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The disaccharide galactose-α-1,3-galactose (alpha-gal) is expressed in mammals other than humans, apes, and old-world monkeys. In humans, elevated immunoglobulin-E (IgE) antibodies specific for alpha-gal can result in allergic hypersensitivity known as alpha-gal syndrome (AGS). Case reports and series suggest that tick bites can induce alpha-gal specific IgE antibodies.Evaluate tick exposure as a risk factor for AGS and elevated alpha-gal specific IgE (sIgE).We conducted a case-control study comparing AGS patients from a North Carolina allergy clinic with controls who were patients at a nearby internal medicine clinic. Cases and controls were administered a questionnaire to obtain information about demographics, home environment, outdoor activities, and recollection of tick bite. Serum samples taken at the time of enrollment were tested for total IgE, alpha-gal sIgE, and antibodies to other tickborne pathogens.AGS patients were more likely to recall finding a tick on themselves (OR=11.20, 95% CI 4.97-25.15), live near wooded forest (OR=2.27, 95% CI 0.92-5.55), and spend 17 or more hours per week outdoors in wooded areas (OR=5.58, 95% CI 2.56-12.19). AGS patients were also more likely to report 4 or more tick bites (OR=33.05, 95% CI 9.92-155.12) and reactions at the site of tick bites (OR=7.93, 95% CI 3.74-16.80). Elevated alpha-gal sIgE was also observed in 33% of controls and was also associated with tick exposure in the controls (OR=4.25, 95% CI 2.21-8.18).The results define tick bite as a risk factor for AGS and elevated alpha-gal sIgE.

Background Alpha-gal syndrome (AGS) is a recently described allergy to galactose-α-1,3-galactose, an oligosaccharide present in mammalian meat. AGS can present with angioedema, urticaria, and anaphylaxis arising 3–6 hours after ingestion, although symptoms such as gastrointestinal distress, fatigue, and arthralgias are also reported. Because AGS appears to be associated with tick bites, patients may present to infectious diseases (ID) clinics for evaluation. Methods We documented a series of 5 patients referred to the University of North Carolina ID Clinic between 2020 and 2022 for various tick-borne infections that were found to have symptoms and laboratory testing consistent with AGS. Patients were subsequently referred to the Allergy and Immunology Clinic. Results Patients were referred to the ID Clinic for persistent symptoms following positive tick-borne disease testing or presumed tick-borne infection. All patients had an elevated alpha-gal immunoglobulin E and clinical presentation consistent with AGS. Common symptoms included episodic gastrointestinal distress (eg, cramping, nausea, diarrhea), fatigue, arthralgias, and subjective cognitive impairment, but a notable absence of severe anaphylaxis. Four patients were seen by at least 1 nonallergy specialist prior to referral to ID. Patients reported substantial improvement in their symptoms following dietary restriction. Conclusions ID physicians should be aware of AGS as a cause of persistent, nonspecific symptoms following a tick exposure or tick-borne illness. Further research is needed to determine the prevalence of alpha-gal sensitization and AGS following tick-borne bites.

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.We performed a chart review and descriptive analysis of 100 randomly selected patients with AGS during 2010-2019.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]).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.

Introduction Alpha‐gal syndrome (AGS) is characterized by delayed hypersensitivity to non‐primate mammalian meat in people having specific immunoglobulin E (sIgE) to the oligosaccharide galactose‐alpha‐1,3‐galactose. AGS has been linked to tick bites from Amblyomma americanum (Aa) in the U.S. A small animal model of meat allergy is needed to study the mechanism of alpha‐gal sensitization, the effector phase leading to delayed allergic responses and potential therapeutics to treat AGS. Methods Eight‐ to ten‐weeks old mice with a targeted inactivation of alpha‐1,3‐galactosyltransferase (AGKO) were injected intradermally with 50 μg of Aa tick salivary gland extract (TSGE) on days 0, 7, 21, 28, 42, and 49. Total IgE and alpha‐gal sIgE were quantitated on Day 56 by enzyme‐linked immunosorbent assay. Mice were challenged orally with 400 mg of cooked pork kidney homogenate or pork fat. Reaction severity was assessed by measuring a drop in core body temperature and scoring allergic signs. Results Compared to control animals, mice treated with TSGE had 190‐fold higher total IgE on Day 56 (0.60 ± 0.12 ng/ml vs. 113.2 ± 24.77 ng/ml; p < 0.001). Alpha‐gal sIgE was also produced in AGKO mice following TSGE sensitization (undetected vs. 158.4 ± 72.43 pg/ml). Further, sensitized mice displayed moderate clinical allergic signs along with a drop in core body temperature of ≥2°C as an objective measure of a systemic allergic reaction. Interestingly, female mice had higher total IgE responses to TSGE treatment but male mice had larger declines in mean body temperature. Conclusion TSGE‐sensitized AGKO mice generate sIgE to alpha‐gal and demonstrate characteristic allergic responses to pork fat and pork kidney. In keeping with the AGS responses documented in humans, mice reacted more rapidly to organ meat than to high fat pork challenge. This mouse model establishes the central role of tick bites in the development of AGS and provides a small animal model to mechanistically study mammalian meat allergy., Alpha‐gal syndrome (AGS) is characterized by delayed hypersensitivity to non‐primate mammalian meat in people having specific IgE (sIgE) to the oligosaccharide galactose‐alpha‐1,3‐galactose and has been linked to tick bites from Amblyomma americanum (Aa) in the U.S. We demonstrate that intradermal injection of Aa tick salivary gland extract (TSGE) in alpha‐gal knockout (AGKO) mice induce alpha‐gal sIgE production and mice displayed moderate clinical allergic signs along with a drop in core body temperature as an objective measure of a systemic allergic reaction. Further, this model recapitulates several aspects of red meat allergy seen in the humans and will be used to mechanistically study this novel food allergy and model therapeutic approaches to treat this disease.

Hunting for a Diagnosis A 47-year-old man in Michigan presented to the ED with a 1-day history of presyncope, swelling of the eyelids, and diffuse pruritic rash. He reported a 3-week history of pos...

INTRODUCTION: Alpha-gal Syndrome (AGS) is a unique allergy to non-primate mammalian meat (and derived-products) that is associated with tick bites and is due to a specific IgE antibody to the oligosaccharide galactose-α-1,3-galactose (alpha-gal). AGS has many novel features that broaden the paradigm of food allergy, including that reactions are delayed 3-6 hours after exposure and patients have frequently tolerated red meat for many years prior to the development of allergic reactions. Due to the ubiquitous inclusion of mammal-derived materials in foods, medications, personal products and stabilizing compounds, full avoidance is difficult to achieve. AREAS COVERED: This review describes the author’s experience with diagnosis, management and design of appropriate avoidance for patients with AGS and provides clinicians with practical advice for care of these patients. EXPERT OPINION: The number of patients with AGS is rising and may have exceeded awareness of the diagnosis amongst healthcare providers. In summarizing experience gained to thus far, we hope to create a resource for identifying and managing this unique allergic syndrome.

Objective To review published studies on galactose α-1,3-galactose (α-gal), a carbohydrate epitope found on proteins and lipids in nonprimate mammals and present in foods (particularly organ or fat-rich red meat) and medications, where it causes delayed-onset and immediate-onset anaphylaxis. Data Sources A literature search for the terms galactose α-1,3-galactose and α-gal using PubMed and Embase was performed. Study Selections Studies on α-gal were included in this review. Results Several species of ticks contain α-gal epitopes and possibly salivary adjuvants that promote high titer sensitization and clinical reactivity. Risk factors for α-gal syndrome include exposure to ticks of particular species. Age and sex differences seen in various cohorts possibly reflect the prevalence of these exposures that vary according to setting. Conclusion The reason and mechanisms for delayed onset of food-related anaphylaxis and the preponderance of abdominal reactions are not clear but may involve the kinetics of allergen digestion and processing or immunologic presentation via a different mechanism from usual immediate-type food allergy.

Although allergic responses to the mRNA COVID-19 vaccines are rare, recent reports have suggested that a small number of individuals with allergy to polyethylene glycol (PEG), a component of the mRNA lipid nanoshell, may be at increased risk of anaphylaxis following vaccination. In this report, we describe the second known case of a patient who received an mRNA COVID-19 vaccine, experienced anaphylaxis, and was subsequently confirmed to have anti-PEG allergy by skin prick testing. The patient had previously noticed urticaria after handling PEG powder for their occupation and had a history of severe allergic response to multiple other allergens. Despite anaphylaxis, serology testing showed that the patient developed anti-spike IgG and was negative for anti-nucleocapsid IgG, indicating immunity from vaccination (and not due to prior infection). Importantly, as many as 70% of people possess detectable levels of anti-PEG antibodies, indicating that the detection of such antibodies does not imply high risk for an anaphylactic response to vaccination. However, in people with pre-existing anti-PEG antibodies, the administration of PEGylated liposomes may induce higher levels of antibodies, which may cause accelerated clearance of other PEGylated therapeutics a patient may be receiving. It is important to improve awareness of PEG allergy among patients and clinicians.

Background Galactose-α-1,3-galactose (alpha-gal) is a carbohydrate that is ubiquitously expressed in all mammals except for primates and humans. Patients can become sensitized to this antigen and develop alpha-gal syndrome (AGS), or a red meat allergy. Symptoms range from generalized gastroenteritis and malaise to anaphylaxis, and in endemic areas, the prevalence can be as high as 20%. Although AGS patients commonly avoid alpha-gal by avoiding meat, patients have also developed symptoms due to animal-derived medical products and devices. With the rise in transcatheter aortic valve replacement, we investigate the immunogenicity of common cardiac materials and valves. Objective To assess the in vitro immunoglobulin E response toward common medical products, including cardiac patch materials and bioprosthetic valves in patients with AGS. Methods Immunoblot and immunohistochemistry techniques were applied to assess immunoglobulin E reactivity to various mammalian derived tissues and medical products for patients with AGS. Results AGS serum showed strong reactivity to all of the commercially available, nonhuman products tested, including various decellularized cardiac patch materials and bioprosthetic aortic valves. AGS serum did not react to tissues prepared using alpha-gal knockout pigs. Conclusions Despite commercial decellularization processes, alpha-gal continues to be present in animal-derived medical products, including bioprosthetic valves. Serum from patients with AGS demonstrates a strong affinity for these products in vitro. This may have serious potential implications for sensitized patients undergoing cardiac surgery, including early valve failure and accelerated coronary artery disease.

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.

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.

Breast milk is a living source of nutrition for babies and is currently recommended by the American Academy of Pediatrics as well as the American Academy of Allergy, Asthma and Immunology. Breast milk complements a baby’s immune system, supplementing undeveloped defenses with immune factors while also creating the foundation for both the innate and adaptive immune systems. Such immune development includes tolerance of the environment and, in the case of food allergy, formation of an IgE antibody response. Breast milk was thought to be protective against food allergy, and recent research with mice strengthens this paradigm. This chapter reviews the immature immune system, the immunology and nutrition of breast milk, the literature exploring breast milk and food allergy, and the current recommendations regarding breast milk and the prevention of food allergy.

Supplemental Digital Content is available in the text., Objective— Emerging evidence suggests a link between coronary artery disease and type 2 immunity. We sought to test the hypothesis that IgE sensitization to the mammalian oligosaccharide galactose-α-1,3-galactose (α-Gal)—the target allergen of delayed anaphylaxis to red meat—is associated with coronary artery disease. Approach and Results— Total IgE and specific IgE to α-Gal were assayed on sera from 118 subjects who presented for cardiac catheterization and underwent intravascular ultrasound. IgE to α-Gal was detected in 26%, and atheroma burden was higher in sensitized subjects (P=0.02). Because α-Gal sensitization relates to an environmental exposure that could be a risk factor for early-onset coronary artery disease (ie, tick bites), we age stratified the cohort. In subjects ≤65 years of age, the strength of the association with atheroma burden was stronger (P

Anaphylactic fatalities are rare; however, mild reactions can rapidly progress to cardiovascular and respiratory arrest. The clinical course of anaphylaxis can be unpredictable. Prompt and early use of epinephrine should be considered. Most anaphylaxis episodes have an immunologic mechanism involving immunoglobulin E (IgE). Foods are the most common cause in children; medications and insect stings are more common in adults. When the cause is not completely avoidable or cannot be determined, a patient should be supplied with autoinjectable epinephrine and be instructed its use. They should keep the device with them at all times and taught the signs and symptoms of anaphylaxis.

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.

Background Alpha-gal syndrome (AGS) is an emerging immunoglobulin E (IgE)–mediated allergy to galactose-alpha-1,3-galactose (alpha-gal). The geographic distribution and burden of AGS in the United States are unknown. Objective To characterize alpha-gal IgE testing patterns and describe the trends and distribution from 2010 to 2018 in the United States. Methods This retrospective analysis included all persons tested for alpha-gal IgE antibodies by Viracor-IBT Laboratories (Lee’s Summit, Missouri), the primary site of testing in the United States. Data included age and sex of person tested, specimen state of origin, collection date, and result value; persons with at least 1 positive test result (≥0.1 kU/L) were compared with negatives. Proportions tested and with positive test results were calculated using the US Census population estimates. Results Overall, 122,068 specimens from 105,674 persons were tested for alpha-gal IgE during July 1, 2010, to December 31, 2018. Nearly one-third (34,256, 32.4%) had at least 1 positive result. The number of persons receiving positive test results increased 6-fold from 1110 in 2011 to 7798 in 2018. Of those receiving positive test results, mean [SD] age was 46.9 (19.8) years; men were more likely to test positive than women (43.3% vs 26.0%). Arkansas, Virginia, Kentucky, Oklahoma, and Missouri had the highest number of persons who were tested and had a positive result per 100,000 population. Conclusion More than 34,000 persons, most presumably symptomatic, have received positive test results for IgE antibodies to alpha-gal, suggesting AGS is an increasingly recognized public health problem. The geographic distribution of persons who tested positive is consistent with exposure to Amblyomma americanum ticks.

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.

In 1906, Von Pirquet1 used the term supersensitivity without immunity to describe (1) symptoms of inhalant allergy, (2) positive immediate skin test results, and (3) the fact that the results of other tests of immunity were not positive in these patients. The other tests he referred to were precipitin tests and complement fixation. Thus, he opened up the question of serum tests for supersensitivity. In 1919, Ramirez2 reported that a patient who had received a blood transfusion from a horse allergic donor became allergic to horse dander. At this point, Prausnitz and Kustner3 set out to investigate whether the serum of allergic individuals contained a factor or factors that could sensitize the skin. In 1921, they reported that the local injection of serum from a fish allergic individual, Kustner, to an individual who was only allergic to pollen, Prausnitz, would transfer specific sensitivity.3 This transfer of sensitivity came to be known as the P-K test and was used widely to study sensitivity not only to common allergens but also to extracts as diverse as those obtained from schistosomes.4,5 Furthermore, in New York, Cooke et al6 identified that there were other antibodies in the serum that increased during desensitization treatment and could block the skin-sensitizing activity. By the 1950s, it was clear that the transferred sensitivity was specific, that it could be diluted extensively, and that the skin remained locally sensitive for days if not weeks after the injection of serum.7,8 It was also already clear that the ability to sensitize the skin was lost after moderate heating of the serum.7 Several studies had also been reported on the physical properties of P-K activity. Indeed, Heimlich et al9 at Cal Tech reported on the sedimentation properties of skin-sensitizing antibodies in 1960. However, the studies before 1964 had not succeeded in defining the nature of these antibodies.

Disease activity may correlate with environmental aeroallergen exposure in eosinophilic esophagitis. The association between seasons and flares of eosinophilic esophagitis (EoE) histologic activity has not been extensively studied.We aimed to assess the frequency of seasonal exacerbations of eosinophilic esophagitis, as well as changes in symptom reporting, endoscopic findings, and histologic findings attributed to aeroallergens in an EoE cohort.In this retrospective cohort study, we analyzed EoE patients in histologic remission (15 eosinophil/high-power field) but who doubled the esophageal eosinophil count between seasons without change in eosinophilic esophagitis-specific therapy. Outcomes were: symptomatic global worsening (yes/no); change in endoscopic severity (EREFS scoring system); and histologic change (peak eosinophil count).Of 782 patients, 13 (4%) met inclusion criteria (mean age: 36.2; 85% male; 86% white; 85% atopic disease diagnosis), and 14 exacerbations were recorded. Of these, 71% occurred in fall and summer months. Peak eosinophil counts increased from 6.8 to 86.8 eosinophil per high-power field (P.001). Four patients (31%) reported worsening of seasonal allergies and 5 (38%) a global worsening of symptoms. Endoscopic severity was also significantly worse during seasonal exacerbations (total EREFS 3.7 vs 1.7; P = .01). Baseline features differed by atopic diagnoses and endoscopic findings between patients with and without seasonal exacerbations.Seasonal exacerbations of eosinophilic esophagitis were uncommon in this cohort and most commonly recorded over the summer and fall months. These data support a role of aeroallergens in the pathogenesis of eosinophilic esophagitis in some patients, and clinicians should consider aeroallergens as a potential cause of disease exacerbation.

Background B cells play a critical role in the development and maintenance of food allergy by producing allergen-specific IgE. Despite the importance of B cells in IgE-mediated food allergy, the identity of sIgE-producing human B cells and how IgE is regulated are poorly understood. Objective To identify the immunophenotypes of circulating B cells associated with the production of galactose-alpha-1,3-galactose-specific IgE production in patients with red meat allergy. Methods B cells in PBMC samples obtained from 19 adults with physician-diagnosed red meat allergy and 20 non-meat allergic healthy controls were assessed by mass cytometry along with a bioinformatics analysis pipeline to identify discrete B cell phenotypes that associated with serum sIgE. Fluorescent flow cytometry was then applied to sort purify discrete B cell subsets, and B cells were functionally evaluated on an individual cell level for the production of sIgE by ELISPOT. Results Discrete B cell phenotypes abundant in meat allergic subjects compared to non-meat allergic controls were found in peripheral blood that do not share typical characteristics of classical isotype-switched memory B cells that express high levels of CD27. These B cell subsets shared higher IgD and lower IgM expression levels coupled with CXCR4, CCR6 and CD25 expression. In vitro polyclonal stimulation of purified B cell subsets from meat allergic subjects demonstrated that these subsets were enriched for cells induced to secrete sIgE. Conclusions and clinical relevance Circulating B cells display increased abundance of discrete B cell subsets in meat allergic subjects. This observation, coupled with the capacity of individual B cell subsets to produce sIgE following activation, implicates these novel B cell phenotypes in promoting IgE in meat allergy.

The goal of this review is to present an updated summary of the natural history of major childhood and adult food allergies and report recent advances in potential treatments for food allergy.The most common childhood food allergies are typically outgrown by adolescence or adulthood. However, peanut/tree nut allergies appear to more commonly persist into adulthood. Adults can develop new IgE-mediated food allergies; the most common is oral allergy syndrome. There are multiple different approaches being tried as possible treatments for food allergy. The prevalence of food allergy appears to be increasing but the varied approaches to treatment are being actively pursued such that an approved modality may not be too far in the future.

Oral tolerance is an active process of local and systemic immune unresponsiveness to orally ingested antigens such as food. The gut immune system must balance responses to commensal bacteria (microbiome), innocuous antigens, and pathogens. Although it is clear that specialized populations of immune cells and lymph nodes create a unique environment in the gut, there remains evidence to suggest that systemic effector sites also are critical to establishing and maintaining oral tolerance.

Breast milk, a living source of nutrition for babies, complements a baby's immune system, supplementing undeveloped defenses with immune factors while creating the foundation for the innate and adaptive immune systems. Such immune development includes tolerance of the environment and, in the case of food allergy, a lack of tolerance. Recent research questions the previous opinion that breast milk is protective against food allergy. This article reviews the immature immune system, the immunology and nutrition of breast milk, the literature exploring breast milk and food allergy, and the current recommendations regarding breast milk and the prevention of food allergy.

SummaryBackground Only limited evidence is available regarding the cytokine repertoire of effector T cells associated with peanut allergy, and how these responses relate to IgE antibodies to peanut components. Objective To interrogate T cell effector cytokine populations induced by Ara h 1 and Ara h 2 among peanut allergic (PA) children in the context of IgE and to evaluate their modulation during oral immunotherapy (OIT). Methods Peanut-reactive effector T cells were analysed in conjunction with specific IgE profiles in PA children using intracellular staining and multiplex assay. Cytokine-expressing T cell subpopulations were visualized using SPICE. Results Ara h 2 dominated the antibody response to peanut as judged by prevalence and quantity among a cohort of children with IgE to peanut. High IgE (> 15 kUA/L) was almost exclusively associated with dual sensitization to Ara h 1 and Ara h 2 and was age independent. Among PA children, IL-4-biased responses to both major allergens were induced, regardless of whether IgE antibodies to Ara h 1 were present. Among subjects receiving OIT in whom high IgE was maintained, Th2 reactivity to peanut components persisted despite clinical desensitization and modulation of allergen-specific immune parameters including augmented specific IgG4 antibodies, Th1 skewing and enhanced IL-10. The complexity of cytokine-positive subpopulations within peanut-reactive IL-4+ and IFN-γ+ T cells was similar to that observed in those who received no OIT, but was modified with extended therapy. Nonetheless, high Foxp3 expression was a distinguishing feature of peanut-reactive IL-4+ T cells irrespective of OIT, and a correlate of their ability to secrete type 2 cytokines. Conclusion Although total numbers of peanut-reactive IL-4+ and IFN-γ+ T cells are modulated by OIT in highly allergic children, complex T cell populations with pathogenic potential persist in the presence of recognized immune markers of successful immunotherapy.

Allergen-specific IgGWe sought to investigate serum food sIgGSera from 71 pediatric patients with EoE and 210 early adolescent children from an unselected birth cohort (Project Viva) were assayed for sIgGIn the EoE cohort high-titer sIgGsIgG

Anaphylactic fatalities are rare and in the vast majority of instances, patients will do well. Nevertheless, fatalities do occur and reactions presenting with mild symptoms can rapidly progress to cardiovascular and respiratory arrest. At the initiation of symptoms it is not possible to know whether an episode will rapidly progress. Because the clinical course of anaphylaxis can be unpredictable, prompt and early use of epinephrine should be considered even with mild symptoms or single-system involvement. Any patient who has experienced an episode of anaphylaxis should be evaluated to determine the causative agent. Most anaphylaxis episodes have an immunologic mechanism involving immunoglobulin E (IgE). Foods are the most common cause in children, while medications and insect stings are more common causes in adults. Any patient who has experienced anaphylaxis when the cause is not completely avoidable or cannot be determined should be supplied with auto-injectable epinephrine (AIE) and should be instructed in the use of this device and told to keep their AIE with them at all times. The patient should be taught to recognize the signs and symptoms of anaphylaxis and when to administer the injection and be given an anaphylaxis action plan.

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

Potential competing interests Dr. Dellon is a consultant for Adare, Alivio, Allakos, Banner, Calypso, Enumeral, EsoCap, GSK, Gossamer Bio, Receptos/Celegene, Regeneron, Robarts, and Shire, receives research funding from Allakos, Adare, GSK, Meritage, Miraca, Nutricia, Receptos/Celgene, Regeneron, and Shire, and has received an educational grant from Allakos, Banner, and Holoclara. None of the other authors report and potential conflicts of interest with this study. Funding Source This study was funded in part by NIH award T32 DK007634 (SE; CCR). It also used services from the NC Translational and Clinical Sciences (NC TraCS) Institute, which is supported by the National Center for Advancing Translational Sciences (NCATS) through Grant Award Number UL1TR002489.