivenom. The IgE initial sensitization is caused by hard-bodied tick bites and symptomatic individuals typically develop delayed pruritus, urticaria, angioedema, anaphylaxis, malaise or gut-related symptoms. Due to inapparent presentation, delayed reactions and a wide variety of patients´ clinical history, the AGS diagnosis and treatment remain challenging. This review covers not only current diagnostic methods used for AGS such as the skin prick test (SPT), the oral food challenge (OFC), anti-α-Gal IgE levels measurement and the basophil activation test (BAT), but also potentially relevant next-generation diagnostic tools like the mast cell activation test (MAT), the histamine-release (HR) assay, omics technologies and model-based reasoning (MBR). Moreover, it focuses on the therapeutical medical and non-medical methods available and current research methods that are being applied in order to elucidate the molecular, physiological and immune mechanisms underlying this allergic disorder. Lastly, future treatment and preventive tools are also discussed, being of utmost importance for the identification of tick salivary molecules, with or without α-Gal modifications, that trigger IgE sensitivity as they could be the key for further vaccine development. Bearing in mind climate change, the tick-host paradigm will shift towards an increasing number of AGS cases in new regions worldwide, which will pose new challenges for clinicians in the future.