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Peanut allergy and anaphylaxis
Fred D Finkelman1,2,3
Peanuts are a frequent cause of food allergy and the most common cause of fatal food-induced anaphylaxis in the U.S. Advances during the past two years have promoted our understanding of peanut allergens and peanut allergy prevalence, etiology, diagnosis, and therapy. The advances highlighted in this review include evidence that the peanut allergens most important in disease differ in different parts of the world, that early oral exposure to peanuts may decrease the frequency of peanut allergy, while early nonoral exposure may have the opposite effect, that complement activation by peanut constituents appears to promote peanut-induced anaphylaxis and that oral immunotherapy, anti-IgE antibody, and a herbal formulation are promising approaches for the treatment of this disorder.
Addresses 1 Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, United States 2 Division of Immunology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States 3 Division of Immunobiology, Cincinnnati Children’s Hospital Medical Center, Cincinnati, OH 45229, United States Corresponding author: Finkelman, Fred D (ffinkelman@pol.net)

endothelial cells (increased permeability and expression of molecules involved in inflammatory cell migration) [1]. The characteristics of an allergic response depend predominantly on the tissues affected and the cytokines produced, which, in turn, determine inflammatory cell and nonimmune cell involvement. Of all of the allergic disorders, anaphylaxis, which affects approximately 150 000 Americans a year [2], is probably the most dramatic. In this disease, rapid production of large quantities of vasoactive mediators, including histamine, platelet-activating factor (PAF), leukotrienes and serotonin, as well as Th2 and inflammatory cytokines and proteolytic enzymes by mast cells, basophils and macrophages causes increases in vascular permeability and smooth muscle contraction that can cause urticaria (hives), swelling of the face, mouth, tongue and pharynx (angioedema), diarrhea, asthma, decreased myocardial function, hypotension and, in approximately 1500 Americans a year, death [3]. Although anaphylaxis can be induced by a variety of antigens delivered through several different routes, the most common causes are insect venoms, drugs, and foods [4]. This review is limited to food allergy, which is thought to cause >50 000 cases of anaphylaxis and approximately 100 deaths a year in the U.S. and focuses on allergy to peanuts (Arachis hypogaea), which affects approximately 1% of children and 0.6% of adults in the U.S. [5]. Foods associated with allergy can be broadly divided into two groups: those, such as milk and eggs, which are the most common causes of food allergy in infants and young children, but rarely cause food allergy in adults (and rarely cause death) and those, including peanuts, tree nuts, fish, and shellfish, that cause food allergy in both children and adults and are more likely to cause severe shock and death. Of the allergens in the second group, peanuts, which are inexpensive and frequently eaten in unmodified form and as components of many different prepared foods, cause the largest number of cases of severe anaphylaxis and death in the U.S. [5]. This along with evidence that the incidence of peanut allergy is increasing has led many students of allergy to focus their research efforts on peanut allergens and their clinical effects. This review, an update on these efforts, concentrates on papers published in the past two years and comments on observations that have extended our knowledge of peanut allergens and peanut allergy prevalence, etiology, diagnosis, prognosis, and treatment.

Current Opinion in Immunology 2010, 22:783–788 This review comes from a themed issue on Allergy and hypersensitivity Edited by Marsha Wills–Karp and Martien Kapsenberg Available online 2nd November 2010 0952-7915/$ – see front matter Published by Elsevier Ltd. DOI 10.1016/j.coi.2010.10.005

Introduction
In allergic disorders, the normal protective role of the immune system is perverted by responses designed to protect against pathogens that are made against generally harmless foreign molecules. These responses, which include increased production of Th2 cytokines (IL-4, IL-5, IL-9, IL-13) and inflammatory cytokines (particularly IL3, TNF and, in some cases, IL-17) induce inflammation characterized by the presence and activation of eosinophils, basophils, mast cells, alternatively activated macrophages and, to a variable extent, neutrophils. Allergyassociated cytokines additionally induce important changes in the function of cells that are not conventionally thought of as elements of the immune system, including epithelial cells (increased permeability and mucus and chemokine production), smooth muscle cells (increased contractility and chemokine production) and vascular
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Peanut allergens
Allergens are typically identified by their ability to bind IgE in the serum of allergic individuals and to activate
Current Opinion in Immunology 2010, 22:783–788

A second concern is that even though the 11 peanut allergens.. three-dimensional epitopes generated by the native folding of the Ara h 2 polypeptide) rather than by linear epitopes (i.e.sciencedirect. they have not yet tested the basic hypothesis that Ara h 2/h 6-depleted peanuts will be less allergenic than conventional peanuts. processed from 64 kDa protein 37 kDa 15 kDa 15 kDa 17 kDa 16 kDa 9. Consequently. Other studies evaluated clinical implications of peanut allergy. In one study.9]. is a more important allergen than Ara h 1. Prevalence Several studies have evaluated the prevalence of peanut allergy in the U.5%) of peanut allergy in siblings of peanut-allergic patients compared to siblings of children not allergic to peanuts [15]. Although these studies suggest that this approach is feasible [7].2% in 2002 and 2. a 2S albumin Member of conglutin family of seed storage proteins. an analysis of hospitalization rates for peanut-related anaphylaxis in New York state showed a >4-fold increase from 1990 to 2006 for individuals <20 years old [12]. a peanut protein that is relatively unimportant as an allergen in the U. the other peanut allergens that bind IgE from a large percentage of peanut allergic individuals [6]. 22:783–788 individuals who have relatively high concentrations of IgE specific for linear epitopes. Another study. 1% of individuals reported peanut allergy in a similar survey in Canada [12]. The authors of this study suggested this frequency was sufficiently high to justify testing of siblings of peanutallergic individuals before they are allowed to eat peanutcontaining foods. 1. however. an 11S globulin Isoform of Ara h 3 Member of profilin family of G-actin-binding proteins Member of conglutin family of seed storage proteins. One concern about this approach is that different geographically defined or ethnically defined populations are predominantly sensitive to different peanut allergens. for the effector phase of peanut allergy). crude peanut extract is considerably more immunogenic in animal studies than any of the purified major allergens tested [10]. Consistent with an increase in peanut allergy prevalence in children. account for the binding of the great majority of the peanut-specific IgE in peanut-allergic individuals (and thus. heteromultimeric protein formed from differently proteolytically processed products of the same gene.S. epitopes generated by consecutive amino acids that do not depend on polypeptide folding). Ara h 2.S.784 Allergy and hypersensitivity Table 1 Characteristics of peanut allergens Allergen Ara h 1 Ara h 2 Ara h 3 Molecular mass 63 kDa 17–19 kDa 14–45 kDa. Ara h 2 and the related allergen. Bet v 1 and other pathogenesis-related proteins Lipid transfer protein Oleosin seed storage protein Oleosin seed storage protein Ara Ara Ara Ara Ara h h h h h 4 5 6 7 8 Ara h 9 Ara h 10 Ara h 11 mast cells and/or basophils that have been sensitized with IgE-containing serum. have been determined to be considerably more potent than Ara h 1 and Ara h 3.8 kDa 16 kDa 14 kDa Characteristics Member of vicilin family of seed storage proteins.4% of subjects in the U. It is not known how this relates to previous evidence that allergic symptoms are usually worst in Current Opinion in Immunology 2010. Ara h 6. www. On the basis of these criteria. a 7S globulin Member of conglutin family of seed storage proteins. Studies aimed at defining the epitopes of Ara h 2 that are bound by IgE from peanut-allergic individuals have demonstrated that most IgE binds to conformational epitopes (i. for example. Of these. a retrospective chart review study found that children with asthma who had peanut allergy had 2.59-fold greater rate of systemic steroid use than asthmatic children without peanut allergy [14]. a 2S albumin Member of glycinin family of seed storage proteins. a survey of parents indicated a 6–7-fold increased incidence (8. especially multiple linear epitopes [5].e. This percentage has not increased for adults. Additionally. 11 peanut allergens have been identified (Table 1). particularly Ara h2 and Ara h 6.6% in 1997 to 1. Only 22% of eight-year-old children considered to be peanut-sensitized on the basis of skin prick testing or IgE measurements had a positive response to oral peanut challenge. other components may be more critical for the sensitization phase. indicated that not all ‘peanut-allergic’ individuals actually develop allergic symptoms following peanut ingestion. have demonstrated that Ara h 9. a 2S albumin Homologous to major birch pollen allergen. reported peanut or tree nut allergy in a random telephone survey [11]. Two groups. or Ara h 3 for peanut-allergic patients from the Mediterranean area [8.S. In this regard. IgE and skin prick responses to Ara h 2 were the best predictor of a positive response to oral challenge in this study [13]. but increased for children less than 18 years old from 0.com . some studies aimed at modifying peanuts to reduce their allergenicity have focused on decreasing Ara h 2 and Ara h 6 concentration.32-fold more frequent hospitalizations for asthma and a 1.1% in 2007. and Canada and investigated whether prevalence is changing. For example.

sciencedirect. these observations suggest that complement activation by peanut components (and by a number of other allergens. It was hypothesized that this difference may be related to the early consumption of a peanut product (bamba. Although the requirements for IgE and mast cells are similar to those demonstrated in previous murine food allergy models. which acts through C3a receptors on mast cells. Patients with this disorder. to produce histamine in in vivo mouse experiments (Figure 1). while infants in the UK have avoided peanuts. and the ability of anti-IL-5 monoclonal antibody to ameliorate eosinophilic esophagitis in clinical trials [31] provides evidence that this Current Opinion in Immunology 2010. Taken together. The first of these demonstrated that the prevalence of peanut allergy in Israeli Jewish children was less than 10% that of Jewish children in the UK [16]. An unrelated line of investigation has shed light on the etiology of a specific allergic disorder. especially peanut butter. These patients usually are allergic to multiple foods. Peanut molecules activate complement. peanut extract acted through a complement-dependent mechanism to considerably exacerbate the severity of IgE-mediated anaphylaxis in mice.Peanut allergy and anaphylaxis Finkelman 785 Etiology Two important British studies evaluated the relationship of peanut exposure to the development of peanut allergy.19]. such as some insect venoms [22]). which induces basophils and macrophages to produce PAF and mast cells. increased availability of peanut allergens caused by the roasting process [25] and dendritic cell activation by Ara h 1 [26] may explain why peanuts are so much more likely to cause severe anaphylaxis than most other foods. because activated complement can act as an adjuvant [27]. contributes importantly to their ability to induce anaphylaxis. during infancy was associated with increased risk of sensitization to peanuts. survival. In contrast. In www. as well as the elicitation phase of peanut allergy. such as peanut allergen resistance to digestion [23. although maternal peanut consumption during pregnancy or lactation did not have a detectable effect [17]. and macrophages to induce the production of PAF and histamine. along with other peanut characteristics. and IL-13 were shown to be required for peanut allergy development [20]. More importantly. causing production of C3a. whose T cells produce considerably more IL-4 than IL-5 in response to peanut allergen stimulation. IL-13 antagonists (along with IgE and mast cell antagonists) may be useful food allergy therapeutics. addition. 22:783–788 . migration and activation. which directly and indirectly increase vascular permeability and smooth muscle contractility. If so. IgE. basophils. have the ability to activate complement in both mouse and human plasma [21].com Figure 1 Peanut Molecules C3 C3a C3aR C3aR C3aR Mast Cell Basophil Macrophage Histamine + PAF PAF PAF Fluid + Protein Increased Smooth Muscle Contractility Increased Vascular Permeability Current Opinion in Immunology Peanut activation of complement exacerbates anaphylaxis. they caused shock in mice made more sensitive to vasoactive mediators by pretreatment with IL-4 and a b-adrenergic antagonist. Because these studies suggest. A separate study revealed that aqueous extracts of peanuts and tree nuts. including peanuts [29]. Although the vasoactive mediators produced by this mechanism were insufficient to cause shock in otherwise untreated mice. mast cells. This. increased nonoral exposure to peanuts. made from peanut butter and puffed corn) by Israeli infants. but neither milk nor eggs. which is characterized histologically by an increased number of eosinophils in the esophagus. T cells from peanut-allergic patients with eosinophilic esophagitis also produce large amounts of IL-5 [30]. to a lesser extent. the requirement for IL-13 had not previously been shown and suggests that IL-13 effects on vascular and epithelial cell permeability and smooth muscle contractility may be critical factors in food allergy pathophysiology. Unlike patients with more typical peanut allergy. Mouse model studies published during the past two years provide mechanistic insight into peanut allergy. typically have severe heartburn that does not respond well to acid neutralization [28]. complement activation by peanut components may contribute to the sensitization phase. but do not prove that ingestion of peanuts or peanut products early in life protects against the development of peanut allergy [18.24]. a prospective trial has been initiated to test this hypothesis with a cohort of infants who are at high risk for food allergy. The ability of IL-5 to promote eosinophilopoiesis. eosinophilic esophagitis. This led to the production of C3a.

IL-4.786 Allergy and hypersensitivity increased T cell IL-5 production leads to the development of eosinophilic esophagitis rather than more typical food allergy. Diagnosis and prognosis Although the gold standard for diagnosing peanut allergy is a double-blinded oral food challenge. an IgE-specific monoclonal antibody that prevents IgE Current Opinion in Immunology 2010. and treatment with a herbal formulation based on traditional Chinese medicine. then decreased [34]. similar study that included home dosing. Food Allergy Herbal Formula-2 (FAHF-2) provided promising results. Symptoms were less common during the buildup phase and occurred with only 3. Oral immunotherapy was discontinued in four of 22 patients because of adverse effects [33]. Upper respiratory tract and abdominal symptoms were experienced by most patients during the initial escalation day.7% of home doses caused symptoms that required treatment. Thus. IL-10. In addition. Additionally. there is a reason to hope that this apparently safe therapy may be useful for the treatment of human food allergy and enable the identification of specific constituents that can be used therapeutically. basophil activation.sciencedirect.5% of home doses. were predictive of the severity of allergic response to oral challenge [32]. experts in this area have suggested that oral immunotherapy for peanut allergy is not ready for clinical use [37]. a phase I. this mouse study creates a rationale to develop PAF antagonists (which were previously tested and found inefficacious as asthma therapeutics [48]) for use as prophylactics in the suppression of food allergy. Effects of treatment included decreased peanut-specific IgE and Th2 cytokine production and increased IgG2a and IFN-g production by CD8+ T cells. binding to FceRI and is FDA-approved for the treatment of asthma.com . and TNF secretion. anti-IgE monoclonal antibody treatment. have improved our understanding of the epidemiology. which included one dose of epinephrine each for two subjects [35]. This seems to confirm the results of a previous study with a different anti-IgE monoclonal antibody [39]. The first. optimal dosing regimen. placebo-controlled doseescalation trial of FAHF-2 showed no unacceptable toxicity as well as decreased IL-5 and increased IFN-g and IL-10 production by PBMCs [43]. reported increased tolerance for food allergens. and optimal patient selection post-desensitization remain uncertain. This observation should be useful for determining which patients should be given an oral challenge and what precautions should be taken. optimal patient selection. Mild to moderate side effects accompanied 2. Decreases in responses to skin prick testing. A final report showed that earlier observations that PAF antagonists suppress food allergy symptoms in mouse models [44] are applicable in a mouse model of peanut allergy. peanut skin prick test wheal size and specific IgE level. and pathophysiology of peanut allergy and anaphylaxis. IL-4. after 12–24 weeks of treatment in patients who had food allergy as well as asthma [38]. a separate report described the decreased efficacy of omalizumab treatment in patients in whom a high percentage of total serum IgE was specific for the offending antigen and noted that 33% of peanut-allergic patients fell in this category [40]. was able to increase tolerance for peanuts an average of 5-fold in 18/22 allergic children age 3–14. an oral immunotherapy protocol for children that featured initial day escalation. Because the relative risks of oral immunotherapy versus avoidance. suggesting that FAHF-2 induces CD8+ T cell production of IFN-g. Twenty of 22 patients completed a third. accepted therapy for this www. Oral immunotherapy over seven months. buildup and maintenance phases was well tolerated and successful for >90% of patients. and peanutspecific IgE were found along with increases in peanut-specific IgG4. and IL-5 production by peripheral blood mononuclear cells. One additional caution to the use of oral immunotherapy is that peanut allergy has been observed to recur even during regular ingestion of significant amounts of peanut protein [36]. had no therapeutic effect. in one study. One study of asthmatic patients treated with omalizumab. although histamine or leukotriene antagonists. 22:783–788 Conclusion Works performed during the past 10 years. but not food allergy. The second study. demonstrated that FAHF-2 treatment of peanut-allergic mice protected them from anaphylaxis for >36 weeks after discontinuing treatment. by themselves.3%. Oral immunotherapy was associated with an increase in peanut-specific IgG4 levels and decreased peanut-specific IL-2. Foxp3+ T cells first increased. In a second study. Efficacy was CD8+ T cell and IFN-g-dependent.6% of doses and symptoms of pulmonary obstruction developed in 1. including peanuts. the combination of histamine and PAF antagonists was more effective than PAF antagonists alone [45]. omalizumab itself has been reported to induce an unusual form of slow-developing anaphylaxis [41]. an Australian study demonstrated that for children. Only 0. randomized double-blinded. Two studies of a herbal formulation. Combined with other animal model studies [46] and a recent human study that shows increased serum PAF during human anaphylaxis and more severe anaphylaxis in individuals who slowly catabolize this mediator [47]. etiology. but have not yet led to a novel. including the recent studies highlighted in this review. which is known to suppress IgE and Th2 cytokine production and effects [42]. Unfortunately. Treatment Advances were reported in the use of oral immunotherapy. IFN-g. but not history of peanut-induced anaphylaxis. a mouse model study.

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