Development Of Peanut Allergy Research Articles

B cells establish, but do not maintain, long-lived murine anti-peanut IgE(a).

Peanut allergy (PNA) has been reported to be transferred to tolerant recipients through organ and bone marrow (BM) transplantation. The roles T and B cells play in establishing, and the roles B cell subsets play in maintaining lifelong anti-peanut IgE levels are unknown. To determine the cellular requirements for the transfer of murine PNA and to determine the role CD20(+) cells play in maintaining long-lived anti-peanut IgE levels. We developed a novel adoptive transfer model to investigate the cellular requirements for transferring murine PNA. We also treated peanut-allergic (PA) mice with anti-CD20 antibody and measured IgE levels throughout treatment. Purified B220(+) cells from PA splenocytes and purified CD4(+) cells from naïve (NA) splenocytes are the minimal requirements for the adoptive transfer of PNA. Prolonged treatment of allergic mice with anti-CD20 antibody results in significant depletion of B cell subsets but does not affect anti-peanut IgE levels, symptoms, or numbers of IgE antibody secreting cells (ASCs) in the BM. Adoptive transfer of BM and spleen cells from allergic donors treated with anti-CD20 antibody does not result in the transfer of PNA in NA recipients, demonstrating that anti-CD20 antibody treatment depletes B cells capable of differentiating into peanut-specific IgE ASCs. Peanut allergy can be established in a NA hosts with B220(+) cells from PA donors and CD4(+) cells from peanut-NA donors. However, long-term depletion of B220(+) cells with anti-CD20 antibody does not affect anti-peanut IgE levels. These results highlight a novel role for B cells in the development of PNA and provide evidence that long-lived anti-peanut IgE levels may be maintained by long-lived ASCs.

Role of Maternal Dietary Peanut Exposure in Development of Food Allergy and Oral Tolerance.

BackgroundThe impact of maternal ingestion of peanut during pregnancy and lactation on an offspring’s risk for peanut allergy is under debate.ObjectiveTo investigate the influence of maternal dietary peanut exposure and breast milk on an offspring’s allergy risk.MethodsPreconceptionally peanut-exposed C3H/HeJ females were either fed or not fed peanut during pregnancy and lactation. The offsprings’ responses to peanut sensitization or oral tolerance induction by feeding antigen prior to immunization were assessed. We also assessed the impact of immune murine milk on tolerance induction pre- or post-weaning. For antigen uptake studies, mice were gavaged with fluorescent peanut in the presence or absence of immune murine milk; Peyer’s patches were harvested for immunostaining.ResultsPreconceptional peanut exposure resulted in the production of varying levels of maternal antibodies in serum (and breast milk), which were transferred to the offspring. Despite this, maternal peanut exposure either preconceptionally or during pregnancy and lactation, when compared to no maternal exposure, had no impact on peanut allergy. When offspring were fed peanut directly, dose-dependent tolerance induction, unaltered by maternal feeding of peanut, was seen. Although peanut uptake into the gut-associated lymphoid tissues was enhanced by immune milk as compared to naïve milk, tolerance induction was not affected by the co-administration of immune milk either pre- or post-weaning.ConclusionMaternal peanut exposure during pregnancy and lactation has no impact on the development of peanut allergy in the offspring. Tolerance to peanut can be induced early, even pre-weaning, by giving moderate amounts of peanut directly to the infant, and this is neither enhanced nor impaired by concurrent exposure to immune milk.

Taking the leap earlier

The paradigm for the primary prevention of peanut allergy was, until recently, strict avoidance of peanut during pregnancy, infancy, and early childhood. However, in countries that had these dietary guidelines, the prevalence of peanut allergy greatly increased in contrast to low prevalence rates of peanut allergy in countries where infant diets included peanut at an early age, suggesting the hypothesis that early introduction of peanut is superior to delayed introduction of peanut as a strategy for the primary prevention of food allergy. This review examines recent high-quality studies that support this hypothesis. Publication of the Learning Early about Allergy to Peanut interventional trial showed that 17% of children avoiding peanut until 5 years of age developed peanut allergy compared with 3% of children who started eating peanut at ages of 4-11 months. Two birth cohort studies demonstrated that high maternal consumption of peanut during the pregnancy period reduced the risk of peanut allergy in offspring by 50-75%. Recent studies indicate that early introduction of peanut enhances the development of tolerance to peanut, reducing the risk of childhood peanut allergy.

Early peanut consumption is protective against peanut allergy development

Early peanut consumption is protective against peanut allergy development

Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy

BackgroundThe prevalence of peanut allergy among children in Western countries has doubled in the past 10 years, and peanut allergy is becoming apparent in Africa and Asia. We evaluated strategies of peanut consumption and avoidance to determine which strategy is most effective in preventing the development of peanut allergy in infants at high risk for the allergy.MethodsWe randomly assigned 640 infants with severe eczema, egg allergy, or both to consume or avoid peanuts until 60 months of age. Participants, who were at least 4 months but younger than 11 months of age at randomization, were assigned to separate study cohorts on the basis of preexisting sensitivity to peanut extract, which was determined with the use of a skin-prick test — one consisting of participants with no measurable wheal after testing and the other consisting of those with a wheal measuring 1 to 4 mm in diameter. The primary outcome, which was assessed independently in each cohort, was the proportion of participants with peanut allergy at 60 months of age.ResultsAmong the 530 infants in the intention-to-treat population who initially had negative results on the skin-prick test, the prevalence of peanut allergy at 60 months of age was 13.7% in the avoidance group and 1.9% in the consumption group (P<0.001). Among the 98 participants in the intention-to-treat population who initially had positive test results, the prevalence of peanut allergy was 35.3% in the avoidance group and 10.6% in the consumption group (P=0.004). There was no significant between-group difference in the incidence of serious adverse events. Increases in levels of peanut-specific IgG4 antibody occurred predominantly in the consumption group; a greater percentage of participants in the avoidance group had elevated titers of peanut-specific IgE antibody. A larger wheal on the skin-prick test and a lower ratio of peanut-specific IgG4:IgE were associated with peanut allergy.ConclusionsThe early introduction of peanuts significantly decreased the frequency of the development of peanut allergy among children at high risk for this allergy and modulated immune responses to peanuts. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00329784.)

Allergy to sunflower seed and sunflower butter as proposed vehicle for sensitization.

BackgroundIt is hypothesized that household exposure to allergenic proteins via an impaired skin barrier, such as atopic dermatitis, may contribute to the development of IgE sensitization. Household presence of peanut is a risk factor for the development of peanut allergy in children. Sunflower seed butter is a peanut-free alternative to peanut butter, and sunflower seed allergy is an uncommon but reported entity.Case presentationA 3 year old boy presented with oral discomfort that developed almost immediately after he ate sunflower seeds for the first time. He was given a dose of diphenhydramine. Subsequently he vomited, and his symptoms gradually resolved. A similar episode occurred to a commercial snack made with sunflower seed butter. Skin prick testing demonstrated a large positive (10 mm wheal) wheal-and-flare response to a slurry of fresh sunflower seed within 3–4 minutes associated with severe pruritus.This child has an older sibling with confirmed peanut allergy (PNA). After the PNA diagnosis was made, the family home became peanut-free. In lieu of peanut butter, sunflower butter was purchased and eaten frequently by family members, but not by the child reported herein.Subsequent to the episodes above, the child ate a bread roll with visible poppy seeds and developed itchy throat, dyspnea, and urticaria. Epicutaneous skin testing elicited a >10 mm wheal size within 3–4 minutes in response to a slurry of whole poppy seeds and 8 mm to fresh pumpkin seed, which had never been consumed.ConclusionsA case of sunflower allergy in the context of household consumption of sunflower butter has not yet been reported. We suggest that homes which are intentionally peanut-safe may provide an environment whereby infants with impaired skin barrier are at increased risk of allergy to alternative “butter” products being used, via cutaneous exposure to these products preceding oral introduction to the child.

Prevalence of Peanut Allergy in Offspring of Peanut Farmers

Introduction: While exposure to environmental peanut during infancy appears to promote sensitization by the epicutaneous route, early and frequent peanut ingestion during infancy may prevent peanut allergy through oral tolerance. Due to parental occupation, the offspring of peanut farmers are likely exposed to peanut protein in their environment, but they may also have early introduction into their diet due to ready access. The purpose of this study was to determine the prevalence of peanut allergy in offspring of peanut farmers. Methods: A survey was mailed by the National Peanut Board to peanut farmers in the United States collecting information on peanut consumption, peanut reactions, physician-confirmed peanut allergy (PA), epinephrine auto-injector prescription and history of other allergies in offspring. Egg allergy (EA) served as a comparator to peanut allergy. Results: Of 10,349 households surveyed, 1050 responses were received (2493 offspring, participation rate 10%). The self-reported prevalence of peanut allergy in the general population in the USA is 0.9%, 1.3%, and 0.7% for children 0 - 5 years, 6 - 10 years, and 11 - 17 years, respectively. In offspring of peanut farmers, PA vs EA was reported in 3.69% (10/271) vs 2.6% (7/271), 2.8% (14/493) vs 2.0% (10/493), and 1.48% (37/2493) vs 1.4% (35/2493) of offspring ≤10 years, offspring ≤15 years and all offspring, respectively. Physician-confirmed PA was reported in 3.3% (9/271), 2.6% (13/493), and 1.24% (31/2493) in the three groups, respectively. Physician-confirmed PA with epinephrine auto-injector prescription was reported in1.8% (5/271), 1.8% (9/493), and 0.68% (17/2493) in the three groups, respectively. Conclusions: We found that the self-reported prevalence of peanut allergy in offspring of peanut farmers was similar to that reported in the general population. This is a unique population that may provide insight into factors that influence development of peanut allergy.

Maternal allergy increases susceptibility to offspring allergy in association with TH2-biased epigenetic alterations in a mouse model of peanut allergy

Although maternal atopy is a risk factor for the development of peanut allergy, this phenomenon has not been well characterized experimentally, and the mechanisms underlying offspring risk are unclear. We sought to determine whether offspring of mothers with peanut allergy (O-PAM mice) are more susceptible to peanut allergy than offspring of naive mothers (O-NM mice) in a murine model and, if so, whether the susceptibility is linked to TH2-biased epigenetic alterations. Five-week-old O-PAM and O-NM mice were intragastrically sensitized to and challenged with peanut. Serum peanut-specific IgE levels, plasma histamine levels, anaphylactic reactions, and splenocyte and MLN cell cytokine production were measured. DNA methylation levels of the Il4 gene promoter from splenocytes and MLN cells from sensitized offspring and splenocytes from unsensitized neonatal offspring were determined by means of pyrosequencing. O-PAM mice exhibited 3-fold higher peanut-specific IgE levels after peanut sensitization, as well as 5-fold higher histamine levels and significantly higher anaphylactic symptom scores after challenge than O-NM mice (P< .05-.01). Cultured splenocytes and MLNs from O-PAM mice produced significantly more TH2 cytokines than cells from O-NM mice (P< .05-.01). Cells from O-PAM mice exhibited significantly reduced DNA methylation at CpG sites of the Il4 gene promoter than cells from O-NM mice. DNA methylation levels were inversely correlated with IL-4 and IgE production. O-PAM neonatal splenocyte hypomethylation of the Il4 gene promoter was also present. This study is the first to demonstrate that increasedsusceptibility to peanut allergy in O-PAM mice is associated with epigenetic alteration of the Il4 gene promoter. This finding might provide insight into preventing the development of early-life allergy.

Allergic Reactions to Foods in Preschool-Aged Children in a Prospective Observational Food Allergy Study

D Fleischer, T Perry, D Atkins. Pediatrics. 2012;130(e25):25–32 To determine the frequency and circumstances of allergic reactions to common food allergens in a multicenter, prospective study of preschool-aged children. The cohort examined was already participating in an observational study to monitor for development of peanut allergy in patients with history of milk/egg allergy. There were 512 infants enrolled between the ages of 3 and 15 months from 5 US sites. In a prospective, 5-site observational study, subjects were scheduled for a clinical evaluation at 6-month intervals for 2 visits, then …

Bayesian Sample Size Determination for Case-Control Studies When Exposure May be Misclassified

Odds ratios are frequently used for estimating the effect of an exposure on the probability of disease in case-control studies. In planning such studies, methods for sample size determination are required to ensure sufficient accuracy in estimating odds ratios once the data are collected. Often, the exposure used in epidemiologic studies is not perfectly ascertained. This can arise from recall bias, the use of a proxy exposure measurement, uncertain work exposure history, and laboratory or other errors. The resulting misclassification can have large impacts on the accuracy and precision of estimators, and specialized estimation techniques have been developed to adjust for these biases. However, much less work has been done to account for the anticipated decrease in the precision of estimators at the design stage. Here, we develop methods for sample size determination for odds ratios in the presence of exposure misclassification by using several interval-based Bayesian criteria. By using a series of prototypical examples, we compare sample size requirements after adjustment for misclassification with those required when this problem is ignored. We illustrate the methods by planning a case-control study of the effect of late introduction of peanut to the diet of children to the subsequent development of peanut allergy.

Increased compound heterozygous filaggrin mutations in severe atopic dermatitis in the United States

534 Filaggrin mutations are common in a US group of white patients with severe atopic dermatitis (48.5%). Filaggrin mutation analysis in patients with severe atopic dermatitis may be useful for the clinician because it provides a genetic basis to the severity of the disease process and predicts the atopic march as a loss of function mutations confer genetic risks to the development of peanut allergy, allergic rhinitis, and asthma in the presence of eczema. New therapies are being developed to augment filaggrin expression in atopic dermatitis skin and patients will filaggrin mutations may benefit the most from this information. 3702delG/WT 0.0 (0.0)

The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis

Cytochrome P450, family 11, subfamily A, polypeptide 1 (Cyp11a1), a cytochrome P450 enzyme, is the first and rate-limiting enzyme in the steroidogenic pathway, converting cholesterol to pregnenolone. Cyp11a1 expression is increased in activated T cells. We sought to determine the role of Cyp11a1 activation in the development of peanut allergy and TH cell functional differentiation. A Cyp11a1 inhibitor, aminoglutethimide (AMG), was administered to peanut-sensitized and challenged mice. Clinical symptoms, intestinal inflammation, and Cyp11a1 levels were assessed. The effects of Cyp11a1 inhibition on T(H)1, T(H)2, and T(H)17 differentiation were determined. Cyp11a1 gene silencing was performed with Cyp11a1-targeted short hairpin RNA. Peanut sensitization and challenge resulted in diarrhea, inflammation, and increased levels of Cyp11a1, IL13, and IL17A mRNA in the small intestine. Inhibition of Cyp11a1 with AMG prevented allergic diarrhea and inflammation. Levels of pregnenolone in serum were reduced in parallel. AMG treatment decreased IL13 and IL17A mRNA expression in the small intestine without affecting Cyp11a1 mRNA or protein levels. In vitro the inhibitor decreased IL13 and IL17A mRNA and protein levels in differentiated T(H)2 and T(H)17 CD4 T cells, respectively, without affecting GATA3, retinoic acid-related orphan receptor γt (RORγt), or T(H)1 cells and IFNG and T-bet expression. Short hairpin RNA-mediated silencing of Cyp11a1 in polarized T(H)2 CD4 T cells significantly decreased pregnenolone and IL13 mRNA and protein levels. Cyp11a1 plays an important role in the development of peanut allergy, regulating peanut-induced allergic responses through effects on steroidogenesis, an essential pathway in T(H)2 differentiation. Cyp11a1 thus serves as a novel target in the regulation and treatment of peanut allergy.

Peanut protein in household dust is related to household peanut consumption and is biologically active

Peanut allergy is an important public health concern. To understand the pathogenesis of peanut allergy, we need to determine the route by which children become sensitized. A dose-response between household peanut consumption (HPC; used as an indirect marker of environmental peanut exposure) and the development of peanut allergy has been observed; however, environmental peanut exposure was not directly quantified. We sought to explore the relationship between reported HPC and peanut protein levels in an infant's home environment and to determine the biological activity of environmental peanut. Peanut protein was quantified in wipe and dust samples collected from 45 homes with infants by using a polyclonal peanut ELISA. Environmental peanut protein levels were compared with peanut consumption assessed by using a validated peanut food frequency questionnaire and other clinical and household factors. Biological activity of peanut protein in dust was assessed with a basophil activation assay. There was a positive correlation between peanut protein levels in the infant's bed, crib rail, and play area and reported HPC over 1 and 6 months. On multivariate regression analysis, HPC was the most important variable associated with peanut protein levels in the infant's bed sheet and play area. Dust samples containing high peanut protein levels induced dose-dependent activation of basophils in children with peanut allergy. We have shown that an infant's environmental exposure to peanut is most likely to be due to HPC. Peanut protein in dust is biologically active and should be assessed as a route of possible early peanut sensitization in infants.

Transfer of Peanut Allergy Following Lung Transplantation: A Case Report

This case study describes a patient who developed peanut allergy following lung transplantation. A 54-year-old woman underwent bilateral lung transplantation on June 2009 owing to severe chronic obstructive pulmonary disease. She had no history of food allergy before transplantation. The donor, however, was a 20-year-old man who was fatally injured during an automobile accident; he was allergic to peanuts. At 3 months after transplantation, the lung recipient presented with acute dyspnea and urticaria 15 minutes after consuming food containing peanut derivatives. Pre- and posttransplantation recipient blood samples analyzed for the presence of IgE antibodies specific for peanut allergens confirmed that the allergy had been passively transfered as a consequence of transplantation. Food allergy following solid organ transplantation is thought to be rare, mostly occurring in children. Two mechanisms may explain the observations described for the patient reported in this study: de novo development of peanut allergies after transplantation, or passive transfer of peanut allergies from a peanut-sensitized organ donor. This case report documenting pre- and posttransplantation IgE status in a lung transplantation case suggested that the allergic status of organ donors should be thoroughly assessed before transplantation, and potential allergy transfer risks must be discussed with the transplant team and the patient.

Antenatal risk factors for peanut allergy in children

BackgroundPrenatal factors may contribute to the development of peanut allergy. We evaluated the risk of childhood peanut allergy in association with pregnancy exposure to Rh immune globulin, folic acid and ingestion of peanut-containing foods.MethodsWe conducted a web-based case-control survey using the Anaphylaxis Canada Registry, a pre-existing database of persons with a history of anaphylaxis. A total of 1300 case children with reported peanut allergy were compared to 113 control children with shellfish allergy. All were evaluated for maternal exposure in pregnancy to Rh immune globulin and folic acid tablet supplements, as well as maternal avoidance of dietary peanut intake in pregnancy.ResultsReceipt of Rh immune globulin in pregnancy was not associated with a higher risk of peanut allergy (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.51 to 1.45), nor was initiation of folic acid tablet supplements before or after conception (OR 0.53, 95% CI 0.19 to 1.48). Complete avoidance of peanut-containing products in pregnancy was associated with a non-significantly lower risk of peanut allergy (OR 0.53, 95% CI 0.27 to 1.03).ConclusionThe risk of childhood peanut allergy was not modified by the following common maternal exposures in pregnancy: Rh immune globulin, folic acid or peanut-containing foods.Clinical implicationsRh immune globulin, folic acid supplement use and peanut avoidance in pregnancy have yet to be proven to modulate the risk of childhood anaphylaxis to peanuts.Capsule SummaryIdentification of prenatal factors that contribute to peanut allergy might allow for prevention of this life-threatening condition. This article explores the role of three such factors.

HEADS UP

HEADS UP

Assessing Peanut Consumption in a Population of Mothers and Their Children in the UK: Validation Study of a Food Frequency Questionnaire

Background Food frequency questionnaires (FFQs) are essential tools to investigate the relationship between peanut consumption and the development of peanut allergy. The aim was to validate a 50-item FFQ for use in peanut protein sensitization studies.Methods There were 38 mother-child pairs visiting a pediatric clinic of a London hospital included. Mothers recorded their own and their child's diet, using a 7 day food diary (7DFDR), completed prospectively over week. Six months later, they tried to recall the consumption of food items for the index week on a FFQ.Results Of these, 33 out of 38 mothers completed both the 7DFDR and the recall FFQ. Although there was considerable variation at the individual level between the 2 tools, there was extremely close agreement between the mean 7DFDR response and the FFQ when considering groups of fives with similar FFQ levels. Agreement was apparent on both peanut and other control foods consumption patterns.Conclusion The FFQ will reliably divide the population into groups with markedly different peanut consumption levels. It accurately reflects true adults and children peanut consumption, especially at low levels of peanut consumption, as it was validated against the gold standard, the 7DFDR. It also provides a good measure of other foods consumption.

Household peanut consumption as a risk factor for the development of peanut allergy

Most children with peanut allergy (PA) react on first known oral exposure to peanut. Recent data suggest cutaneous exposure as a route of sensitization. This study aimed to establish the relevant route of peanut exposure in the development of allergy. Questionnaires were administered to children with PA and to high-risk controls (with egg allergy) and controls without allergy. Questionnaires were completed before subjects were aware of their PA status, avoiding recall bias. Questionnaires recorded maternal peanut consumption during pregnancy, breast-feeding, and the first year of life. Peanut consumption was determined among all household members, allowing quantification of environmental household exposure (household peanut). Median weekly household peanut in the 133 PA cases was significantly elevated (18.8 g) compared with 150 controls without allergy (6.9 g) and 160 high-risk controls (1.9 g). There were no differences in infant peanut consumption between groups. Differences in maternal peanut consumption during pregnancy (and lactation) were significant but become nonsignificant after adjusting for household peanut. A dose-response relationship was observed between environmental (nonoral) peanut exposure and the development of PA, which was strongest for peanut butter. Early oral exposure to peanut in infants with high environmental peanut exposure may have had a protective effect against the development of PA. High levels of environmental exposure to peanut during infancy appear to promote sensitization, whereas low levels may be protective in atopic children. No effect of maternal peanut consumption during pregnancy or lactation is observed, supporting the hypothesis that peanut sensitization occurs as a result of environmental exposure.

In Vitro Evidence For Different Routes Of Sensitization To Peanut In Children

Despite the requirement for prior contact with an allergen for sensitization to occur, the majority of peanut allergic children react to their first known peanut ingestion. Evidence suggests that sensitization may occur by contact with allergen through the skin. Individuals thus sensitized may be predisposed to developing peanut allergy, whilst tolerance to peanut may be induced by oral exposure. We employ the use of skin and gastrointestinal homing memory T cell markers (Cutaneous Lymphocyte Antigen (CLA) and α4β7 respectively) to indicate the likely route of initial sensitization and examine the evidence for this theory. Immunomagnetic beads are used to isolate CLA+ and α4β7+ memory T cells from peripheral blood mononuclear cells. The cells are stimulated with peanut extract in the presence of antigen presenting cells. Thymidine incorporation is assayed to measure lymphocyte proliferation. Stimulation indices to peanut in the CLA+ cells are compared to those in the α4β7+ cells in both peanut allergic and peanut tolerant children. Peanut specific cytokine production including IL4, IL5, IFN-γ, TFN-α, IL10 and TGF-β is batched and measured in the cell culture supernatants of both groups. Higher proliferation is observed in the CLA+ memory T cells relative to the α4β7+ memory T cells in peanut allergy. This trend appears to be reversed in non-allergic patients. In vitro evidence supports the hypothesis that sensitization to peanut via the skin may be associated with the development of peanut allergy, whilst oral sensitization may induce tolerance. Such studies may help to facilitate the diagnosis of peanut allergy.

Factors Affecting Incidence of Peanut Allergy: Priorities for Research and Policy

As peanuts are one of the most common foods to cause an allergic reaction both in children and adults, this paper reviews the research evidence related to factors in the production, processing and consumption of peanuts that may play a role in the reported increase in prevalence of peanut allergy in the western world. A structured literature review to examine the research evidence related to developments in the production, processing and consumption of peanuts over the past 30 years that may have an influence on peanut allergy. An evaluation of the importance of various factors for the development of peanut allergy and the identification of gaps in the literature. This paper shows that the development of peanut sensitization may depend on a number of factors including: genetic or environmental background, peanut containing products, peanut consumption; early exposure, immunological status, dietary exposure of the mother and antigen transmission via breast milk. Research evidence suggests that the nature of the cultivars does not play a major role in peanut allergenicity, but that various aspects of peanut processing methods and peanut consumption are more important. Information on changes in the processing and consumption of peanuts can be combined with peanut allergy prevalence data and data on environmental factors to provide a greater understanding of the causal factors influencing the prevalence of peanut allergy. This paper sets a priority for researchers to focus their research on and therefore might help in the long term to provide hope for peanut allergy sufferers and their families.