INTRODUCTION — Grain allergies are common food allergies that are typically, but not only, seen in individuals with other food allergies. The immunologic responses to grain proteins can be immunoglobulin E (IgE) mediated and/or non-IgE mediated. This topic highlights wheat and also covers other cereal grains including rye, barley, oat, rice, corn, millet, and sorghum, as well as non-cereal grains including quinoa, amaranth, and buckwheat.
An overview of grains, grain taxonomy, and grain allergens is presented in this topic review. The epidemiology, clinical manifestations, diagnosis, and management of grain allergies are discussed in detail separately. (See "Grain allergy: Clinical features, diagnosis, and management".)
General discussions of food allergy are presented separately in other topics.
Wheat allergy related to occupational exposure is presented separately, as is food-dependent (including wheat) exercise-induced anaphylaxis and celiac disease (gluten-sensitive enteropathy):
●(See "Occupational asthma: Definitions, epidemiology, causes, and risk factors" and "Occupational asthma: Pathogenesis" and "Occupational asthma: Clinical features, evaluation, and diagnosis" and "Occupational asthma: Management, prognosis, and prevention".)
●(See "Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, pathogenesis, and diagnosis" and "Exercise-induced anaphylaxis: Management and prognosis".)
●(See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults" and "Diagnosis of celiac disease in adults" and "Management of celiac disease in children".)
CLASSIFICATION — Cereal grains and various grasses are taxonomically classified in the Gramineae (Poaceae) family (figure 1).
The cereals form part of the Gramineae family and are divided into four subfamilies [1]:
●Pooideae, which are further divided into the tribes Triticeae/Hordeae (wheat, barley, and rye) and Aveneae (oats)
●Ehrhartoideae (rice)
●Chloridoideae (including ragi and teff)
●Panicoideae (most millets, corn/maize, and sorghum)
Non-cereal grains refer to grains from families other than that of the Gramineae family, including buckwheat from the Polygonaceae family, quinoa from the Chenopodiaceae family, and amaranth from the Amaranthaceae family (figure 1).
OVERVIEW OF GRAINS — Grains and many seeds are used in similar ways, but they technically are not identical parts of a plant. A single grain is comprised of an individual fruit containing a single seed. The fruit wall and seed coat are fused and cannot be separated. Seeds, on the other hand, can be separated from the fruit. Despite this distinction, many seeds are called grains because of how they are used. In this topic, the term "grain" is used for true grains and also for seeds that are used as grains. Wheat, rye, barley, oat, rice, and corn are grains, whereas millet, amaranth, quinoa, and buckwheat are seeds.
Grain use worldwide — Grains constitute a staple food for most of the world's population. Wheat, rice, and corn are the most commonly produced and consumed grains [1-3].
●Corn originated in the Americas. It is the most widely grown grain crop worldwide but is primarily grown for livestock and poultry consumption and industrial uses (eg, ethanol).
●Wheat originated in the Levant region of the Near East and Ethiopia and is now cultivated worldwide. It is the second most produced grain crop. Most of the world production is consumed by humans in the form of breads and other baked products, pasta, wheat noodles, bulgur, and couscous. Wheat starch and gluten proteins are also used in food processing.
●Rice originated in China from where it spread to the rest of Asia, Europe, and the Americas. It is the third most produced and second most consumed grain crop worldwide. Rice is primarily consumed as a cooked whole grain, although raw rice is also ground into flour that is used in various products (eg, noodles, rice milk).
●Millet ranks as the sixth most important "grain" in the world and is a major crop in Africa and the Indian subcontinent. In Western countries, it is mainly used as bird and cattle feed. However, it is starting to become a more popular product in Western populations because millet contains various high-quality proteins.
●Amaranth is another seed commonly consumed in India, where it is cooked as a cereal, ground into flour, popped like popcorn, sprouted, or toasted in confectionary.
●Common buckwheat is a non-cereal grain crop that is taxonomically unrelated to wheat, despite a name that suggests otherwise. The seed is used to make a dark flour that is the main ingredient of several Asian, Russian, and European dishes (eg, crepes, small pancakes, bagels, breads, breakfast cereals, and noodles).
●Quinoa is a plant that originated in the Andean region of Bolivia and Peru. Its seed is often eaten in the United States as a grain substitute.
GRAIN ALLERGENS — Acute allergic responses to grains are due to IgE directed against various allergens in grains. This section reviews the grain allergens. The pathogenesis of non-IgE-mediated grain allergy and grain allergy due to mixed IgE and non-IgE-mediated processes is less well understood. (See "Pathogenesis of food allergy" and "Grain allergy: Clinical features, diagnosis, and management", section on 'Clinical features'.)
Cereal grains — Cereal grains include wheat, barley, rye, oat, corn (maize), rice, millet, and sorghum. Crossreactivity is more common among certain grains, probably reflecting grain taxonomy (figure 1). (See 'Classification' above and 'Allergenic similarities between cereal grains' below.)
Wheat — Wheat (Triticum aestivum, Tri a) proteins are classified into different fractions [1]:
●The water-soluble albumins and saline-soluble globulins. These include beta-amylase; inhibitors of hydrolytic enzymes, such as alpha-amylase/trypsin inhibitors; lipid transfer proteins (LTPs); and puroindolines [1]. Many of these proteins are considered to have protective functions such as resistance to fungal infections.
●The water-insoluble fraction that contains the prolamins including gliadins, such as omega-5-gliadin (Tri a 19) and glutenins [4,5]. The term "gluten" refers to the water-insoluble fraction that is comprised of approximately equal amounts of gliadin and glutenin [1]. The gliadins are further divided into three groups: alpha/beta-gliadins, gamma-gliadins, and omega-gliadins [1]. The glutenins are polymers of individual proteins linked by disulphide bonds. They are divided into high-molecular-weight (HMW) and low-molecular-weight (LMW) proteins [1].
Food-allergic responses appear to be due to a range of different proteins in wheat (table 1) [1]. Alpha-amylase inhibitor is one of the most important wheat allergen in IgE-mediated food allergy in the albumin/globulin fractions [4-6]. This wheat protein is implicated in baker's asthma. Other important allergens include LTP (Tri A 14) [4,5,7], which is a dominant allergen associated with severe allergic reactions, especially in the Mediterranean area, and alpha-purothionin (Tri a 37), which is also associated with severe allergy [8].
Within the gliadin/glutenins fraction, omega-5-gliadin is a major allergen in wheat-dependent, exercise-induced anaphylaxis in adults and older children. (See "Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, pathogenesis, and diagnosis", section on 'Food-dependent forms'.)
Omega-5-gliadin is also a major allergen in children with immediate allergic reactions [9] and anaphylaxis to wheat unrelated to exercise [10].
Sensitization (a positive-specific IgE test) to omega-5-gliadin is associated with severe reactions to wheat in children [11,12]. Sensitization to Tri a 19 is associated with a higher probability of severe reactions. Tri a 14 has a higher crossreactivity with other foods. Patients sensitized to Tri A 14 are frequently asymptomatic [13] or need cofactors to present with severe reactions [14].
An LMW glutenin, Tri a 36, cross-reacts with oat and rice proteins and is associated with IgE-mediated reactivity to wheat in children [15,16]. HMW glutenins are only minor allergens [4].
Spelt — Spelt (Triticum spelta), also called dinkel wheat or hulled wheat, is a species of wheat that is closely related to common wheat (T. aestivum). It is sometimes considered a subspecies of common wheat. These two wheats are allergenically similar.
Barley and rye — Trypsin/alpha-amylase inhibitors are also known to be the major allergens in barley [17]. Barley and rye also contain prolamines (hordeins and secalins, respectively). The crossreactivity among wheat, barley, and rye is discussed below. (See 'Allergenic similarities between cereal grains' below.)
Oat — Oat allergens are not well characterized. In one study, intensive IgE staining to neutral/acidic soluble proteins was seen, with major IgE binding to 46 and 66 kDa proteins in oats, but no specific IgE-staining patterns correlating with clinical cereal sensitivity were found [18].
Corn (maize) — LTP was identified by IgE immunoblotting as the major corn allergen in Italian populations in two studies [19,20] but was not recognized by any of the Swiss patients in one of the studies [20]. Other allergens identified in patients with a history of corn-induced anaphylaxis or positive double-blind, placebo-controlled food challenge (DBPCFC) to corn are 14 kDa alpha-amylase inhibitor, 30 kDa endochitinases A and B, 19 kDa zein-beta precursor, and 26 kDa zein-alpha precursor [20]. Endochitinases are pathogenesis-related proteins, and zein is a storage protein.
Rice — Approximately 80 percent of the total protein content in rice grain corresponds to oryzenins, which are a type of glutelin (prolamin-like proteins). Of the remaining proteins, 15 percent represent salt-soluble globulins and albumins, and 5 percent include alcohol-soluble prolamins. The alpha-amylase/trypsin inhibitor in the albumin fraction is the major allergen in rice grain extracts and belongs to the same cereal alpha-amylase inhibitor family as the wheat allergen [17,21]. Other known rice allergens include a novel type of plant glyoxalase I and an alpha-globulin [21,22]. An LTP was identified as the major allergen in 10 patients with peach allergy and anaphylaxis to rice [23]. Several patients also reacted to other rice proteins, including an alpha-amylase/subtilisin inhibitor.
Millet — Millet allergy is rare [24,25], and its allergens are not well defined.
Sorghum — Allergy to sorghum has not been described in the literature, and, as such, no allergens have been identified.
Allergenic similarities between cereal grains — Significant sequence homology exists among corresponding prolamins of wheat (omega-5-gliadin), rye (secalins), and barley (hordeins) in the Hordeae/Triticeae tribe (figure 1) [26]. These prolamins are less closely related to prolamins of oats (Aveneae tribe). The prolamins of rice (Ehrhartoideae subfamily) are not closely related to the other cereals, whereas the prolamins of the subfamilies Chloridoideae and Panicoideae appear to be closely related to each other [1]. The wheat allergen Tri a 36 has IgE crossreactivity with related allergens in rye, barley, oat, spelt, and rice [15]. There is also some crossreactivity between rice and millet [27]. (See "Food allergens: Clinical aspects of cross-reactivity", section on 'Grains'.)
Allergenic similarities to grasses — Cereal grains share homologous proteins with grass pollen, which may account for a high rate of sensitization [28-32]. However, rates of clinical reactivity are much lower. As an example, sensitization to rice is often seen in asymptomatic subjects due to a high degree of crossreactivity among wheat, corn, and grasses, which may be due to cross-reactive thioredoxins or LTP [33].
Non-cereal grains — Non-cereal grains are traditionally uncommon triggers of food-allergic reactions. However, allergic reactions to these grains are seen with increasing frequency with expanded use of various types of non-cereal grains as alternatives for subjects with food allergies and celiac disease and growing interest in natural food diets.
Buckwheat — Buckwheat allergy is increasing in prevalence [34]. Several buckwheat proteins are able to bind IgE in allergic patients, and those proteins with molecular weights of 9, 16, 19, and 24 kDa are considered major allergens [35,36]. The 19 kDa protein is relatively specific for buckwheat-allergic patients. IgE binding to the 16 kDa band was seen in patients who primarily had gastrointestinal symptoms with buckwheat ingestion and had cosensitization to grass pollen and wheat [37]. In contrast, cosensitization was uncommon in patients who had IgE binding to 25 kDa and 40 kDa bands [38], which were associated with predominantly cutaneous and anaphylactic reactions to buckwheat, respectively.
Quinoa — Quinoa allergy is rare [39-41], and its allergens are not well defined.
Amaranth — Three IgE-binding protein fractions were detected in roasted amaranth seed flour extract [42]. These fractions may contain allergens that trigger anaphylaxis.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Food allergy".)
SUMMARY
●Grains are typically divided into cereal grains that include wheat, barley, rye, oat, rice, teff, corn (maize), millet, and sorghum and the non-cereal grains (seeds) that include buckwheat, quinoa, and amaranth (figure 1). (See 'Classification' above.)
●Grains constitute a staple food for most of the world's population. The most commonly consumed grain worldwide is wheat, followed by rice and then corn. (See 'Overview of grains' above.)
●Acute allergic responses to grains are due to immunoglobulin E (IgE) directed against various allergens in grains. The pathogenesis of non-IgE-mediated grain allergy and grain allergy due to mixed IgE and non-IgE-mediated processes is less well understood. Omega-5-gliadin, alpha-amylase/trypsin inhibitors, and lipid transfer proteins (LTPs) are common allergens in wheat. (See 'Grain allergens' above.)
●Crossreactivity is more common among certain grains, probably reflecting grain taxonomy. (See 'Allergenic similarities between cereal grains' above.)
●Cereal grains share homologous proteins with grass pollen, which may account for the high rate of sensitization to cereal grains but lower rate of clinical reactivity. (See 'Allergenic similarities to grasses' above.)
