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Research and Development, Ross Products Division, Abbott Laboratories, Columbus, OH 43215
3To whom correspondence should be addressed. E-mail: chris.cordle{at}abbott.com.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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100 times), indicating lower allergenic reactivity. Extensive investigations of soy immunological reactivity have also been carried out using animal models. Consistent with clinical results, all of these data show substantially diminished immunological reactivity for soy proteins. Biochemical and immunochemical analyses indicate no striking differences between soy and other food proteins that would explain these unexpected differences in allergenic reactivity.
KEY WORDS: • soy • food allergy • clinical results • animal models
Food allergy (FA)4 is a relatively rare and sometimes violent immune system reaction to food proteins. In its broadest definition FA includes syndromes involving several immune mechanisms, each causing a variety of symptoms. Although all types of FA must be effectively managed, the most dangerous is immediate-type hypersensitivity (type I) mediated by IgE antibodies to food proteins. Most type I FA appears in the first 2 y of life and occurs in 6–8% of infants (1). As their immune systems mature (by 5 y), 80% of allergic infants will lose their FAs (2). Symptoms range from mild rashes to life-threatening systemic anaphylaxis and are of 4 main types: dermatological (hives, local swelling, dermatitis, and eczema), gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), respiratory (runny nose, asthma, and tightening of the throat), and systemic (anaphylactic shock, organ failure, cardiac arrhythmia, and death).
Foods vary in clinical allergy significance. Although all food proteins have the potential to be allergenic for some people, 8 foods have been identified as the most frequent human food allergens and account for 90% of FAs. These foods are milk, eggs, fish, crustacea, wheat, peanuts, tree nuts, and soy (3). This article describes the allergenic potential of soy proteins compared with some of the other major food allergens.
Immunology of food allergy
A detailed description of the mechanisms of food allergy is beyond the scope of this article, but several excellent reviews of clinical aspects are available (4–6). Briefly, type I food allergies involve a 3-step process. The first step is sensitization, which begins with transit of relatively intact food antigens across the intestinal barrier. The gut may be unable to effectively exclude intact antigens because of immaturity, injury, or infection. Some intact food antigen uptake is normal, even in adults. Factors affecting whether the antigens stimulate the usual antibody responses (IgG and IgA) and immune tolerance or an allergic response are not clearly understood. In individuals predisposed to allergy, food antigens generate activated antigen-specific B cells and a special set of helper T cells that direct B cells to differentiate into IgE-producing plasma cells. Once secreted, IgE is quickly bound by high-affinity IgE receptors mainly on the surface of mast cells. These cells contain large amounts of histamine and other allergic reaction mediators and are the main inducers of symptoms of allergy. The end result of sensitization is the presence in circulation and tissues of large numbers of mast cells armed by allergen-specific IgE antibodies on the cell surface.
In the second step, triggering, which occurs some time after sensitization, allergen or multivalent allergen fragments are again absorbed after ingestion. IgE antibodies on mast cells bind the allergen so that the allergen cross-links at least 2 receptor-bound IgE molecules. This creates a signal causing the mast cell to release histamine and other inflammatory mediators (degranulation). Timing and magnitude of the release is defined by allergen dose and a number of poorly understood host factors.
The final step, the initiation of clinical symptoms, occurs when histamine and other inflammatory mediators stimulate the wide variety of allergic symptoms in other cells and organs. With this basic understanding of the allergy process we can now consider soy allergy.
Soy allergy characterization
Soy protein is allergenic. The first allergic reactions to soy in humans were described in 1934 (7). Anti-soy IgE antibodies have been identified but allergen specificity patterns are variable and complex. As many as 28 soy proteins bind to IgE from soy-allergic patients (8). Soy is also an aeroallergen, although the pathologies and allergen reactivity profiles are different for ingestion versus inhalation, where soy hull antigens not present in soy protein isolates seem to dominate (9). A small number of fatal allergic reactions to soy have been reported (10,11), but in all cases victims also had severe peanut allergies and asthma.
What is the relative allergenic reactivity of soy proteins compared with other major food proteins? The answer depends on what clinical and laboratory outcomes are used and which patient populations are studied.
Clinical and laboratory indicators of allergy. Clinical indicators of food allergy include cumulative clinical history of atopic symptoms; history of allergic symptoms soon after specific food ingestion; positive skin prick test (SPT) with food protein extracts; unblinded food challenges; and double-blinded, placebo-controlled, food challenges (DBPCFCs; the gold standard for food allergy diagnosis). Laboratory indicators of food allergy are radio allergosorbent test (RAST), which measures allergen-specific IgE antibodies using radioisotopes; ELISA, which also measures allergen-specific IgE using antibody-conjugated enzymes and chromatic substrates; and immunoblotting of polyacrylamide gel electrophoresis-separated proteins to reveal IgE-allergen binding.
Patient populations. Allergy assessment outcomes can be influenced by the criteria used to define patient enrollment. A variety of clinical populations have been used to study food allergy. Within specific populations, enrollment standards for inclusion and exclusion also vary. When comparing similar studies, it is important to clearly understand the characteristics used to qualify and enroll study subjects. Five clinical populations have been used for most food allergy research: 1) "high-risk" asymptomatic infants (defined variably based on the atopic history status of parents and/or siblings; 2) patients with atopic symptoms (defined variably to include 1 to several allergy-associated symptoms); 3) patients with positive DBPCFCs (a relatively rigorous criterion); 4) patients with cow’s milk allergy (a subset of group 3 that have been rigorously identified using DBPCFCs); and 5) whole-population birth cohorts.
Clinical results
High-risk infants fed cow’s milk protein–based formula (CMF) versus soy protein-based formula (SF). Concern exists about the sensitivity of cumulative atopic symptom scores as indicators of food allergy status, especially for older infants. These subjects may no longer be taking formula and have been exposed to a wide variety of nonfood environmental allergens that may contribute to their atopic symptoms. Some studies show no difference in the cumulative history of atopic symptoms (12–15). Other studies report significantly less asthma, less rhinitis, or generally reduced atopy for SF-fed infants (16–18). In the Halpern study (18) where milk allergy in CMF-fed infants was compared with soy allergy in SF-fed infants, food allergy was reduced 3.6 fold with soy. A meta-analysis of allergen reactivity patterns in 17 studies of high-risk infants shows soy allergy occurring in 3–4% of subjects versus 25% for cow’s milk (19).
Patients with atopic symptoms. These studies surveyed the clinical reactivity specificities of infants and children with atopic symptoms; the diagnostic tests used were RAST, SPT, or DBPCFC. Four studies demonstrate the overall incidence of reactivity to soy. Giampietro et al. (20) studied 317 atopic children and found 22% positive to soy by RAST but only 3% were positive by DBPCFC. Magnolfi et al. (21) tested 704 atopic children and found 21% soy positive by SPT and only 1.3% soy positive by DBPCFC. Bruno et al. (22) tested 505 atopic children and found 6% soy positive by SPT and 1.2% soy positive by DBPCFC. Burks et al. (23) found 13% soy positive by SPT and 1.8% soy positive by DBPCFC in a study of 165 atopic patients. Overall, these data show a relatively low rate of soy allergy in atopic infants (28 of 1691 patients, 1.7%) and a relatively high rate of false-positive results when SPT and RAST are used to diagnose symptomatic soy food allergy.
Soy reactivity in DBPCFC-positive subjects. Two reports summarized results of DBPCFC patient evaluations performed at major tertiary care allergy centers. Bock and Adkins (24) describe 185 positive food challenges conducted over 16 y, where 31% were positive for cow’s milk proteins and 8% (15 patients) were positive for soy. Sicherer et al. (25) reported on 196 positive DBPCFCs completed over 13 y, with 23% positive for cow’s milk proteins and 10% (20 patients) positive for soy proteins. With fewer than 35 soy-positive patients identified by DBPCFC over 13 y by 2 of the prominent academic food allergy research groups in the United States, it is apparent that extensive studies of soy-allergic subjects in America would be a daunting task. Patients with soy allergy confirmed by DBPCFC seem very rare.
Soy allergy in patients with cow’s milk allergy.
Most often, SF is used clinically to manage intolerance to CMF. A variety of mechanisms are involved in CMF intolerance, which currently affects as many as 36% of infants at some point in y 1 of life. Infants with type I milk protein allergy are estimated to be 6–8% of the total population, so most (80%) CMF intolerance is not caused by allergy and is effectively managed using SF. Infants with type I allergy to CMF are a rigorous test population for evaluating the allergenic reactivity of SF.
Several studies have measured the proportion of infants with documented CMF allergy that will develop soy allergy when SF is substituted for CMF. Bock and Adkins (24) reported 4 of 54 (7%) CMF-allergic infants developed soy allergy when switched to SF. Cantini et al. (26) found 1 of 20 (5%) who developed soy allergy in a similar study. Zeiger et al. (27) observed 13 of 93 (14%) infants allergic to CMF who developed soy allergy. In the study by Kleinola et al. (28), 8 of 80 (10%) developed SF allergy. Together these studies reported that 221 of 247 (89.5%) infants allergic to CMF could be effectively managed with SF. This overall performance approaches the clinical standard for hypoallergenic formula [95% confidence that 90% of allergic infants will not react (29)].
Frequency of allergy in a whole birth cohort. Arshad et al. (30) conducted an interesting study on the Isle of Wight, where a whole birth cohort of 981 infants (64% of total births agreed to participate during the 14-mo enrollment period) was followed to age 4 y. The study recorded histories of allergic disorders and assessed the correlation between these data and results of SPT to a variety of common allergens. Data were not adjusted for relative allergen exposure rates and, as mentioned earlier, SPT is known to overestimate the true incidence of food allergy. SPT results for the various allergens were as follows: house dust mite, 11.9%; grass, 7.9%; Alternaria, 4.8%; milk, 1.4%; and peanut, 1.2%. The lowest sensitization rate was for soy at 0.25%.
Food allergen reaction thresholds.
Another method for ranking the potency of food allergens determines the minimum oral allergen dose required to initiate allergic symptoms. This dose will vary across a population of allergic patients, so the best comparator becomes the dose-response distribution within the allergic population. These data are difficult to obtain because patients with severe allergies must be challenged with increasing allergen doses until a positive reaction occurs. These types of experiments have been reported for only 5 food allergens (Fig. 1). The most important evidence concerns threshold doses for the most sensitive patients. No standards have been set for acceptable minimum allergen doses. However, for comparative purposes, we can apply the "safe for 90% of allergic patients" rule (the hypoallergenic infant formula standard) to the data in Figure 1 to estimate the following "safe" protein doses: peanut, 0.1 mg; hazelnut, 1 mg; egg and milk, 3 mg; and soy, 400 mg. Although the number of patients in these studies is relatively low, the >100-fold difference between the safe protein dose for soy and other allergens is striking. If confirmed, this difference should be considered when setting standards and selecting analytical methods appropriate for measuring soy allergens in food products and food production environments. A partial confirmation of this approach is found in a recent statistical analysis of published data by Blindslev-Jensen et al. (34). This report presented estimates of allergen doses causing reactions at rates of 1 per 1,000,000 and 1 per 100 of population. These data, summarized in Table 1, seem to be consistent with the 90% reactivity threshold numbers predicted for soy protein (1 in 10 at 400 mg protein vs. 1 in 100 at 40 mg protein).
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Animal data
The basis for diminished immunological reactivity for soy protein in humans is unexplained. Is this a general property of soy or is low soy reactivity species specific? Data from 2 animal models of food allergy have been used to address these questions.
Oral sensitization model. The model using oral sensitization of guinea pigs, best described by Devey et al. (35), involves feeding an experimental protein for 33 d and then administering a rapid systemic antigen challenge on day 35. If sensitization has occurred, IgE and IgG1 antibodies will be produced. Both antibody classes will trigger anaphylactic reactions if activated by the presence of a cross-linking antigen. Antigen is injected and the animals are observed for anaphylactic symptoms, scoring for severity on a 0–5 scale (0 = no symptoms, 5 = death). The advantage of this model is that sensitization simulates antigen digestion and intestinal uptake. Disadvantages are that the model is not very sensitive, it does not include an oral challenge, and the anaphylactic response is usually dominated by an IgG1 response rather than an IgE response.
Results of feeding and challenge trials with CMF and SF are shown in Table 2. Two intact cow’s milk-based formulas (Similac and Enfamil) stimulated strong immune responses that caused fatal anaphylactic reactions in all animals fed these products. A formula based on partially hydrolyzed cow’s milk whey protein (Good Start) stimulated weaker but still significant reactions. Animals fed a hypoallergenic formula based on extensively hydrolyzed cow’s milk casein (Alimentum) did not become sensitized as indicated by the absence of allergic symptoms. Interestingly, animals challenged after being fed a formula based on intact soy proteins demonstrated the lowest measurable symptoms of allergy, indicating very low relative reactivity. The significance of this result was confirmed with an important positive control: Guinea pigs were immunized by injection with soy formula mixed with an alum adjuvant on day 0 and challenged as before on day 35. These animals responded with severe allergic symptoms (4 deaths and 1 near death per 5 challenges), indicating that the lack of response to oral soy sensitization was not due to the inability of guinea pigs to produce antibodies to soy.
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Biochemistry and immunochemistry of soy allergens
Food allergens are always complex mixtures of many potentially immunoreactive proteins. Within a food allergen system, individual allergens will also be affected differently by various processing methods. Therefore, the identity and the processing history of food proteins will determine their allergenic potentials and both must be considered in assessing allergen specificity and potency. Individual protein allergens are also complex, with several to many antibody recognition sites (epitopes) per protein. Epitopes can be either sequential (a particular linear amino acid sequence) or conformational (a group of nonlinear amino acids that are in proximity because of protein folding or assembly) and, for glycoproteins, may contain or be influenced by sugar moieties. This extensive complexity makes study results, immunochemical reagents, and control samples difficult to standardize and compare.
Understanding the working definitions of immunological terms used to describe FA and how these definitions relate to the analytical tools used to study FA helps promote experimental consistency and applicability. The first sentence of this article defined food allergy in terms of a clinical reaction to food. However, it is unsafe, unethical, and impractical to perform extensive basic and controlled research by challenging food-allergic patients. Model and surrogate experimental systems have been developed to address this problem. It is important to understand the strengths and weaknesses of these approaches. This is facilitated by a clear definition of terms. Unfortunately, definitions vary throughout the literature. For this article, the following represent simple, immunochemically logical descriptions: antigenicity is the ability of molecules (antigens) to interact with immunologically specific antibodies; immunogenicity is the ability of molecules (immunogens) to initiate antibody or cellular immune responses; and allergenicity is the ability of molecules (allergens) to initiate clinical allergic responses through IgE-mediated mechanisms.
Note that for this discussion, allergenicity is restricted to clinical indications of immediate-type hypersensitivity involving IgE. This is not a comprehensive definition, but is appropriate here because IgE-mediated type I reactions are the critical life-threatening clinical components of FA and because technologies effective in controlling type I allergy are likely effective with other forms of FA. An interesting debate concerns whether the presence of IgE antibody to a particular antigen is an indicator that the antigen is a type I allergen. The absence of an IgE response is strong evidence that the antigen is not a type I allergen but the presence of IgE antibody does not establish the capacity of the antigen to trigger allergic symptoms. A number of investigators have reported lack of correlation between in vitro (ELISA, RAST, and immunoblotting) and in vivo (SPT) measures of IgE reactivity and cross-reactivity, and clinical reactions detected using DBPCFC (40–43). Allergenic potency and specificity are most often measured using ELISA, RAST, or immunoblotting. However, without strong correlation with DBPCFC, these data must be considered only as indicators of allergenic potential and not proof of allergenic potency. This is particularly difficult for soy, where separation and purification of individual soy proteins is a significant challenge and where the number of soy-allergic patients to support DBPCFC research to identify individual allergens is very small. At this point, despite their known flaws, allergen potency measurements by ELISA and RAST and allergen specificity analysis by immunoblotting are the only analytical methods widely used.
At least 16 IgE-binding soy proteins with molecular masses from 7.5 to 97 kD may be involved in clinical allergy (44). Some of the major soy allergens are shown in Table 3. Key goals of research aimed at controlling soy allergy are to identify soy protein allergens, rank soy protein allergenic potency, and assess methods to decrease soy allergenic reactivity.
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Conclusions and future directions
A substantial and consistent body of human clinical and animal model data indicates that soy proteins tend to be less immunologically reactive than many other food proteins. The biochemical and immunological basis for these differences is currently unknown. Improved biochemical methods and immunochemical reagents will be required to better characterize and understand soy protein’s unique immunological properties. In vitro methods that correlate better with DBPCFCs are needed, and these methods should be quantitative. Techniques must also allow for detection of conformational allergen epitopes. Finally, DBPCFC-positive patient antisera sample numbers available for study must be increased substantially and standardized antisera pools must be assembled and characterized.
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FOOTNOTES |
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2 Supported by Ross Products Division, Abbott Laboratories.
4 Abbreviations used: CMF, cow milk protein–based formula; DBPCFC, double-blinded, placebo-controlled, food challenge; FA, food allergy; RAST, radioallergosorbent test; SF, soy protein-based formula; SPT, skin prick test.
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TOPABSTRACTLITERATURE CITED |
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