Alpha-gal syndrome (AGS) is an emerging, noninfectious tickborne disease characterized by an allergic reaction to galactose-α-1,3-galactose (alpha-gal), an oligosaccharide found in red (mammalian) meat and other mammalian products such as dairy and gelatin. As of 2022, AGS was estimated to affect up to 450,000 persons in the United States (1). Anaphylactic AGS reactions can be fatal, and AGS allergic reactions encompass a range of symptoms including urticaria, angioedema, wheezing, and gastrointestinal distress. AGS is primarily managed through an avoidance diet. The U.S. geographic distribution of AGS is closely associated with the range of the lone star tick (Amblyomma americanum); bites from this tick introduce alpha-gal through its saliva, which can trigger the allergy. Diagnosis of AGS requires both the presence of clinically compatible symptoms and the detection of serologic immunoglobulin E (IgE) antibodies against alpha-gal. Persons can have alpha-gal-specific IgE antibodies without clinical symptoms. The proportion of persons in the United States who are seropositive for alpha-gal IgE is unknown. To better understand the distribution and seroprevalence of alpha-gal IgE among U.S. adults, 3,000 serum samples collected during November 2024-April 2025 from blood donors living in 10 states were tested for the presence of alpha-gal IgE antibodies. States previously reported to have high numbers of suspected AGS cases were found to have correspondingly high seroprevalences. Among the 10 states, the highest estimated seroprevalences among persons aged ≥16 years were detected in Arkansas (31.2%) and Missouri (26.0%). These findings can guide the development of surveillance systems for AGS and help identify regions at increased risk.

Alpha-gal Syndrome (AGS) is a potentially life-threatening allergy caused by an IgE-mediated immune response to galactose-α-1,3-galactose (alpha-gal), a carbohydrate epitope present in most mammalian meats. Currently, strict avoidance of mammalian meat remains the primary management strategy for affected individuals, and alpha-gal-free beef is not commercially available. Here, we leverage cultivated meat as a biotechnology platform to address this unmet clinical need by engineering alpha-gal-free bovine muscle cells. Using CRISPR/Cas9 genome editing, we disrupted GGTA1, the gene encoding α1,3-galactosyltransferase, in immortalized bovine satellite cells (iBSCs). High-efficiency editing produced clonal GGTA1 knockout iBSCs harboring a homozygous frameshift mutation. Flow cytometry and immunofluorescence confirmed loss of the alpha-gal epitope, while bulk RNA-seq indicated minimal disruption of global gene expression and preserved myogenic differentiation capacity. Importantly, lysates from GGTA1 knockout iBSCs elicited substantially reduced basophil activation in assays using plasma from a patient with AGS, indicating reduced basophil activation consistent with reduced allergenic potential. Together, these findings establish a proof of concept for engineering AGS-compatible cultivated meat and demonstrate the potential of cultivated meat technologies to address human health challenges.

Alpha-gal syndrome (AGS) is a tick-associated, IgE-mediated allergy to galactose-α-1,3-galactose (alpha-gal), an oligosaccharide found on non-primate mammalian cells expressed by various bacteria and parasites, including ticks. First identified in 2009, cases are primarily associated with tick bites, which can sensitize the human immune system to alpha-gal. Subsequent exposure to alpha-gal, typically through red meat consumption, can cause severe allergic reactions, including hives, angioedema, gastrointestinal distress, and life-threatening anaphylaxis. Alpha-gal syndrome is a global phenomenon, with cases reported on six continents. In North America, AGS is most prevalent in the Southern, Central, and Eastern regions of the USA with regional pockets of higher prevalence. The number of reported cases has steadily increased owing to improved awareness, diagnostics, and the expanding range of Amblyomma americanum (L., 1758), the primary tick associated with the incidence of AGS. Alpha-gal syndrome remains underdiagnosed because of low provider and public awareness, cross-disciplinary disconnects, and the atypical clinical presentation. Although the link between tick bites and AGS is well established, critical questions remain. Why do ticks trigger this reaction among the many organisms that express alpha-gal? What has caused the rapid increase in cases and why do only some individuals develop an allergic immune response? This scoping review explores the history of alpha-gal and AGS, the role of multiple tick species and other parasites, AGS etiology and pathogenesis, and the ecological-epidemiological landscape of this emerging tick-associated allergy.

BACKGROUND:In alpha-gal syndrome (AGS), IgE antibodies form against the glycan galactose-α-1,3-galactose (alpha-gal) in mammal products rather than food proteins. Alpha-gal glycolipids and glycoproteins activate human basophils sensitized with AGS plasma in an IgE-dependent fashion. However, it is unknown whether alpha-gal specific IgE (sIgE), independent of other blood proteins, is sufficient for mediating basophil and mast cell activation. OBJECTIVE:We sought to determine whether alpha-gal antigens could activate passively sensitized rat basophilic leukemia (RBL) SX-38 cells, which express human IgE receptors and are commonly used to model allergen/IgE-mediated mast cell activation in food protein allergy. METHODS:Using the clustered regularly interspaced short palindromic repeats technology, we created a novel, alpha-gal-deficient RBL cell line, alpha-gal knockout RBL SX-38, passively sensitizing cells with sera from AGS donors or with novel alpha-gal sIgE clones, and then stimulated with alpha-gal glycoproteins. To assess effector cell activation, we measured cell surface expression of activation marker CD63 by flow cytometry and mediator release through β-hexosaminidase release assays. RESULTS:After alpha-gal antigen stimulation, the percentage of CD63+ alpha-gal knockout RBL SX-38 cells sensitized with AGS sera increased 3-fold compared with cells sensitized with control serum. Select human AGS IgE clones facilitated alpha-gal antigen-dependent and antigen-independent CD63 upregulation. Cells sensitized with pooled AGS sera released β-hexosaminidase in an alpha-gal-independent fashion. We saw no β-hexosaminidase release above background in cells sensitized with alpha-gal sIgE clones. CONCLUSIONS:Certain alpha-gal-specific human IgE clones may partially activate allergic effector cells independent of antigen, potentially lowering thresholds for subsequent alpha-gal-induced or antigen-independent allergic effector cell degranulation. This may affect duration and severity of allergic symptoms in patients with AGS.

Allergen-specific monoclonal antibodies (mAbs) that block IgE binding to allergens are emerging as new therapeutics for treating allergies to pollen, peanuts, and cats. Alpha-Gal syndrome (AGS) is an allergy to galactose-α-1,3-Galactose (α-Gal), which is present in mammalian meat and tissue-derived products. Initially aiming to identify mAbs targeting α-Gal on malaria parasites, we isolated 42 α-Gal-specific mAbs from B cells of individuals who had been exposed to malaria but found that they bound weakly to the Plasmodium falciparum parasite. These mAbs predominantly used the IGHV3 gene family and had a wide range of mutation frequencies. We then screened these mAbs for their ability to bind α-Gal on AGS allergens and to block the binding of serum IgE of patients with AGS to AGS allergens. Thirteen mAbs bound to the AGS allergens angiotensin-I-converting enzyme (ACE), aminopeptidase-N (AP-N), and cetuximab, and 2 mAbs- AG028 as both IgA2 and IgM, and AG050 IgA1 - blocked the binding of serum IgE from patients with AGS to ACE and AP-N. Additionally, AG028 IgA2 and AG028 IgM suppressed ACE-mediated activation of basophils sensitized with serum of patients with AGS. This study supports the development of α-Gal-specific mAbs as a new intervention to prevent α-Gal allergy.

In the United States, alpha-gal syndrome (AGS) is primarily associated with lone star tick (Amblyomma americanum) bites. We describe AGS onset after an Ixodes scapularis tick bite and present AGS surveillance in Maine, 2014-2023. US health and public health professionals should be aware of AGS outside the established lone star tick range.

IntroductionAlpha-gal syndrome (AGS) is an IgE-mediated allergy to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Alpha-gal is found in the tissues of non-catarrhine mammals, and the characteristic delayed reactions are caused by the consumption of red meat, visceral organs, dairy, gelatin, and other products, including medications sourced from non-primate mammals. Although the syndrome is not nationally notifiable, it is estimated that 450,000 cases exist, making AGS the tenth-most common food allergy in the US. The syndrome is profoundly influenced by geographic locale, reflecting the important role of tick bites in sensitization. However, the specific immune cells, their interactions, and the downstream signaling cascades triggered by tick bites are not well understood. To address this gap, we conducted a comprehensive study to analyze the immune cells in the blood of AGS subjects compared to those of healthy controls.MethodsPeripheral blood mononuclear cell preparations were enriched for B cells from the same patient and sequentially labeled with sample tags and BD AbSeq oligo-conjugated antibodies. Sequencing libraries were prepared to targeted mRNA, antibody-oligonucleotides, and sample tags from AGS and control subjects. Multimodal analysis of both transcriptomes and surface marker expression of immune cells at the single-cell level was used to profile the immune response in AGS.ResultsSeveral clusters of cells were unique to AGS subjects, including natural killer B (NKB) cells, natural killer T (NKT) cells and most notably, a circulating mast cell progenitor population. In addition, subjects with AGS had increased expression of several genes involved in immunomodulation and type 2 immunity. Although rare, we identified and characterized alpha-gal-specific memory B cells and alpha-gal-specific IgE-secreting cells. Our findings also revealed the presence of IgE-secreting transcripts, along with other classes of immunoglobulins (Ig), in a single cell, suggesting a unique pattern of Ig gene arrangements and class switching in B cells.ConclusionsTick bites appear to induce a population of circulating mast cell progenitors and innate-like cells, such as NKT and NKB cells, that may play a critical role in sensitization to alpha-gal. Furthermore, alpha-gal-specific IgE is secreted by a heterogeneous population of B cells, including CCR6-proficient B cells and CCR6-deficient plasmablast/plasma cells.

BACKGROUND:The bites of certain tick species can induce galactose-α-1,3-galactose (alpha-gal) IgE formation. Individuals with alpha-gal IgE can become allergic to meat, a condition termed alpha-gal syndrome. Alpha-gal is structurally related to B antigen. Recent case reports (Gilstad et al., 2023 and Miller et al., 2024) suggest that transfusing group B plasma or platelets to group O individuals with alpha-gal IgE can trigger severe allergic transfusion reactions. However, mechanistic evidence is lacking. STUDY DESIGN AND METHODS:A 76-year-old group O man undergoing heart surgery became profoundly hypotensive after receiving 50 mL of a group B platelet unit. He recovered with diphenhydramine treatment. We investigated potential causes of anaphylaxis (alpha-gal syndrome; IgA deficiency; protamine, and rocuronium allergies). The platelet unit and patient samples were analyzed by flow cytometry. Indirect basophil activation tests (iBATs) were performed on the patient's plasma. RESULTS:The patient's serum tryptase level spiked, consistent with anaphylaxis. His serum tested positive for alpha-gal IgE (1.49 kU/L). Flow cytometric analyses demonstrated that: (1) the transfused platelets expressed substantial B antigen, and (2) the patient's plasma contained IgE-recognizing alpha-gal and B antigen > A antigen. In iBATs, resting allogeneic basophils incubated with the patient's plasma showed equivalent (albeit weak) activation when stimulated with either alpha-gal or B antigen. DISCUSSION:We report a case of anaphylactic shock in an O patient transfused with a B platelet unit. The in vitro data suggest, but do not prove, that the reaction was mediated by recipient alpha-gal IgE. Further studies are needed to establish whether transfusion-related alpha-gal syndrome ("TRAGS") is a true clinical entity.

Abstract Background The trend of human tick-borne disease (TBD) incidence has increased exponentially over the past two decades. Limited healthcare access, substandard housing, socioeconomic fragility, and absence of government-backed tick control initiatives significantly contribute to the high disease burdens nationwide. Given the wide prevalence of socioeconomic and health inequalities in the USA, the risk of TBDs often goes undetected in impoverished and minority communities. Alpha-gal syndrome (AGS) is one TBD that is often overrepresented in white, middle-income individuals, and little information on the incidence in populations of Color exists. Therefore, the current study aims to estimate the seroprevalence and exposure-associated risk factors of AGS among vulnerable populations in South Carolina. Methods First, a five-year retrospective clinical chart abstraction of AGS patients within a large healthcare system covering half of South Carolina was completed to characterize the clinical burden and natural history of AGS. Next, banked serum samples and associated surveys from a cross-sectional minority-represented COVID-19 study were analyzed for AGS seropositivity. Results Fifty patients with positive AGS IgE labs were identified via retrospective chart review. Of these, the majority were male (70%), covered by Medicare (84%), and had a history of tick bites or spent extended periods outdoors (46%). The cross-sectional AGS seroprevalence study detected 3.5% seropositivity among 753 serum samples. Risk factors associated with a positive titer included being male (58%), and regularly spending time outdoors (58%). Notably, the seroprevalence cohort consisted of primarily Black residents and individuals who live below the poverty line. Conclusion These findings highlight the growing issue of TBDs, namely AGS, among minority populations in South Carolina, urging healthcare providers to be more informed. Disclosures All Authors: No reported disclosures

This case series investigates trends in time from onset of alpha-gal syndrome to diagnosis among patients with disease onset from 1977 to 2019.

Alpha-gal syndrome (AGS), commonly referred to as the tick bite red meat allergy, has been reported worldwide with the number of suspected cases in the United States increasing from 24 in 2009 to over 34,000 in 2019. Within the US, AGS is associated with the bite of two tick species, Amblyomma americanum and Ixodes scapularis , and has particularly high incidence rates in the mid-Atlantic region. Because AGS is associated with tick bites, the risk of developing AGS is affected by the environment individuals visit. Despite this, as well as the numerous studies associating the environment with Am. americanum , no work to-date has evaluated AGS risk factors associated with the surrounding landscape. We test the hypothesis that AGS risk is associated with habitat fragmentation typically seen in areas classified as open space and low intensity development that are suitable for human-tick interactions, using a combination of generalized linear modeling (GLM), boosted regression trees (BRT), and Maximum Entropy (MaxEnt). We qualitatively compare results from the models, as well as their predictions within the mid-Atlantic region. We found that models mostly agree when determining important environmental variables, with open space development and population density being highly predictive across all models. BRT and GLM predicted a strong east to west gradient of risk across the mid-Atlantic, which largely mirrors the environmental transition from mountains to coastal plains. MaxEnt predicted a much patchier distribution across the region with no discernable patterns. These results provide evidence that AGS is associated with land uses that are associated with habitat fragmentation, the preferred habitat of Am. americanum . This information can be used to inform future education programs aimed at reducing AGS incidence in the region.

We describe a case of alpha-gal syndrome (AGS) in a resident of Washington, USA, after local Ixodes pacificus tick bites, which were associated with IgE increases after diagnosis. AGS should be considered a potential cause of anaphylactic and allergic reactions in persons with tick exposures, regardless of geographic residence.

The lone star tick is associated with development of elevated IgE to galactose-alpha-1,3-galactose (alpha-gal), which can cause delayed-onset allergy to mammalian meat. While the lone star tick is endemic in North Carolina and South Carolina, we explore why there are fewer suspected cases of Alpha-gal syndrome (AGS) in South Carolina.

Alpha-gal syndrome (AGS) is a delayed allergic response to red meat caused by the production of alpha-gal-specific IgE following certain tick bites. We have recently reported the presence of α-gal in the saliva of Amblyomma americanum (Aa) but not in Amblyomma maculatum (Am). We designed this study to characterize the underlying immune response to tick bites associated with AGS.

IntroductionAlpha-Gal Syndrome (AGS) is a delayed allergic reaction due to specific IgE antibodies targeting galactose-α-1,3-galactose (α-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 α-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.MethodsLone-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 to mRNA gene expression analysis to assess the host immune response. Antibody responses in sensitized mice were also determined.ResultsOur results showed a significant increase in the total IgE, IgG1, and α-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 α-gal antigen.ConclusionThis study supports the hypothesis that specific tick species may increase the risk of developing α-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.

Background:Alpha-gal syndrome from tick bites, due to sensitivity to alpha-gal, can cause severe allergies. Heart valve implants contain alpha-gal, yet alpha-gal syndrome screening is not standard before valve replacement. This study examines perioperative outcomes in patients with alpha-gal antibodies. Methods:This is a single-institution prospective cohort study of patients undergoing bioprosthetic aortic valve replacement between January 2022 and January 2023. Anti-alpha-gal immunoglobulin E levels were measured, with primary outcomes being severe allergic reactions and in-hospital mortality, and secondary outcomes including intensive care unit and hospital stay. Results:Of 155 patients, 32.7% (n = 19) of surgical aortic valve replacement and 29.9% (n = 29) of transcatheter aortic valve replacement patients had detectable immunoglobulin E levels without subsequent serious allergic reactions or in-hospital mortality. Postoperative hospital stay and valve function were similar across groups. Conclusions:In this study, sensitization to alpha-gal was not associated with serious allergic reactions and did not affect immediate aortic valve function after surgical aortic valve replacement or transcatheter aortic valve replacement.

Polyethylene glycol (PEG) is frequently used in various protein and nanomedicine therapeutics. However, various studies have shown that select PEGylated therapeutics can induce production of anti-PEG antibodies (APA), potentially culminating in rapid clearance from the systemic circulation, loss of efficacy and possibly increased risks of allergic reactions. Although IgE is a frequent cause of immediate hypersensitivity reactions (IHR), the role of IgE APA in PEG-related IHR is not well understood, due in part to a lack of standardized assays for measuring IgE APA. Here, we developed a rigorous competitive ELISA method to measure the concentrations of various APA isotypes, including IgE, with picomolar sensitivities. In a small number of serum samples from patients with known PEG allergy, the assay allowed us to detect a strong correlation between IgG and IgE APA in individuals with history of allergic reactions to PEG or PEGylated drugs, but not between IgM and IgE APA. We detected appreciable levels of IgG and IgM APA in individuals with history of alpha-gal allergy, however, they were not elevated relative to those detected in other healthy controls, and we found no pre-existing IgE APA. While preliminary and should be further investigated, these results suggest that differences in the route and mechanism of PEG exposure may drive variability in APA response.