Genetic and structural basis of the human anti-α-galactosyl antibody response.

Humans lack the capacity to produce the Galα1-3Galß1-4GlcNAc (α-gal) glycan, and produce anti-α-gal antibodies upon exposure to the carbohydrate on a diverse set of immunogens, including commensal gut bacteria, malaria parasites, cetuximab, and tick proteins. Here we use X-ray crystallographic analysis of antibodies from α-gal knockout mice and humans in complex with the glycan to reveal a common binding motif, centered on a germline-encoded tryptophan residue at Kabat position 33 (W33) of the complementarity-determining region of the variable heavy chain (CDRH1). Immunoglobulin sequencing of anti-α-gal B cells in healthy humans and tick-induced mammalian meat anaphylaxis patients revealed preferential use of heavy chain germline IGHV3-7, encoding W33, among an otherwise highly polyclonal antibody response. Antigen binding was critically dependent on the presence of the germline-encoded W33 residue for all of the analyzed antibodies; moreover, introduction of the W33 motif into naive IGHV3-23 antibody phage libraries enabled the rapid selection of α-gal binders. Our results outline structural and genetic factors that shape the human anti-α-galactosyl antibody response, and provide a framework for future therapeutics development.

IgE and anaphylaxis specific to the carbohydrate alpha-gal depend on IL-4.

BACKGROUND: Alpha-gal (Galα1-3Galß1-4GlcNAc) 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. OBJECTIVE: We aimed to establish a mouse model of alpha-gal allergy for in-depth immunologic analyses. METHODS: 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. RESULTS: Alpha-gal-sensitized mice displayed increased levels of alpha-gal-specific IgE and IgG1 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 IgG1 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. CONCLUSION: These findings establish IL-4 as a potential target to interfere with alpha-gal allergy elicited by tick bites.

Tick bites, IgE to galactose-alpha-1,3-galactose and urticarial or anaphylactic reactions to mammalian meat: The alpha-gal syndrome.

The recent recognition of a syndrome of tick-acquired mammalian meat allergy has transformed the previously held view that mammalian meat is an uncommon allergen. The syndrome, mediated by IgE antibodies against the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal), can also involve reactions to visceral organs, dairy, gelatin and other products, including medications sourced from non-primate mammals. Thus, fittingly, this allergic disorder is now called the alpha-gal syndrome (AGS). The syndrome is strikingly regional, reflecting the important role of tick bites in sensitization, and is more common in demographic groups at risk of tick exposure. Reactions in AGS are delayed, often by 2-6 h after ingestion of mammalian meat. In addition to classic allergic symptomatology such as urticaria and anaphylaxis, AGS is increasingly recognized as a cause of isolated gastrointestinal morbidity and alpha-gal sensitization has also been linked with cardiovascular disease. The unusual link with tick bites may be explained by the fact that allergic cells and mediators are mobilized to the site of tick bites and play a role in resistance against ticks and tick-borne infections. IgE directed to alpha-gal is likely an incidental consequence of what is otherwise an adaptive immune strategy for host defense against endo- and ectoparasites, including ticks.

Increasing prevalence of galactose-α-1,3-galactose sensitization in the Danish general adult population.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Alpha-Gal, epitope responsible for allergy to red meat, in the Mediterranean tick Hyalomma lusitanicum.

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.

Tick bite induced α-gal syndrome highlights anticancer effect of allergy.

Tick bite induced α-gal syndrome (AGS) following consumption of mammalian meat is a recently described intriguing disease occurring worldwide. Here we argue that AGS and delayed allergy in general is an adaptive defence method against cancer. Our hypothesis synthesizes two lines of supporting evidence. First, allergy has been shown to have direct anti-cancer effects with unknown mechanism. Second, eating processed meat was shown to be linked to developing cancer. Humans lost their genes encoding molecules α-gal 30 MYA and Neu5Gc 2 MYA, the latter co-occurring with the start of using fire. These molecules are acquired from external sources, as tick bite for α-gal and mammalian meat for Neu5Gc, the latter accumulating in tumors. The resulting specific delayed allergic response is a molecular adaptation to fight cancer. By further testing and applying our hypothesis, new avenues in cancer research and therapy will open that might save lives and decrease human suffering.

Alpha-gal syndrome: when treatment of hypovolemic shock can lead to anaphylaxis.

Delayed anaphylaxis after ingestion of red meat because of galactose-alpha-1,3-galactose (alpha-gal) syndrome has increased in recent years. The mechanism involves an immunoglobulin E reaction to alpha-gal, a molecule found in mammalian meat, dairy products, medications and excipients containing mammalian-derived components, and tick salivary glycans. Sensitization occurs due to the bite of a lone star tick and the transmission of alpha-gal molecules into person's bloodstream. We describe a case of alpha-gal syndrome with severe food, drug, and perioperative allergy in which anaphylaxis with hypovolemic shock occurred immediately after an emergency surgical procedure, when a gelatin-containing drug was injected. This case study confirms that the clinical manifestations of alpha-gal syndrome could be different depending on the route of administration, with immediate reactions if an alpha-gal-containing drug is injected and delayed type allergic manifestations occurring several hours after oral intake. The purpose of this report is to highlight the importance of risk communication in case of exposure to medical products and surgical procedures of patients with alpha-gal syndrome and to encourage drug manufacturers to indicate clearly the origin of excipients in product literature.

[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.

Clinical and laboratory features of patients diagnosed with alpha-gal syndrome-2010-2019.

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.

Alpha-gal syndrome: A review for the dermatologist.

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.

Food Allergies and Alpha-gal Syndrome for the Gastroenterologist.

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. Alpha-gal syndrome can cause a delayed allergic response that is increasingly recognized worldwide, including among patients with predominant GI symptoms.

Ascaris lumbricoides and ticks associated with sensitization to galactose α1,3-galactose and elicitation of the alpha-gal syndrome.

BACKGROUND: IgE to galactose alpha-1,3 galactose (alpha-gal) causes alpha-gal syndrome (delayed anaphylaxis after ingestion of mammalian meat). Development of sensitization has been attributed to tick bites; however, the possible role of other parasites has not been well studied. OBJECTIVE: Our aims were to assess the presence, relative abundances, and site of localization of alpha-gal-containing proteins in common ectoparasites and endoparasites endemic in an area of high prevalence of alpha-gal syndrome, as well as to investigate the ability of ascaris antigens to elicit a reaction in a humanized rat basophil in vitro sensitization model. METHODS: Levels of total IgE, Ascaris-specific IgE, and alpha-gal IgE were measured in sera from patients with challenge-proven alpha-gal syndrome and from controls without allergy. The presence, concentration, and localization of alpha-gal in parasites were assessed by ELISA, Western blotting, and immunohistochemistry. The ability of Ascaris lumbricoides antigen to elicit IgE-dependent reactivity was demonstrated by using the RS-ATL8 basophil reporter system. RESULTS: Alpha-gal IgE level correlated with A lumbricoides-specific IgE level. Alpha-gal protein at 70 to 130 kDa was detected in A lumbricoides at concentrations higher than those found in Rhipicephalus evertsi and Amblyomma hebraeum ticks. Immunohistochemistry was used to localize alpha-gal in tick salivary acini and the helminth gut. Non-alpha-gal-containing A lumbricoides antigens activated RS-ATL8 basophils primed with serum from subjects with alpha-gal syndrome. CONCLUSION: We demonstrated the presence, relative abundances, and site of localization of alpha-gal-containing proteins in parasites. The activation of RS-ATL8 IgE reporter cells primed with serum from subjects with alpha-gal syndrome on exposure to non-alpha-gal-containing A lumbricoides proteins indicates a possible role of exposure to A lumbricoides in alpha-gal sensitization and clinical reactivity.

α-Gal present on both glycolipids and glycoproteins contributes to immune response in meat-allergic patients.

BACKGROUND: The α-Gal syndrome is associated with the presence of IgE directed to the carbohydrate galactose-α-1,3-galactose (α-Gal) and is characterized by a delayed allergic reaction occurring 2 to 6 hours after ingestion of mammalian meat. On the basis of their slow digestion and processing kinetics, α-Gal-carrying glycolipids have been proposed as the main trigger of the delayed reaction. OBJECTIVE: We analyzed and compared the in vitro allergenicity of α-Gal-carrying glycoproteins and glycolipids from natural food sources. METHODS: Proteins and lipids were extracted from pork kidney (PK), beef, and chicken. Glycolipids were purified from rabbit erythrocytes. The presence of α-Gal and IgE binding of α-Gal-allergic patient sera (n = 39) was assessed by thin-layer chromatography as well as by direct and inhibition enzyme-linked immunosorbent assay. The in vitro allergenicity of glycoproteins and glycolipids from different meat extracts was determined by basophil activation test. Glycoprotein stability was evaluated by simulated gastric and intestinal digestion assays. RESULTS: α-Gal was detected on glycolipids of PK and beef. Patient IgE antibodies recognized α-Gal bound to glycoproteins and glycolipids, although binding to glycoproteins was more potent. Rabbit glycolipids were able to strongly activate patient basophils, whereas lipid extracts from PK and beef were also found to trigger basophil activation, but at a lower capacity compared to the respective protein extracts. Simulated gastric digestion assays of PK showed a high stability of α-Gal-carrying proteins in PK. CONCLUSION: Both α-Gal-carrying glycoproteins and glycolipids are able to strongly activate patient basophils. In PK and beef, α-Gal epitopes seem to be less abundant on glycolipids than on glycoproteins, suggesting a major role of glycoproteins in delayed anaphylaxis upon consumption of these food sources.

α-Gal specific-IgE prevalence and levels in Ecuador and Kenya: Relation to diet, parasites, and IgG4.

BACKGROUND: IgE to α-Gal is a cause of mammalian meat allergy and has been linked to tick bites in North America, Australia, and Eurasia. Reports from the developing world indicate that α-Gal sensitization is prevalent but has been little investigated. OBJECTIVE: We sought evidence for the cause(s) of α-Gal sensitization and lack of reported meat allergy among children in less developed settings in Ecuador and Kenya. METHODS: IgE to α-Gal and total IgE were assessed in children from Ecuador (n = 599) and Kenya (n = 254) and compared with children with (n = 42) and without known (n = 63) mammalian meat allergy from the southeastern United States. Information on diet, potential risk factors, and helminth infections was available for children from Ecuador. IgG4 to α-Gal and antibodies to regionally representative parasites were assessed in a subset of children. RESULTS: In Ecuador (32%) and Kenya (54%), α-Gal specific IgE was prevalent, but levels were lower than in children with meat allergy from the United States. Sensitization was associated with rural living, antibody markers of Ascaris exposure, and total IgE, but not active infections with Ascaris or Trichuris species. In Ecuador, 87.5% reported consuming beef at least once per week, including 83.9% of those who had α-Gal specific IgE. Levels of α-Gal specific IgG4 were not high in Ecuador, but were greater than in children from the United States. CONCLUSIONS: These results suggest that in areas of the developing world with endemic parasitism, α-Gal sensitization is (1) common, (2) associated with Ascaris exposure, and (3) distinguished by a low percentage of specific/total IgE compared with individuals with meat allergy in the United States.

A dynamic relationship between two regional causes of IgE-mediated anaphylaxis: α-Gal syndrome and imported fire ant.

BACKGROUND: A syndrome of mammalian meat allergy relating to IgE specific for galactose-α-1,3-galactose (α-Gal) was first reported 10 years ago in the southeastern United States and has been related to bites of the lone star tick (Amblyomma americanum). OBJECTIVE: Here we investigated the epidemiology of the "α-Gal syndrome" in the United States and sought additional evidence for the connection to tick bites. METHODS: A survey of allergists was conducted by using a snowball approach. A second tier of the survey included questions about anaphylaxis to imported fire ants (IFAs). History of tick bites and tick-related febrile illness were assessed as part of a case-control study in Virginia. Antibody assays were conducted on sera from subjects reporting allergic reactions to mammalian meat or IFA. RESULTS: In North America the α-Gal syndrome is recognized across the Southeast, Midwest, and Atlantic Coast, with many providers in this area managing more than 100 patients each. The distribution of cases generally conformed to the reported range of A americanum, although within this range there was an inverse relationship between α-Gal cases and cases of IFA anaphylaxis that were closely related to the territory of IFA. The connection between tick bites and α-Gal sensitization was further supported by patients' responses to a questionnaire and the results of serologic tests. CONCLUSIONS: The α-Gal syndrome is commonly acquired in adulthood as a consequence of tick bites and has a regional distribution that largely conforms to the territory of the lone star tick. The epidemiology of the syndrome is expected to be dynamic and shifting north because of climate change and ecologic competition from IFA.

Unusual and Unexpected Allergic Reactions Can Be Unraveled by Molecular Allergy Diagnostics.

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.

On the cause and consequences of IgE to galactose-α-1,3-galactose: A report from the National Institute of Allergy and Infectious Diseases Workshop on Understanding IgE-Mediated Mammalian Meat Allergy.

The mammalian meat allergy known as the "α-Gal syndrome" relates to IgE specific for galactose-α-1,3-galactose (α-Gal), an oligosaccharide that is present in cells and tissues of nonprimate mammals. The recognition of delayed reactions to food derived from mammals in patients with IgE to α-Gal and also the association with tick bites have been increasing worldwide. In 2018, the National Institute of Allergy and Infectious Diseases, Division of Allergy, Immunology and Transplantation, sponsored a workshop on this emerging tick-related disease. International experts from the fields of tick biology, allergy, immunology, infectious disease, and dermatology discussed the current state of our understanding of this emerging medical condition. The participants provided suggestions for specific research priorities and for the development of resources to advance our knowledge of the mechanisms, diagnosis, management, and prevention of this allergic disease. This publication is a summary of the workshop and the panel's recommendations are presented herein.

Gal d 7-a major allergen in primary chicken meat allergy.

BACKGROUND: Poultry meat can induce severe allergic reactions. So far, the molecules causing poultry meat allergy are largely unknown. OBJECTIVE: Our aim was to identify and characterize poultry meat allergens. METHODS: Profiles of patients' IgE reactivity to chicken muscle were analyzed in immunoblots, and proteins recognized by the majority of patients were subjected to peptide mass fingerprinting. A 23-kDa IgE-reactive protein was identified as myosin light chain 1, designated Gallus domesticus 7 (Gal d 7). Recombinant Gal d 7 was produced in Escherichia coli. The protein's IgE reactivity was analyzed in ELISA experiments, and cross-reactivity with allergens of other poultry species was assessed in inhibition immunoblots. Fold and thermal stability were evaluated by circular dichroism analysis, and enzymatic stability was investigated using in vitro gastrointestinal digestion assays. RESULTS: Recombinant Gal d 7 represents a properly folded, predominantly α-helical protein and displays IgE-binding activity comparable to that of its natural counterpart. IgE reactivity analysis in 28 patients allergic to chicken meat revealed that Gal d 7 is a major allergen for patients primarily sensitized to chicken meat. Furthermore, Gal d 7-cross-reactive allergens were also detected in other poultry species, suggesting that recombinant Gal d 7 can be used as a diagnostic marker allergen for poultry meat allergy. The high thermal stability, refolding capacity, and resistance to gastrointestinal enzymes might explain why Gal d 7 can act as a potent sensitizing agent. CONCLUSION: Gal d 7 represents a novel major chicken meat allergen. Recombinant Gal d 7 could be used for diagnosis of genuine poultry meat sensitization.

T and B Lymphocyte Transcriptional States Differentiate between Sensitized and Unsensitized Individuals in Alpha-Gal Syndrome.

The mechanisms of pathogenesis driving alpha-gal syndrome (AGS) are not fully understood. Differences in immune gene expression between AGS individuals and non-allergic controls may illuminate molecular pathways and targets critical for AGS development. We performed immune expression profiling with RNA from the peripheral blood mononuclear cells (PBMCs) of seven controls, 15 AGS participants, and two participants sensitized but not allergic to alpha-gal using the NanoString nCounter PanCancer immune profiling panel, which includes 770 genes from 14 different cell types. The top differentially expressed genes (DEG) between AGS subjects and controls included transcription factors regulating immune gene expression, such as the NFκB pathway (NFKBIA, NFKB2, REL), antigen presentation molecules, type 2/allergic immune responses, itch, and allergic dermatitis. The differential expression of genes linked to T and B cell function was also identified, including transcription factor BCL-6, markers of antigen experience (CD44) and memory (CD27), chemokine receptors (CXCR3, CXCR6), and regulators of B-cell proliferation, cell cycle entry and immunoglobulin production (CD70). The PBMCs from AGS subjects also had increased TNF and IFN-gamma mRNA expression compared to controls. AGS is associated with a distinct gene expression profile in circulating PBMCs. DEGs related to antigen presentation, antigen-experienced T-cells, and type 2 immune responses may promote the development of alpha-gal specific IgE and the maintenance of AGS.

Galactose-α-1,3-galactose (alpha-gal) allergy: first pediatric case in a series of patients in Spain.

INTRODUCTION AND OBJECTIVES: Allergy to galactose-α-1,3-galactose (alpha-gal) is a peculiar form of food allergy generally manifesting as an anaphylactic reaction hours after mammalian meat consumption, due to the presence of specific IgE against this oligosaccharide. In addition, immediate anaphylaxis may develop after exposure to other sources of alpha-gal, such as monoclonal antibody cetuximab, vaccines, plasma expanders or anti-snake venoms. Sensitization to alpha-gal has also been implicated in the rapid degeneration of biological valve implants, and recognized as a cause of occupational disease in cattle raisers. The implication of tick bites in this type of sensitization has been accepted by all the research groups dedicated to this disease. PATIENTS AND METHOD: The present study describes the clinical and sensitization characteristics of 39 patients diagnosed with alpha-gal allergy in the hospitals of our province (Lugo, Monforte de Lemos and Burela, Spain). RESULTS: Most patients were middle-age males. Of note, is the fact that the series includes the first pediatric patient reported in Spain to date. The predominant clinical manifestations were urticaria or delayed anaphylaxis after consumption of mammalian meat. Seventy-four percent of the patients reported having suffered a previous tick bite, and the clinical presentation of anaphylaxis was significantly more prevalent in those with a persistent local reaction following the bite than in those with no such reaction (p = 0.032). CONCLUSIONS: A review is also made of the disorder which, due to its variable clinical expression, is referred to as alpha-gal syndrome. The study concludes that a diagnosis of alpha-gal allergy should be considered in patients with urticaria-anaphylaxis of uncertain origin or manifesting after the administration of vaccines or products of bovine/porcine origin.