From the earliest days of studying the reagins in allergic sera that give rise to the Prausnitz-Kuestner reaction, there was evidence that there were other types of antibodies (Ab) specific for allergens, particularly those induced by immunotherapy. By 1980, not only was IgE recognized and could be measured, but the presence of other isotypes including IgG and IgA in patients with IgE was well established. From that time onwards the development of monoclonal antibodies made it possible to distinguish and measure antibodies of other isotypes such as IgG4, IgG2, and IgG3. Over the past 40 years two things have dominated the field- firstly, the techniques for measuring isotype specific antibodies to allergens have improved steadily. Secondly, several different allergic diseases or phenomena have been identified in which isotype diversity of the antibodies has become a major issue. Prior to 1990 only occasional cases of eosinophilic esophagitis (EoE) had been identified, but since then they have become common. Most of the cases have positive skin tests and/or IgE Ab to cow's milk or wheat, but it became obvious that most cases of EoE are not primarily related to IgE. Today it is clear that IgG4 Ab to these allergens play a significant role in cases of EoE. In 2000 the first reports of children developing tolerance to cat allergen appeared. Today it is clear that this tolerance depends on high levels of IgG4 antibodies and there is increasing evidence that the IgG4 response is primarily against Fel d 1. The most recent novel allergic disease is the alpha-gal syndrome (AGS). This condition is based on IgE antibodies specific for the oligosaccharide galactose alpha,1-3-galactose, which are primarily induced by tick bites. However, in this case it was already well known that all immunocompetent primates have made IgG and IgM antibodies to this oligosaccharide. Furthermore, it is not clear whether the IgG isotypes, particularly IgG1 and IgG3, play a role in the inflammatory response to the oligosaccharide. Overall, it is clear that current and future investigation of allergic diseases requires careful assessment of allergen specific antibodies of diverse isotypes in addition to IgE.

Background: Antibodies to galactose-alpha-1,3-galactose (alpha-gal), particularly the IgM and IgG isotypes, are abundant in human sera. These antibodies are known to be an important xenotransplantation barrier, but the full implications of these antibodies to health and disease remain incompletely understood. By contrast, IgE to alpha-gal is uncommon in the population but has been associated with tick bites and causally linked with mammalian meat allergy, often now known as alpha-gal syndrome (AGS). To date, there have been few population-based studies that have investigated alpha-gal IgG levels in relation to demographic factors, diet, tick bites, and mammalian meat allergy. Methods: Adults, predominantly healthcare workers, were recruited for a COVID-19 vaccine study. At least one serum sample was collected, and subjects completed questionnaires to provide demographic, diet, and tick exposure data. Alpha-gal IgG, IgE, and total IgG were measured using the ImmunoCAP platform, and blood group was assessed via reverse typing using stored serum. We also assessed alpha-gal IgG levels among subjects with AGS, recruited from an allergy clinic. Results: The median age of the 267 subjects in the vaccine cohort was 42 years, and median alpha-gal IgG levels were 3.0 μg/mL. Alpha-gal IgG levels were higher among the 43 (16.1%) subjects who had alpha-gal IgE sensitization (≥0.1 IU/mL) and among subjects lacking the B blood group antigen (blood groups A and O). Alpha-gal IgG levels did not differ between the subjects who had asymptomatic alpha-gal IgE sensitization and those who had meat allergy. However, both groups had higher alpha-gal IgG levels than subjects who lacked alpha-gal IgE sensitization. Subjects who reported prior tick or chigger bites had higher alpha-gal IgG levels than those without a bite history, regardless of alpha-gal IgE sensitization status. Conclusions: In a population-based cohort, alpha-gal IgG antibodies were found to be prevalent, and levels were increased in subjects with blood groups A and O, subjects who were alpha-gal IgE sensitized, and those who reported a history of tick bites.

Summary: Background: Although proteins derived from cats are an important contributor to indoor allergen exposure in relation to asthma, it has been known for at least twenty years that some children who live in a house with a cat can become clinically tolerant to these animals. In 2001, we reported that children exposed to high levels of cat allergens made high levels of IgG4 antibodies to the cat allergen Fel d 1, and we coined the term “a modified Th2 response”. However, this phenomenon is still poorly understood. Methods: We studied serum antibodies among 616 individuals in the Viva unselected birth cohort recruited at their early teen visit (mean age 13.1 SD 0.8). IgE and IgG4 antibodies were measured by ImmunoCAP to inhaled allergens as well as the best characterised component allergens of cat, Fel d 1, Fel d 2, Fel d 4, and Fel d 7, and the dust mite allergens Der p 1, Der p 2, Der p 10, and Der p 23. Findings: The results confirm that young teens living in a home with a cat make high levels of IgG4 specific for cat allergens, and that those antibodies, and specifically those to Fel d 1 are negatively associated with asthma. By contrast, the IgG4 responses to Fel d 4 and Fel d 7 are significantly lower and have no significant association with asthma. Perhaps more surprisingly, a similar effect is seen in relation to dust-mite allergens. Although the allergen Der p 1 is a major part of the IgE response to mite allergens, this protein also induced high prevalence and levels of IgG4 antibodies and has a less strong relationship to asthma than IgE to Der p 2 or Der p 23. Indeed, values of specific IgE to Der p 1 >3.5 IU/mL were not significantly related to asthma (OR 1.5 CI 0.8–2.8, p = 0.3, Chi2 test). The prevalence and levels of specific IgG4 to these less abundant allergens are significantly lower for Der p 2 and almost absent for Der p 23. Interpretation: High exposure to specific allergens in household dust can enhance production of both sIgE and sIgG4 antibodies, while allergens where abundance is significantly lower in dust can induce sIgE with limited or no sIgG4. The result is that the less abundant allergens, i.e., Fel d 4, Fel d 7, Der p 2, and Der p 23, may have a significantly higher relevance to asthma than expected because they induce less sIgG4. Funding: This work was funded by R01-AI20565 (TPM) and support for the IgE and IgG4 assays provided by Phadia/Thermo Fisher Kalamazoo, Michigan. Project Viva is also supported by NIH R01HD034568 and R24ES.

Study objectives North American pit viper antivenoms, CroFab® and ANAVIP®, contain galactose-α-1,3-galactose (α-GAL) oligosaccharide. We compared adverse drug reactions, including presumed anaphylaxis, following administration of these antivenoms and investigated biological plausibility of these antivenoms leading to anaphylaxis in α-GAL-immunoglobulin (Ig) E-sensitized individuals. Methods We performed 2 studies. A retrospective chart review from the Arkansas Poison Center (May 2021 to July 2023) identified adverse drug reactions and presumed anaphylaxis in patients treated with crotaline antivenom. Two allergists (JK, LM), blinded to the antivenom used, adjudicated presumed anaphylaxis cases. To assess whether antivenoms could activate basophils from α-GAL-IgE-sensitized individuals, basophil activation tests were performed on blood from 5 α-GAL-IgE-sensitized participants with a history of mammalian meat allergy. Basophil activation was assessed by %CD63 upregulation. Results Adverse drug reactions without presumed anaphylaxis occurred in 7 out of 171 (4.1%) Fab recipients versus 8 out of 37 (21.6%) F(ab’)2 recipients (Δ=17.5%, 95% confidence interval [CI] [4.0 to 31.0]). Presumed anaphylaxis was observed in 3 out of 171 (1.8%) for Fab and 6/37 (16.2%) for F(ab’)2 (Δ=14.3%, 95% CI 2.5 to 26.2). In the basophil activation tests, the mean EC50 for basophil CD63 activation was 144-fold higher for Fab (mean, [standard deviation]; 647 μg/mL of antivenom [627]) compared to F(ab’)2 (4.48 μg/mL of antivenom [2.75]). Conclusion We demonstrate a substantial incidence of adverse drug reactions and presumed anaphylaxis to crotaline antivenoms in an α-GAL endemic region, with F(ab’)2 antivenom associated with more reactions than F(ab). Clinicians in α-GAL endemic regions should be cautious in the use of antivenoms, especially for patients with α-GAL allergy.

There are limited longitudinal data from non-industrialized settings on patterns and determinants of gut bacterial microbiota development in early childhood. We analysed epidemiological data and stool samples collected from 60 children followed from early infancy to 5 years of age in a rural tropical district in coastal Ecuador. Data were collected longitudinally on a wide variety of individual, maternal, and household exposures. Extracted DNA from stool samples were analysed for bacterial microbiota using 16S rRNA gene sequencing. Both alpha and beta diversity indices suggested stable profiles towards 5 years of age. Greater alpha diversity and lower beta diversity were associated with factors typical of rural poverty including low household incomes, overcrowding, and greater agricultural and animal exposures. Consumption of unpasteurized milk was consistently associated with greater alpha diversity indices. Delivery method and antibiotic exposures during pregnancy and early childhood appeared to have limited effects on developmental trajectories of gut microbiota. Infants living in a non-industrialized setting in conditions of greater poverty and typically rural exposures appeared to acquire more rapidly a stable and diverse gut bacterial microbiome during childhood.

In cross-sectional studies, patients with alpha-gal syndrome (AGS) consistently have higher levels of total IgE (tIgE) than control populations. Atopic individuals could be at higher risk of becoming sensitized to alpha-gal. Alternatively, tIgE levels may rise, concurrent with alpha-gal sensitization, as a consequence of tick bites. We explored this question in a cohort of military personnel who had longitudinal samples available.

Food allergy is understudied in lower- and middle-income countries such as Honduras. We carried out a pilot study to determine the prevalence of food sensitization and its correlation with self-reported food allergy in a school-aged population in this country.

BACKGROUND:IgE to galactose-alpha-1,3-galactose (alpha-gal) is linked to tick bites and an important cause of anaphylaxis and urticarial reactions to mammalian meat. The alpha-gal syndrome (AGS) is recognized as being common in the southeastern United States. However, prevalence studies are lacking and open questions remain about risk factors and clinical presentation of alpha-gal sensitization. OBJECTIVE:Here we characterized the prevalence as well as the presentation and risk factors of AGS and alpha-gal IgE sensitization in adults in central Virginia recruited without regard to the history of allergic disease. METHODS:Adults in central Virginia, primarily University of Virginia Health employees, were recruited as part of a COVID-19 vaccine study. Subjects provided at least one blood sample and answered questionnaires about medical and dietary history. We used ImmunoCAP for IgE assays and assessed the ABO blood group by reverse typing using stored serum. We also investigated biobanked serum from COVID-19 patients. RESULTS:Median age of the 267 enrollees was 42 years, 76% were female, and 43 (16%) were sensitized to alpha-gal (cutoff of 0.1 IU/mL), of which mammalian meat allergy was reported by seven (2.6%). Sensitized subjects (1) were older, (2) had higher total IgE levels but a similar frequency of IgE to common respiratory allergens, and (3) were more likely to report tick bites than were nonsensitized subjects. Among those who were sensitized, alpha-gal IgE levels were higher among meat-allergic than nonallergic subjects (geometric mean, 9.0 vs 0.5 IU/mL; P < .001). Mammalian meat and dairy consumption was common in individuals with low-level sensitization. CONCLUSION:In central Virginia, AGS is a dominant cause of adult food allergy with a prevalence approaching or exceeding 2%.

Background/Objectives: IgE to galactose-alpha-1,3-galactose (alpha-gal) is associated with Amblyomma americanum (lone star tick) bites, accounting for the regional distribution of the alpha-gal syndrome (AGS). Longitudinal studies describing risk factors for incident alpha-gal sensitization are lacking. The objective of this project was to assess the incidence of alpha-gal IgE seroconversion and identify associated demographic, occupational, and geographical risk factors among US military personnel. Methods: Samples from the Department of Defense Serum Repository were evaluated at two time points at least 3 years apart. In total, 3000 service members stationed at 10 military installations within the A. americanum tick range were included. Installation, sex, race and ethnicity, rank, military occupation, and branch of service were evaluated. Alpha-gal IgE seroconversion was defined as a change from <0.1 kU/L) to ≥0.1 kU/L. Results: Among the 2821 personnel who were alpha-gal IgE-negative at baseline, 138 (4.9%) seroconverted over a mean interval of 3.4 years. Seroconversion was more frequent in males (5.5% vs. 1.9%), White individuals (6.6% vs. 1.0% in Black people and 1.5% in Hispanics), and individuals in occupations with higher presumed outdoor exposure (e.g., infantry/law enforcement: 12.7% vs. administrative: 1.2%). Differences were not significant between sexes when accounting for military installation/occupation, but differences in race and ethnicity remained significant. Conclusions: This study demonstrates that alpha-gal IgE seroconversion is occurring within the A. americanum tick range and is associated with White race and ethnicity, and occupations with higher outdoor exposure. Further research is needed to elucidate the influence of race and ethnicity on alpha-gal sensitization and develop effective prevention and treatment strategies for AGS.

BACKGROUND: IgE to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) is an important cause of allergic re-actions to mammalian meat. The "alpha-gal syndrome" is strongly associated with a preceding history of tick bites and in the United States is most commonly reported in parts of the southeast, but there has been limited investigation into national alpha-gal sensitization patterns and the relevance of other risk factors. OBJECTIVE: To systematically investigate alpha-gal IgE prevalence, regional patterns, and risk factors. METHODS: Alpha-gal IgE was measured by ImmunoCAP in biobanked serum samples collected from 3000 service members who presented for intake to 1 of 10 military bases in the central/ eastern United States. Alpha-gal IgE sensitization (cutoff 0.1 international units/mL) was related to home of record at enlistment. RESULTS: Of the cohort, 2456 (81.9%) subjects were male, median age was 19 years (interquartile range: 18-22 years), and alpha-gal IgE was detected in 179 (6.0%). Home of record spanned all 50 states, with a median of 36 recruits per state (range: 3-261). The highest prevalence rates were in Arkansas (39%), Oklahoma (35%), and Missouri (29%), with several other southeastern states >10%. Granular mapping revealed sensitization patterns that closely mimicked county-level Amblyomma americanum reports and Ehrlichia chaffeensis in-fections. Sensitization was associated with male sex, rural residence, and White race in univariate and multivariable models. CONCLUSIONS: In this systematic survey, the prevalence of alpha-gal IgE among incoming military personnel was 6.0%. There were significant regional differences, with an overall pattern consistent with the known range of the lone star tick (A. americanum) and highest frequency in an area including Arkansas, Oklahoma, and Missouri.

Most of the investigators involved in studying different forms of food allergy are unaware that these syndromes were not a significant part of allergic disease as little as 40 years ago. Thus, a major focus of this report is to understand when and why different forms of food allergy became common. Focusing on (i) peanut as a major cause of rapid reactions in subjects with IgE antibodies to protein antigens; (ii) eosinophilic esophagitis in children and adults where the dominant foods are cow's milk and wheat and the immune responses include high titer IgG4 to protein antigens with only modest titers of slgE; and (iii) delayed reactions to red meat which occur in subjects who have had bites from Lone Star ticks and have high titers of IgE ab to the oligosaccharide galactose alpha-1,3-galactose, or alpha-gal. The approximate dates for increase of these three forms of food allergy are 1980; 1995; and 2010. In each case, these dates are long after the rise in allergic rhinitis or the rise in asthma among school children. A further striking feature of the history is that the hypotheses about the causes of increases in these three syndromes are completely different.

IgE sensitization to galactose-alpha-1,3-galactose (alpha-gal), a cause of mammalian meat allergy, is strongly linked with tick bites, particularly bites from Amblyomma americanum (the lone star tick) in the United States. We sought to investigate the serologic prevalence of IgG to spotted fever group Rickettsia (SFGR), a genus of bacteria carried by A americanum, in a cohort of military personnel who were found to have developed alpha-gal sensitization in longitudinal sampling. Biobanked serum was available from 3000 individuals who were stationed at military bases within the A americanum range. After ∼3.5 years, 138 individuals had seroconverted from negative to positive alpha-gal IgE (cut-off ≥0.1 IU/mL) by ImmunoCAP testing. A nested control group that did not seroconvert was matched for age, sex, race and base. Samples were tested for the presence of IgG to Rickettsia using an ELISA (Fuller Laboratories). Among the 138 incident alpha-gal cases, median age was 23.4; 128 were male (93%) and 119 were white (86%). The largest number of recruits who seroconverted (n=76 [55%]) were from Fort Liberty, NC, which exceeded the proportion from Ft. Liberty in the parent cohort (n=871 [29%]), P<0.001. Age, sex, race and military base were similar among the 163 in the matched control group. The prevalence of IgG to SFGR was 26.8% in those who seroconverted and 12.9% in the controls (P=0.002). Supporting a role for tick bites in promoting IgE sensitization to alpha-gal, the frequency of IgG to SFGR was more than twice as common in military personnel who developed alpha-gal sensitization.

Background: In individuals without symptomatic food allergy, food -specific IgE is considered clinically irrelevant. However, recent studies have suggested that galactose -a -1,3 -galactose (alpha -gal) IgE is associated with cardiovascular (CV) disease. Objective: We sought to determine whether sensitization to common food allergens is associated with CV mortality. Methods: The association between IgE sensitization to foods and CV mortality ascertained to 2019 was examined in the National Health and Examination Survey (NHANES) 2005-2006 and the Wake Forest site of the Multi -Ethnic Study of Atherosclerosis (MESA) cohort; MESA enrolled adults without baseline clinical CV diseases between 2000 and 2002. Total and specific IgE was measured to cow's milk, egg, peanut, shrimp, and a panel of aeroallergens (NHANES), and to cow's milk, alpha -gal, peanut, dust mite, and timothy grass (MESA). Cox proportional hazard models were constructed, adjusting for sex, age, race/ethnicity, smoking, education, and asthma. Results: A total of 4414 adults from NHANES (229 CV deaths) and 960 from MESA (56 CV deaths) were included. In NHANES, sensitization to at least 1 food was associated with higher CV mortality (hazard ratio [HR], 1.7 [95% confidence interval (CI), 1.2-2.4], P = .005). Milk sensitization was particularly associated (HR, 2.0 [95% CI, 1.1-3.8], P = .026), a finding replicated in MESA (HR, 3.8 [95% CI, 1.6-9.1], P = .003). Restricting analyses in NHANES to consumers of the relevant allergen strengthened food sensitization relationships, unmasking shrimp and peanut sensitization as additional risk factors for CV mortality. Conclusions: The finding that food sensitization is associated with increased risk of CV mortality challenges the current paradigm that sensitization without overt allergy is benign. Further research is needed to clarify mechanisms of this association. (J Allergy Clin Immunol 2024;153:471-8.)

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.