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Background Methods Results Conclusion 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 kUA/L; ≥0.35 kUA/L; ≥0.7 kUA/L; ≥3.5 kUA/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 kUA/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. [ABSTRACT FROM AUTHOR]

Alpha‐Gal/α‐Gal is an oligosaccharide produced by non‐primate mammals. Humans have developed an immune response mediated by anti‐α‐Gal antibodies that can trigger an allergic reaction and cause anaphylaxis. In recent years, cases of patients with delayed allergic reaction to mammalian meat have been reported worldwide. In Spain, these cases have been related to the species Ixodes ricinus L. (Ixodida: Ixodidae), whose distribution is located in the north of the country. In this work, the presence of α‐Gal in water‐soluble extracts from samples of salivary glands and digestive tracts of Hyalomma lusitanicum Koch (Ixodida: Ixodidae) both engorged and collected from vegetation were studied. The presence of that epitope was confirmed by the presence of reactive proteins of >250 kDa in both samples. The highest concentrations of α‐Gal were detected in salivary glands. Neither sex nor diet influenced the concentration of α‐Gal, which seems to indicate its endogenous production and its possible inoculation to the host during tick feeding. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The prevalence of food allergy is rising and is estimated to approach 10%. Red meat allergy is the first known food allergy elicited by immunoglobulin E (IgE) antibodies recognizing a carbohydrate. Due to the loss of function of the alpha -1,3-galactosyltransferase (GGTA1) gene in humans, the disaccharide galactosea-1,3-galactose (α-Gal) cannot be synthesized and therefore became immunogenic. IgE sensitization is elicited through the skin by repetitive tick bites transmitting α-Gal. The underlying mechanisms regarding innate and adaptive immune cell activation, including the B-cell isotype switch to IgE, are poorly understood, requiring further research and physiologically relevant animal models. Here, we describe a new animal model of red meat allergy using percutaneous α-Gal sensitization of gene-edited GGTA1-deficient pigs. Total and α-Gal-specific IgG, IgG1, IgG2, IgG4, and IgE levels were tracked. Further key factors associated with allergic skin inflammation, type 2 immunity, and allergy development were measured in PBMCs and skin samples. Significant increases in α-Gal-specific IgG1 and IgE levels indicated successful sensitization to the allergen α-Gal. Intracutaneous sensitizations with α-Gal recruited lymphocytes to the skin, including elevated numbers of T helper 2 (Th2) cells. Finally, α-Galsensitized pigs not only recognized α-Gal as non-self-antigen following α-Gal exposure through the skin but also developed anaphylaxis upon antigen challenge. Based on the similarities between the porcine and human skin, this new large animal model for α-Gal allergy should help to unveil the consecutive steps of cutaneous sensitization and aid the development of prophylactic and treatment interventions. [ABSTRACT FROM AUTHOR]

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.

Abstract 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.

Introduction: Alpha-Gal Syndrome (AGS) is a delayed allergic reaction due to specific IgE antibodies targeting galactose-a-1,3-galactose (a-gal), a carbohydrate found in red meat. This condition has gained significant attention globally due to its increasing prevalence, with more than 450,000 cases estimated just in the United States alone. Previous research has established a connection between AGS and tick bites, which sensitize individuals to a-gal antigens and elevate the levels of specific IgE. However, the precise mechanism by which tick bites influence the host's immune system and contribute to the development of AGS remains poorly understood. This study investigates various factors related to ticks and the host associated with the development of AGS following a tick bite, using mice with a targeted disruption of alpha-1,3-galactosyltransferase (AGKO) as a model organism. Methods: Lone-star tick (Amblyomma americanum) and gulf-coast tick (Amblyomma maculatum) nymphs were used to sensitize AGKO mice, followed by pork meat challenge. Tick bite site biopsies from sensitized and non-sensitized mice were subjected tomRNA gene expression analysis to assess the host immune response. Antibody responses in sensitized mice were also determined. Results: Our results showed a significant increase in the total IgE, IgG1, and a-gal IgG1 antibodies titers in the lone-star tick-sensitized AGKO mice compared to the gulf-coast tick-sensitized mice. Pork challenge in Am. americanum -sensitized mice led to a decline in body temperature after the meat challenge. Gene expression analysis revealed that Am. americanum bites direct mouse immunity toward Th2 and facilitate host sensitization to the a-gal antigen. Conclusion: This study supports the hypothesis that specific tick species may increase the risk of developing a-gal-specific IgE and hypersensitivity reactions or AGS, thereby providing opportunities for future research on the mechanistic role of tick and host-related factors in AGS development. [ABSTRACT FROM AUTHOR]

Introduction: Alpha-gal syndrome (AGS) arises from tick bites, triggering excessive IgE antibodies to galactose-α-1,3-galactose (α-Gal). Symptoms vary, often appearing post-α-Gal ingestion, ranging from mild to severe, including urticaria, angioedema and respiratory issues. Delayed symptom onset complicates diagnosis, posing challenges for patients. AGS can also result from contact with medical animal-derived products, such as bovine-derived heart valves, necessitating heightened healthcare provider awareness, especially in tick-exposed regions. Management involves allergen avoidance and emergency medications like epinephrine. Further research is needed to refine diagnostic and therapeutic approaches. Purpose: Through literature review and clinical presentation description, we aim to raise awareness and enhance understanding of alpha-gal syndrome. Description of the state of knowledge: AGS, an emerging atypical food allergy, stems from immune reactions to α-Gal oligosaccharide in mammalian meat and other animal products. Avoiding medical items containing alpha-gal is crucial to prevent iatrogenesis. Summary: Understanding AGS etiology and symptoms is vital for diagnosis and management. Healthcare providers' lack of awareness may lead to underdiagnosis, inadequate patient care, and underestimation of affected individuals.

Alpha-gal syndrome (AGS) is an allergy to "red meat" and other mammalian products due to immunoglobulin E (IgE) antibodies against the sugar moiety galactose-alpha-1,3-galactose (alpha-gal), which is acquired following tick bites. Clinically, AGS presents with urticaria, abdominal pain, nausea, and occasionally anaphylaxis, and has wide inter- and intra-personal variability. Because symptom onset is generally delayed by 2 to 6 hours after meat consumption, AGS can be easily confused with other causes of urticaria and anaphylaxis, such as chronic spontaneous urticaria (CSU) and mast cell activation syndrome (MCAS). Diagnosis relies on a combination of clinical history, positive alpha-gal IgE blood testing and improvement on a mammalian-restricted diet. Management of the syndrome centers primarily on avoidance of mammalian meats (and occasionally dairy and other products) as well as acute management of allergic symptoms. Counseling about tick avoidance measures is also important as AGS will wane over time in many patients. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alpha-gal syndrome is an immunoglobulin E (IgE)-mediated delayed hypersensitivity reaction to nonprimate mammalian products, which has a newly established gastrointestinal (GI) phenotype in adults. We assessed the GI presentation and treatment response in children. METHODS: This is a retrospective study of patients presenting in a pediatric gastroenterology clinic tested for alpha-gal IgE. RESULTS: Forty of199patients (20%) tested had apositive alpha-gal-specific IgE,with77.5%reportingGIsymptomsin isolation. Of the 30 that attempted dietary elimination, 8 (27%) experienced full resolution of symptoms. DISCUSSION: Alpha-gal syndrome can present with isolated GI symptoms in children. [ABSTRACT FROM AUTHOR]

Jessica D Macdougall,1,2,* Kevin O Thomas,1,2,* Onyinye I Iweala1,2 1Department of Medicine, Thurston Arthritis Research Center, Division of Rheumatology, Allergy, and Immunology, Chapel Hill, NC, 27599, USA; 2Department of Pediatrics, University of North Carolina Food Allergy Initiative, Division of Allergy and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA*These authors contributed equally to this workCorrespondence: Onyinye I Iweala, Department of Medicine, University of North Carolina at Chapel Hill, 3300 Thurston Building, CB#7280, Chapel Hill, NC, 27599-7280, USA, Tel +1-984-974-2645, Fax +1-984-974-2660, Email onyinye.iweala@med.unc.eduAbstract: 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.Keywords: mammalian meat, red meat allergy, galactose-alpha-1, 3-galactose, tick

Background: Alpha‐gal syndrome (AGS) is an IgE‐mediated allergy to galactose‐alpha‐1,3‐galactose. Clinical presentation ranges from hives to anaphylaxis; episodes typically occur 2–6 h after exposure to alpha‐gal‐containing products. In the United States, lone star tick bites are associated with the development of AGS. To characterize features of AGS, we evaluated a cohort of patients presenting for care at the University of North Carolina, focusing on symptoms, severity, and identifying features unique to specific alpha‐gal‐containing product exposures. Methods: We performed a chart review and descriptive analysis of 100 randomly selected patients with AGS during 2010–2019. Results: Median age at onset was 53 years, 56% were female, 95% reported White race, 86% reported a history of tick bite, and 75% met the criteria for anaphylaxis based on the involvement of ≥2 organ systems. Those reporting dairy reactions were significantly less likely to report isolated mucocutaneous symptoms (3% vs. 24%; ratio [95% CI]: 0.1 [0.1, 0.3]) than those who tolerated dairy, and were more likely to report gastrointestinal symptoms (79% vs. 59%; ratio [95% CI]: 1.3 [0.7, 2.6]), although this difference was not statistically significant. Dairy‐tolerant patients demonstrated higher alpha‐gal sIgE titers (as a percentage of total IgE) than dairy‐reactive patients (GM 4.1 [95% CI: 2.7, 6.1] vs. GM 2.5 [95% CI: 1.3, 4.8], respectively; ratio −1.6 [95% CI: −1.0, 3.9]). Conclusion: While tick exposure is common in the southern United States, nearly all AGS patients reported a tick bite. Gastrointestinal symptoms were prominent among those reporting reactions to dairy. Anaphylaxis was common, underscoring the severity and need to raise awareness of AGS among patients and providers. [ABSTRACT FROM AUTHOR]

Purpose of Review: Food allergies are typically not considered as a cause of gastrointestinal (GI) distress without additional allergic symptoms, apart from celiac disease and eosinophilic esophagitis. However, recent reports of patients with alpha-gal syndrome who presented with GI-only symptoms like abdominal pain, vomiting, and diarrhea challenge this paradigm. Alpha-gal syndrome is an IgE-mediated allergy characterized by delayed reactions after eating mammalian meat or mammalian-derived products that contain galactose-alpha-1,3-galactose (alpha-gal). The purpose of this review is to discuss our current understanding of food allergies, GI illness, and the GI manifestations of alpha-gal syndrome. Recent Findings: Among Southeastern U.S. GI clinic patients who screened positive for serum alpha-gal IgE, a majority of patients reported significant symptom improvement on an alpha-gal-avoidant diet, suggesting that the allergy had played a role in their GI symptoms. Diagnosis of alpha-gal syndrome is typically made with concerning allergic symptoms, elevated alpha-gal specific IgE in the serum, and symptom improvement on an alpha-gal avoidant diet. Summary: Alpha-gal syndrome can cause a delayed allergic response that is increasingly recognized worldwide, including among patients with predominant GI symptoms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Little is known about α‐gal (galactose‐α‐1,3‐galactose) sensitization in patients with chronic urticaria (CU). The aim of this study was to examine the prevalence, predictors and clinical relevance of α‐gal sensitization in patients with CU. Methods: Two consecutive cohorts of newly referred patients with CU from a primary care allergology practice and a tertiary hospital dermatology department, plus a control group with allergic disease, but not CU, from the allergology practice, were interviewed and screened for α‐gal sensitization (serum specific‐IgE ≥0.35 KU/L). Results: Of 733 patients included, 21 (5.6%) and 11 (3.9%) of CU patients from private practice and hospital, respectively, were α‐gal sensitized. In total, 8 patients (38.1% of sensitized patients, and 2.1% of all CU patients) from private practice, and 2 patients (18.2% of sensitized patients, and 0.7% of all CU patients) from hospital, had clinically relevant α‐gal allergy. In private practice, male sex (47.6 vs. 24.7%), p = 0.020, obesity (33.3 vs. 23.6%), p = 0.302, and frequency of angioedema (61.9 vs. 51.4%), p = 0.350; and in hospital, male sex (72.7 vs. 27.9%), p = 0.003, and high total immunoglobulin E (median 168 vs. 70.5 KU/L), p = 0.022 were associated with α‐gal sensitization. Conclusion: α‐gal sensitization is observed in a small fraction of CU patients with only few patients experiencing clinically relevant sensitization. Certain patients, particularly from primary care, may constitute a relevant population for aimed testing. [ABSTRACT FROM AUTHOR]

Abstract Background Little is known about α‐gal (galactose‐α‐1,3‐galactose) sensitization in patients with chronic urticaria (CU). The aim of this study was to examine the prevalence, predictors and clinical relevance of α‐gal sensitization in patients with CU. Methods Two consecutive cohorts of newly referred patients with CU from a primary care allergology practice and a tertiary hospital dermatology department, plus a control group with allergic disease, but not CU, from the allergology practice, were interviewed and screened for α‐gal sensitization (serum specific‐IgE ≥0.35 KU/L). Results Of 733 patients included, 21 (5.6%) and 11 (3.9%) of CU patients from private practice and hospital, respectively, were α‐gal sensitized. In total, 8 patients (38.1% of sensitized patients, and 2.1% of all CU patients) from private practice, and 2 patients (18.2% of sensitized patients, and 0.7% of all CU patients) from hospital, had clinically relevant α‐gal allergy. In private practice, male sex (47.6 vs. 24.7%), p = 0.020, obesity (33.3 vs. 23.6%), p = 0.302, and frequency of angioedema (61.9 vs. 51.4%), p = 0.350; and in hospital, male sex (72.7 vs. 27.9%), p = 0.003, and high total immunoglobulin E (median 168 vs. 70.5 KU/L), p = 0.022 were associated with α‐gal sensitization. Conclusion α‐gal sensitization is observed in a small fraction of CU patients with only few patients experiencing clinically relevant sensitization. Certain patients, particularly from primary care, may constitute a relevant population for aimed testing.

The alpha-Gal epitope (α-Gal) with the determining element galactose-α1,3-galactose can lead to clinically relevant allergic reactions and rejections in xenotransplantation. These immune reactions can develop because humans are devoid of this carbohydrate due to evolutionary loss of the enzyme α1,3-galactosyltransferase (GGTA1). In addition, up to 1% of human IgG antibodies are directed against α-Gal, but the stimulus for the induction of anti-α-Gal antibodies is still unclear. Commensal bacteria have been suggested as a causal factor for this induction as α-Gal binding tools such as lectins were found to stain cultivated bacteria isolated from the intestinal tract. Currently available tools for the detection of the definite α-Gal epitope, however, are cross-reactive, or have limited affinity and, hence, offer restricted possibilities for application. In this study, we describe a novel monoclonal IgG1 antibody (27H8) specific for the α-Gal epitope. The 27H8 antibody was generated by immunization of Ggta1 knockout mice and displays a high affinity towards synthetic and naturally occurring α-Gal in various applications. Using this novel tool, we found that intestinal bacteria reported to be α-Gal positive cannot be stained with 27H8 questioning whether commensal bacteria express the native α-Gal epitope at all. [ABSTRACT FROM AUTHOR]

The alpha-Gal epitope (α-Gal) with the determining element galactose-α1,3-galactose can lead to clinically relevant allergic reactions and rejections in xenotransplantation. These immune reactions can develop because humans are devoid of this carbohydrate due to evolutionary loss of the enzyme α1,3-galactosyltransferase (GGTA1). In addition, up to 1% of human IgG antibodies are directed against α-Gal, but the stimulus for the induction of anti-α-Gal antibodies is still unclear. Commensal bacteria have been suggested as a causal factor for this induction as α-Gal binding tools such as lectins were found to stain cultivated bacteria isolated from the intestinal tract. Currently available tools for the detection of the definite α-Gal epitope, however, are cross-reactive, or have limited affinity and, hence, offer restricted possibilities for application. In this study, we describe a novel monoclonal IgG1 antibody (27H8) specific for the α-Gal epitope. The 27H8 antibody was generated by immunization of Ggta1 knockout mice and displays a high affinity towards synthetic and naturally occurring α-Gal in various applications. Using this novel tool, we found that intestinal bacteria reported to be α-Gal positive cannot be stained with 27H8 questioning whether commensal bacteria express the native α-Gal epitope at all.

Food allergy typically arises as an adverse reaction mediated by food proteins. However, in the case of meat allergy, not only proteins have been identified as causal antigens, but also the carbohydrate galactose-alpha-1,3-galactose (α-Gal), which remains poorly studied as an allergen. We aimed to investigate the effect of different cooking methods on the digestibility and immunogenicity of meat. Our results reveal that the ability of α-Gal in roasted beef to be recognized by specific antibodies does not decrease after simulated gastrointestinal digestion. Furthermore, in the case of boiled or roasted pork, antibody binding to α-Gal even increases, underscoring the influence of temperature, cooking method, and animal species. This suggests that the exposure of glycans due to the proteolytic degradation of the amino acid chain increases their accessibility for antibody binding. Such findings may offer a complementary explanation for the delayed anaphylactic responses observed in meat allergic patients in comparison with the reactions that suffer allergic patients to other foods. • Boiling and roasting reduce the binding of pork, beef, and lamb meat extracts to anti-α-Gal. • Exposure of glycans during meat digestion increases their accessibility for antibody binding. • Exposure of α-Gal during digestion could explain the delay in the onset of meat allergy symptoms. [ABSTRACT FROM AUTHOR]

Recent studies have provided strong evidence indicating that lone star tick bites are a cause of AGS (alpha-gal syndrome, also known as red meat allergy RMA) in humans. AGS is characterized by an increase in IgE antibody production against galactose-alpha-1,3-galactose (aGal), which is a common glycan found in mammalian tissue, except in Old World monkeys and humans. The main causative factor of AGS, the lone star tick (Amblyomma americanum), is broadly distributed throughout the east and midwest of the United States and is a vector of a wide range of human and animal pathogens. Our earlier glycomics study of the salivary glands of partially fed male and female ticks revealed relatively high levels of aGal epitopes. In this study, we found that partially fed males of A. americanum on bovine blood, which engage in multiple intrastadial feedings, carry a large amount of aGal in the salivary glands. In our current work, we aimed to test whether ticks mediate the transmission of the aGal sensitizer acquired from nonhuman blood to humans in the intrastadial host switch (referred to as the "transmission" hypothesis). To test this hypothesis, we used an alpha-galactosyltransferase knockout mutant mouse (aGT-KO) model system infested with ticks that were unfed or partially fed on bovine blood. Based on the levels of total IgE and specific IgG and IgE antibodies against aGal after tick feedings, aGT-KO mice significantly responded to tick feeding and injection of aGal (Galα1-3Galβ1-4GlcNAc) conjugated to human serum albumin or mouse serum albumin (aGal-HSA or aGal-MSA) by increasing total IgE and aGal-specific IgE levels compared to those in C57BL/6 control mice. All of the treatments of aGT-KO mice involving the feeding of partially fed and unfed ticks functioned as sensitizers that increased the levels of specific IgE against aGal, with large individual variations. The data in this study do not support the "transmission" component of AGS, although they confirmed that aGT-KO mice can be used as a model for RMA studies. [ABSTRACT FROM AUTHOR]

Recent studies have provided strong evidence indicating that lone star tick bites are a cause of AGS (alpha-gal syndrome, also known as red meat allergy RMA) in humans. AGS is characterized by an increase in IgE antibody production against galactose-alpha-1,3-galactose (aGal), which is a common glycan found in mammalian tissue, except in Old World monkeys and humans. The main causative factor of AGS, the lone star tick (Amblyomma americanum), is broadly distributed throughout the east and midwest of the United States and is a vector of a wide range of human and animal pathogens. Our earlier glycomics study of the salivary glands of partially fed male and female ticks revealed relatively high levels of aGal epitopes. In this study, we found that partially fed males of A. americanum on bovine blood, which engage in multiple intrastadial feedings, carry a large amount of aGal in the salivary glands. In our current work, we aimed to test whether ticks mediate the transmission of the aGal sensitizer acquired from nonhuman blood to humans in the intrastadial host switch (referred to as the “transmission” hypothesis). To test this hypothesis, we used an alpha-galactosyltransferase knockout mutant mouse (aGT-KO) model system infested with ticks that were unfed or partially fed on bovine blood. Based on the levels of total IgE and specific IgG and IgE antibodies against aGal after tick feedings, aGT-KO mice significantly responded to tick feeding and injection of aGal (Galα1-3Galβ1-4GlcNAc) conjugated to human serum albumin or mouse serum albumin (aGal-HSA or aGal-MSA) by increasing total IgE and aGal-specific IgE levels compared to those in C57BL/6 control mice. All of the treatments of aGT-KO mice involving the feeding of partially fed and unfed ticks functioned as sensitizers that increased the levels of specific IgE against aGal, with large individual variations. The data in this study do not support the “transmission” component of AGS, although they confirmed that aGT-KO mice can be used as a model for RMA studies.

Background: 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. Methods: Sera from 136 Swedish AGS patients and 29 wasp‐positive non‐AGS control sera were analyzed for IgE‐reactivity against wasp venom (Vespula spp.), the European tick Ixodes ricinus (Streptavidin ImmunoCAP), α‐Gal and total IgE by ImmunoCAP. The presence of α‐Gal on wasp venom proteins (Vespula vulgaris) 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. Results: 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 in silico approach. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Max release after peanut ingestion was observed after 30 min, whereas max releases for pork kidney smoothie and fried pork kidney were seen 3 and 4 h after ingestion, respectively. Delayed reaction in alpha-gal allergy is reflected in serum levels after ingestion of pork kidney, and absorption is dependent on food processing Both pork kidney smoothie and fried pork kidney are considered low-fat food matrices, although the latter was served with vegetable garniture, and the culprit amount of pork kidney was identical. [Extracted from the article]

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Alpha-Gal Syndrome (AGS) is an IgE-mediated delayed-type hypersensitivity reaction to the oligosaccharide galactose-α-1, 3-galactose (α-gal) injected into humans from the lone-star tick (Amblyomma americanum) bite. Indeed, α-gal is discovered in salivary glands of lone-star tick; however, the tick's specific intrinsic factors involved in endogenous α-gal production and presentation to host during hematophagy are poorly understood. This study aimed to investigate the functional role of two tick enzymes, α-D-galactosidase (ADGal) and β-1,4 galactosyltransferases (β-1,4GalT), in endogenous α-gal production, carbohydrate metabolism, and N-glycan profile in lone-star tick. The ADGal enzyme cleaves terminal α-galactose moieties from glycoproteins and glycolipids, whereas β-1,4GalT transfers α-galactose to a β1,4 terminal linkage acceptor sugars—GlcNAc, Glc, and Xyl—in various processes of glycoconjugate synthesis. An RNA interference approach was utilized to silence ADGal and β-1,4GalT in Am. americanum to examine their function in α-gal metabolism in tick and AGS onset. Silencing of ADGal led to the significant downregulation of genes involved in galactose metabolism and transport in Am. americanum. Immunoblot and N-glycan analysis of the Am. americanum salivary glands showed a significant reduction in α-gal levels in silenced tissues. However, there was no significant difference in the level of α-gal in β-1,4GalT-silenced tick salivary glands. A basophil-activation test showed a decrease in the frequency of activated basophil by ADGal-silenced salivary glands. These results provide an insight into the roles of ADGal and β-1,4GalT in α-gal production and presentation in ticks and the probable involvement in the onset of AGS. [ABSTRACT FROM AUTHOR]

Abstract Background Alpha-gal is an oligosaccharide implicated in delayed anaphylaxis following red meat consumption. Exposure to tick bites has been correlated with development of an allergic response to alpha-gal. However, evidence prospectively linking exposure to a single tick species and an immune response to alpha-gal is lacking. Methods We used serum samples from a prior study cohort of outdoor workers in North Carolina, USA, with high exposure to the lone star tick, Amblyomma americanum, to prospectively evaluate the relationship between tick bites and anti-alpha-gal IgE antibodies. Results Individuals who reported exposure to one or more tick bites were significantly more likely to have a positive change in anti-alpha-gal IgE compared to individuals with no reported tick bites. This relationship was not dependent on time. A trend toward increasing number of tick bites and increased anti-alpha-gal IgE levels was observed but not statistically significant. Conclusion To our knowledge, this is the first study to prospectively link documented exposure to A. americanum bites and increased sensitization to alpha-gal in a cohort of outdoor workers. Our results support the role of A. americanum as likely agents for eliciting an allergic response to red meat, and highlight the importance of preventing tick bites.

Alpha-Gal Syndrome (AGS) is an IgE-mediated delayed-type hypersensitivity reaction to the oligosaccharide galactose-α-1, 3-galactose (α-gal) injected into humans from the lone-star tick (Amblyomma americanum) bite. Indeed, α-gal is discovered in salivary glands of lone-star tick; however, the tick’s specific intrinsic factors involved in endogenous α-gal production and presentation to host during hematophagy are poorly understood. This study aimed to investigate the functional role of two tick enzymes, α-D-galactosidase (ADGal) and β-1,4 galactosyltransferases (β-1,4GalT), in endogenous α-gal production, carbohydrate metabolism, and N-glycan profile in lone-star tick. The ADGal enzyme cleaves terminal α-galactose moieties from glycoproteins and glycolipids, whereas β-1,4GalT transfers α-galactose to a β1,4 terminal linkage acceptor sugars—GlcNAc, Glc, and Xyl—in various processes of glycoconjugate synthesis. An RNA interference approach was utilized to silence ADGal and β-1,4GalT in Am. americanum to examine their function in α-gal metabolism in tick and AGS onset. Silencing of ADGal led to the significant downregulation of genes involved in galactose metabolism and transport in Am. americanum. Immunoblot and N-glycan analysis of the Am. americanum salivary glands showed a significant reduction in α-gal levels in silenced tissues. However, there was no significant difference in the level of α-gal in β-1,4GalT-silenced tick salivary glands. A basophil-activation test showed a decrease in the frequency of activated basophil by ADGal-silenced salivary glands. These results provide an insight into the roles of ADGal and β-1,4GalT in α-gal production and presentation in ticks and the probable involvement in the onset of AGS.

The α-Gal syndrome is a complex allergic disease characterized by the development of specific IgE antibodies against the carbohydrate galactose-α-1,3-galactose (α-Gal), an oligosaccharide present in cells and tissues of non-primate mammals. Individuals with IgE antibodies to α-Gal suffer from a delayed form of anaphylaxis following red meat consumption. There are several features that make the α-Gal syndrome such a unique allergic disease and distinguish it from other food allergies: (1) symptoms causing IgE antibodies are directed against a carbohydrate moiety, (2) the unusual delay between the consumption of the food and the onset of the symptoms, and (3) the fact that primary sensitization to α-Gal occurs via tick bites. This review takes a closer look at the immune response against α-Gal, in healthy and in α-Gal allergic individuals. Furthermore, the similarities and differences between immune response against α-Gal and against the other important glycan moieties associated with allergies, namely cross-reactive carbohydrate determinants (CCDs), are discussed. Then different mechanisms are discussed that could contribute to the delayed onset of symptoms after consumption of mammalian meat. Moreover, our current knowledge on the role of tick bites in the sensitization process is summarized. The tick saliva has been shown to contain proteins carrying α-Gal, but also bioactive molecules, such as prostaglandin E2, which is capable of stimulating an increased expression of anti-inflammatory cytokines while promoting a decrease in the production of proinflammatory mediators. Together these components might promote Th2-related immunity and trigger a class switch to IgE antibodies directed against the oligosaccharide α-Gal. The review also points to open research questions that remain to be answered and proposes future research directions, which will help to get a better understanding and lead to a better management of the disease.

The alpha-gal syndrome is an allergic syndrome that comprises two clinical pictures: an immediate hypersensitivity to drugs containing alpha-gal and a delayed hypersensitivity to the ingestion of red mammalian meat. This allergic syndrome is often under-recognized, and patients are mislabeled with diagnosis as spontaneous urticaria or idiopathic anaphylaxis. Even though less frequently, children could also be of interest, especially in tick-endemic areas. In most cases, a positive anamnesis for tick bites months before the onset of symptoms is recorded. The clinical manifestations could range from asymptomatic cases to severe anaphylaxis. The most frequently used diagnostic test is the determination of specific IgE for alpha-gal. Oral provocation test is usually reserved to unclear cases or to verify tolerance after diet. No long-term follow-up studies have been published, although an elimination diet could lead to a decrease of specific IgE for alpha-gal and a possible reintroduction of some avoided foods. This paper provides a literature review, focused on pediatric age, and an evaluation of available diagnostic tests. We analyze the correlation between tick bites and symptom onset and unfold the different clinical pictures to help clinicians to promptly recognized this syndrome. Lastly, we address unmet needs in this specific allergy.

The fifth class of immunoglobulin, immunoglobulin E (IgE) was discovered in 1967 and has had immense importance for the understanding, diagnosis, and treatment of allergic disease. More than 50 years have passed and efforts to characterize, standardize, and refine allergens with the aim to improve clinical diagnosis and allergen-specific immunotherapy are still ongoing. Another important breakthrough was made in 1999 with the introduction of component-resolved diagnostics (CRD), making it possible to quantify IgE antibodies against individual allergen proteins for diagnostic purposes at a molecular level. The progress and developments made in allergy diagnosis often originate from clinical observations and case studies. Observant physicians and health-care personnel have reported their findings in the medical literature, which in turn has inspired researchers to become involved in clinical research. Allergists continuously encounter new allergies and are often asked by their patients how to prevent new reactions. In the current article, we focus on recent clinical observations that can now be explained by CRD. The examples taken concern allergic reactions toward peanuts, tree nuts, lemon kernels, health drinks, meat, insects, dog dander, cannabis, and semen. We now have an improved understanding of why patients may react in a serious or unexpected way, as illustrated by these examples, yet many other clinical observations remain unexplained. The aim of this review is to highlight the importance of clinical observations among allergic patients, focusing on systemic, or unusual and unexpected allergic reactions, where component-testing has further refined the diagnosis of IgE-mediated allergy. [ABSTRACT FROM AUTHOR]

Alpha‐gal syndrome should be suspected also in children in case of typical allergic symptoms in the evening or night during tick seasons and the event of recall urticaria. It is, however, still a challenge for both patients and clinicians. [ABSTRACT FROM AUTHOR]

Background. It was reported that prevalence of red meat allergy in children was higher in our country than in western populations. However, the diagnosis of these patients is often delayed. The aim of the study was to present the clinical and laboratory characteristics of our red meat allergy patients. Methods. The data were collected retrospectively from the files of children with red meat allergy. Also, 6 adults with red meat allergies were recorded in the families of the children. Patients with symptoms associated with red meat allergy and sensitive to beef or mutton in prick-to-prick tests were recorded. Results. The median age of the 43 patients was 12 years (2-37), and 51% were male. Most of the patients were children (n=37, 86%). The median age was 10 years in children (2-17), and 54% were male. All of the children had dermatologic manifestations, 51% had respiratory symptoms, and 64% had anaphylaxis upon exposure to red meat. The anaphylaxis history was not associated with demographic, clinical and laboratory data. A total of 63% children had additional allergic diseases, and 75% of them were sensitive to both mutton and beef in prickto-prick tests. The median total IgE level of the children was 327 (20-3550) IU/mL, median eosinophil count was 210/mm3 (40-990) and mean vitamin D was 13.1 ± 1.2 mcg/L (n=27). Anaphylaxis occurred in 3 of 9 patients who received the open oral food challenge (OFC) test. After OFC, 3 patients continued to eat red meat without issues, and 1 patient was recommended to eat alternatives to red meat. Conclusions. Clinical and laboratory findings were heterogeneous in children with red meat allergy. Anaphylaxis risk seems to be higher than other food allergies. OFC test is more helpful in both diagnosis and alternative red meat selection compared to laboratory findings. [ABSTRACT FROM AUTHOR]

Abstract Alpha‐gal syndrome should be suspected also in children in case of typical allergic symptoms in the evening or night during tick seasons and the event of recall urticaria. It is, however, still a challenge for both patients and clinicians.

Ticks and tick-borne diseases are significant public health concerns. Bioactive molecules in tick saliva facilitate prolonged blood-feeding and transmission of tick-borne pathogens to the vertebrate host. Alpha-gal syndrome (AGS), a newly reported food allergy, is believed to be induced by saliva proteins decorated with a sugar molecule, the oligosaccharide galactose-⍺-1,3-galactose (α-gal). This syndrome is characterized by an IgE antibody-directed hypersensitivity against α-gal. The α-gal antigen was discovered in the salivary glands and saliva of various tick species including, the Lone Star tick (Amblyomma americanum). The underlying immune mechanisms linking tick bites with α-gal-specific IgE production are poorly understood and are crucial to identify and establish novel treatments for this disease. This article reviews the current understanding of AGS and its involvement with tick species.

Ticks and tick-borne diseases are significant public health concerns. Bioactive molecules in tick saliva facilitate prolonged blood-feeding and transmission of tick-borne pathogens to the vertebrate host. Alpha-gal syndrome (AGS), a newly reported food allergy, is believed to be induced by saliva proteins decorated with a sugar molecule, the oligosaccharide galactose-⍺-1,3-galactose (α-gal). This syndrome is characterized by an IgE antibody-directed hypersensitivity against α-gal. The α-gal antigen was discovered in the salivary glands and saliva of various tick species including, the Lone Star tick (Amblyomma americanum). The underlying immune mechanisms linking tick bites with α-gal-specific IgE production are poorly understood and are crucial to identify and establish novel treatments for this disease. This article reviews the current understanding of AGS and its involvement with tick species. [ABSTRACT FROM AUTHOR]

[Display omitted] Alpha-gal (Galα1-3Galβ1-4GlcNAc) is a carbohydrate with the potential to elicit fatal allergic reactions to mammalian meat and drugs of mammalian origin. This type of allergy is induced by tick bites, and therapeutic options for this skin-driven food allergy are limited to the avoidance of the allergen and treatment of symptoms. Thus, a better understanding of the immune mechanisms resulting in sensitization through the skin is crucial, especially in the case of a carbohydrate allergen for which underlying immune responses are poorly understood. We aimed to establish a mouse model of alpha-gal allergy for in-depth immunologic analyses. Alpha-galactosyltransferase 1–deficient mice devoid of alpha-gal glycosylations were sensitized with the alpha-gal–carrying self-protein mouse serum albumin by repetitive intracutaneous injections in combination with the adjuvant aluminum hydroxide. The role of basophils and IL-4 in sensitization was investigated by antibody-mediated depletion. Alpha-gal–sensitized mice displayed increased levels of alpha-gal–specific IgE and IgG 1 and developed systemic anaphylaxis on challenge with both alpha-gal–containing glycoproteins and glycolipids. In accordance with alpha-gal–allergic patients, we detected elevated numbers of basophils at the site of sensitization as well as increased numbers of alpha-gal–specific B cells, germinal center B cells, and B cells of IgE and IgG 1 isotypes in skin-draining lymph nodes. By depleting IL-4 during sensitization, we demonstrated for the first time that sensitization and elicitation of allergy to alpha-gal and correspondingly to a carbohydrate allergen is dependent on IL-4. These findings establish IL-4 as a potential target to interfere with alpha-gal allergy elicited by tick bites. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Supported by the Independent Research Fund Denmark (grant 2034-00031B [to K.B.L-M.]), the 10.13039/501100010234Swedish Asthma and Allergy Association Research Foundation (to M.vH.), the Swedish Cancer and 10.13039/501100013499Allergy Foundation (to M.vH.), the King Gustaf V 80th Birthday Foundation (to M.vH.), the 10.13039/501100003793Swedish Heart-Lung Foundation (to M.vH.), and the Hesselman Foundation (to M.vH.). Disclosure of potential conflict of interest: K. B. Leth-Møller has received lecture fees from 10.13039/100011033Thermo Fisher Scientific. M. van Hage has received lecture fees from 10.13039/100011033Thermo Fisher Scientific and 10.13039/100004325AstraZeneca outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest. Informed patient consent for publication: Signed informed consent was obtained from the patient., (© 2024 The Authors.)

Introduction: It is unknown whether late adolescents represent a particular risk group for the development of red meat hypersensitivity (RMH) and alpha-gal syndrome (AGS). This age group's physiological changes and eating habits could play a determining role. This study aimed to estimate the self-reported prevalence of RMH and probable AGS among late adolescents., Methods: A cross-sectional study analyzed a sample of 1992 Mexican adolescents between 15 and 18 years of age. The data were obtained with a previously validated questionnaire that asked about the clinical manifestations related to red meat intake. Confidence intervals at 95% (95% CI) were estimated for proportions., Results: In total, there were 19 adolescents with RMH, a prevalence of 1.0% (95% CI: 0.6-1.5%). The main red meats related to symptoms were pork (89.5%), beef (21.1%), lamb (10.5%), and mutton (5.1%). The most frequent manifestations of RMH were gastrointestinal (73.7%), respiratory (63.2%), and cutaneous (63.2%). Once the symptoms were grouped, there were two cases of urticaria (2/19, 10.5%) and six cases with probable anaphylaxis (6/19, 31.6%). Finally, three adolescents were considered probable cases of AGS, which represents a prevalence of 0.15% (95% CI: 0.1-0.4%)., Conclusion: Although the prevalence of RMH in late adolescents is low, early detection is justified because approximately one-third present with severe symptoms., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Bedolla-Barajas et al.)

The alpha-Gal Syndrome is a delayed meat allergy characterized by the presence of sIgE against α-Gal epitope. It is known that the α-Gal present in tick saliva induces the sensitization to this epitope ending in the production of sIgG and sIgE to α-Gal. It could be considered that the more times a person is bitten by tick species, the higher the probability of making the switch from sIgG to sIgE to α-Gal and developing allergy, but it is no clear when the switch occurs. To determine the likelihood that a subject bitten by ticks but without AGS be at risk of developing this allergy, we quantified the levels of sIgG to α-Gal by an automated system (ImmunoCap). To stablish a cut-off value for sIgG to α-Gal, a receiving operating curve (ROC) was constructed. The statistical analysis demonstrated that the risk of suffering AGS in individuals bitten by ticks was 35% when the sIgG to α-Gal was greater than or equal to 40 µg/mL. Our data indicate that the sIgG values against α-Gal could be used as a prognostic marker for developing mammalian meat allergy.

Alpha-gal allergy or syndrome is associated with production of IgE antibodies against the galactose-alpha-1,3-galactose allergen or alpha-gal. 1 Oligosaccharide is present on the surface of most mammalian cells. 1 The first alpha-gal antibodies were identified in patients who developed immediate-onset anaphylactic reactions to cetuximab. 1 The same antibodies were found in patients who developed delayed-onset anaphylaxis after consuming red meat. Delayed allergic reactions have also occurred in patients who received perioperative medications that contained inactive ingredients such as gelatin. 2 Anesthesia practitioners should increase their knowledge about alpha-gal allergy so that they can select and safely administer medications without triggering an allergic response. [ABSTRACT FROM AUTHOR]

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Development of specific IgE antibodies to the oligosaccharide galactose-α-1, 3-galactose (α-gal) following tick bites has been shown to be the source of red meat allergy. In this study, we investigated the presence of α-gal in four tick species: the lone-star tick (Amblyomma americanum), the Gulf-Coast tick (Amblyomma maculatum), the American dog tick (Dermacentor variabilis), and the black-legged tick (Ixodes scapularis) by using a combination of immunoproteomic approach and, carbohydrate analysis. Anti-α-gal antibodies identified α-gal in the salivary glands of both Am. americanum and Ix. scapularis, while Am. maculatum and De. variabilis appeared to lack the carbohydrate. PNGase F treatment confirmed the deglycosylation of N-linked α-gal-containing proteins in tick salivary glands. Immunolocalization of α-gal moieties to the salivary secretory vesicles of the salivary acini also confirmed the secretory nature of α-gal-containing antigens in ticks. Am. americanum ticks were fed on human blood (lacks α-gal) using a silicone membrane system to determine the source of the α-gal. N-linked glycan analysis revealed that Am. americanum and Ix. scapularis have α-gal in their saliva and salivary glands, but Am. maculatum contains no detectable quantity. Consistent with the glycan analysis, salivary samples from Am. americanum and Ix. scapularis stimulated activation of basophils primed with plasma from α-gal allergic subjects. Together, these data support the idea that bites from certain tick species may specifically create a risk for the development of α-gal-specific IgE and hypersensitivity reactions in humans. Alpha-Gal syndrome challenges the current food allergy paradigm and broadens opportunities for future research.

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.

The prevalence of food allergy is rising and is estimated to approach 10%. Red meat allergy is the first known food allergy elicited by immunoglobulin E (IgE) antibodies recognizing a carbohydrate. Due to the loss of function of the alpha-1,3-galactosyltransferase ( GGTA1) gene in humans, the disaccharide galactose-α-1,3-galactose (α-Gal) cannot be synthesized and therefore became immunogenic. IgE sensitization is elicited through the skin by repetitive tick bites transmitting α-Gal. The underlying mechanisms regarding innate and adaptive immune cell activation, including the B-cell isotype switch to IgE, are poorly understood, requiring further research and physiologically relevant animal models. Here, we describe a new animal model of red meat allergy using percutaneous α-Gal sensitization of gene-edited GGTA1 -deficient pigs. Total and α-Gal-specific IgG, IgG1, IgG2, IgG4, and IgE levels were tracked. Further key factors associated with allergic skin inflammation, type 2 immunity, and allergy development were measured in PBMCs and skin samples. Significant increases in α-Gal-specific IgG1 and IgE levels indicated successful sensitization to the allergen α-Gal. Intracutaneous sensitizations with α-Gal recruited lymphocytes to the skin, including elevated numbers of T helper 2 (Th2) cells. Finally, α-Gal-sensitized pigs not only recognized α-Gal as non-self-antigen following α-Gal exposure through the skin but also developed anaphylaxis upon antigen challenge. Based on the similarities between the porcine and human skin, this new large animal model for α-Gal allergy should help to unveil the consecutive steps of cutaneous sensitization and aid the development of prophylactic and treatment interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Hils, Fischer, Wölbing, Biedermann, Schnieke and Fischer.)

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.

A growing number of tick species have now been demonstrated to induce red meat allergies through biting humans. During the course of the bite, Galactose alpha-1,3-Galactose, commonly abbreviated as alpha-Gal, a carbohydrate not found in humans, but common in four-legged mammals, makes its way through to the bloodstream, triggering antibody production. Subsequent consumption of red meat by bite victims sets off a peculiarly delayed immunological reaction that may range from hives through to anaphylaxis. This paper documents the discovery of its linkage with tick bites. The spread of this syndrome worldwide warrants the attention of scientific and clinical librarians serving allergists, immunologists, dieticians, and entomologists. [ABSTRACT FROM AUTHOR]

Background: The oligosaccharide galactose‐α‐1,3‐galactose (α‐Gal), present in mammalian proteins and lipids, causes an unusual delayed allergic reaction 3 to 6 hours after ingestion of mammalian meat in individuals with IgE antibodies against α‐Gal. To better understand the delayed onset of allergic symptoms and investigate whether protein‐bound or lipid‐bound α‐Gal causes these symptoms, we analyzed the capacity of α‐Gal conjugated proteins and lipids to cross a monolayer of intestinal cells. Methods: Extracts of proteins and lipids from beef were prepared, subjected to in vitro digestions, and added to Caco‐2 cells grown on permeable supports. The presence of α‐Gal in the basolateral medium was investigated by immunoblotting, thin‐layer chromatography with immunostaining and ELISA, and its allergenic activity was analyzed in a basophil activation test. Results: After addition of beef proteins to the apical side of Caco‐2 cells, α‐Gal containing peptides were not detected in the basolateral medium. Those peptides that crossed the Caco‐2 monolayer did not activate basophils from an α‐Gal allergic patient. Instead, when Caco‐2 cells were incubated with lipids extracted from beef, α‐Gal was detected in the basolateral medium. Furthermore, these α‐Gal lipids were able to activate the basophils of an α‐Gal allergic patient in a dose‐dependent manner. Conclusion: Only α‐Gal bound to lipids, but not to proteins, is able to cross the intestinal monolayer and trigger an allergic reaction. This suggests that the slower digestion and absorption of lipids might be responsible for the unusual delayed allergic reactions in α‐Gal allergic patients and identifies glycolipids as potential allergenic molecules. [ABSTRACT FROM AUTHOR]