Gly m 5
Summary
Gly m 5 is one of the major allergens of soy (Glycine max), mainly associated with severe allergic reactions to soy. It is a vicilin-like protein (β-conglycinin) belonging to the 7S seed storage protein group. This β-conglycinin has three subunits, namely α, α’, and β, each of which are potential food allergens and can stimulate IgE antibodies in patients sensitive to soy. These subunits are classified as isoallergens for Gly m 5 viz., Gly m 5.0101, Gly m 5.0201 and Gly m 5.0301, respectively. Of note, Gly m 5 has been found to be more resistant to pepsin-digestion than other soy proteins. Soy-allergic patients sensitized to Gly m 5 may present mild oral allergy, skin and gastrointestinal reactions, to more severe forms such as severe cardiovascular or respiratory reactions and even anaphylaxis. Gly m 5 is cross-reactive with peanuts due to similarity with its allergens like Ara h 1 and Ara h 3. Further, Gly m 5-sIgE can better identify soy allergy compared to IgE towards soy extract. Importantly, Gly m 5 has been recognized as a diagnostic marker for severe allergies caused by soy, both, in children and adults.
Epidemiology
Worldwide distribution
Soybean is one of the “big eight” foods, considered to be accountable for 90% of all food allergies. It forms a major allergen in the United States (US) and Canada and is responsible for the most important food allergies in the US, Europe, and Japan. Soy allergy can trigger anaphylaxis in severe cases, which may be life-threatening.
Gly m 5 is a principal soya protein that acts as a primary sensitizer. The presence of this soy allergen possibly suggests severe allergic reactions and can accord for one of the major immediate-type soybean allergy in children.
In a study conducted on 91 Japanese children with soybean sensitization, Gly m 5 sensitization was found to be between 60-93% in the symptomatic patients (40 out of 91) depending on its different isoallergens while it was between 55-81% in the non-symptomatic patients (51 out of 91). The patients with a positive oral food challenge (OFC) were considered as symptomatic while those with negative OFC were considered non-symptomatic.
Usually, soybean allergy is observed in young children and by 10 years of age, they are most often tolerant, and thus, soybean allergy is rarely observed in adults. However, a study was conducted on 10 soy-allergic adults (4 from Switzerland and 6 from the US). IgE binding to Gly m 5 was observed in 6 out of the 10 samples. Further another study on 30 European subjects (25 adults and 5 children) found Gly m 5-sIgE in 43% (13 out of 30) of soybean-allergic patients.
Clinical Relevance
Disease Severity
Gly m 5, together with Gly m 6 is one of the major allergens of soybean leading to food allergy and is mainly responsible for severe systemic reactions in allergic individuals. The severe symptoms were manifested as a combination of skin, gastrointestinal, respiratory, or cardiovascular symptoms and sometimes even anaphylaxis.
A European study on 30 soybean-allergic participants (25 adults and 5 children) found 40% (12 out of 30) suffering from mild symptoms, 37% (11 out of 30) having moderate symptoms, and 23% (7 out of 30) having severe symptoms. Gly m 5 or Gly m 6 sensitization was found in 86% (6 out of 7) of patients with severe allergic reactions like anaphylaxis while the same was observed in only 33% (4 out of 12) of patients with mild symptoms. Furthermore, it was found all the 5 children demonstrated IgE-binding to Gly m 5. Thus, postulating them to be major allergens of soybean in children.
Some studies have shown that sIgE levels to Gly m 5 are found to be significantly higher in symptomatic soy allergic patients as compared to non-symptomatic individuals. This was reported in a study conducted on 74 soybean-sensitized Japanese individuals. Out of 74 individuals, 33 individuals were found symptomatic (severe symptoms in 14 and mild symptoms in 19) while 41 were non-symptomatic based on OFC. IgE reactivity to Gly m 5 was observed in 67% of symptomatic patients and 49% of non-symptomatic individuals. Gly m 5-sIgE levels were significantly higher (p<0.01) in symptomatic patients as compared to non-symptomatic soy-sensitized individuals. Similarly, in another study in Japan conducted on 55 soy-sensitized children, significantly high (p<0.05) levels of sIgE to Gly m 5 was observed in symptomatic (19 out of 55) as compared to non-symptomatic children (36 out of 55).
Interestingly, in contrast to the above studies, a study in Utrecht, The Netherlands found significantly high sIgE for Gly m 5 in the soy-allergic patients with mild symptoms as compared to patients with severe symptoms (p=0.02). The study was conducted on 35 soy-allergic adults with 15 patients presenting mild symptoms while 20 patients presenting severe symptoms to soy food challenge.
Furthermore, Gly m 5 is known to be involved in baker’s asthma. A study on 135 soy flake processing workers (SPWs) in the age range of 19–66 years in Tennessee, US, found that IgE binding for soybean was evident in all the SPWs, especially for Gly m 5 and Gly m 6. The study highlighted that exposure to Gly m 5 and Gly m 6 at the workplace, may result in respiratory morbidity in the soy-sensitized individuals by causing occupational sensitization.
Gly m 5, together with Gly m 6 has recently been reported to be the causative allergens for soybean related food-dependant exercise-induced anaphylaxis in 2 children (9–10-year-old boys). It was observed after the consumption of soy-containing food (tofu) which contains more storage proteins (Gly m 5 and Gly m 6) as compared to other soy products.
Cross-reactive molecules
Clinical cross-reactivity has been reported among patients allergic to peanuts, soybean, and other legumes. A study on 35 soy-allergic adults in the Netherlands found co-existing peanut allergy in 60% (21 out of 35) of the individuals. The sIgE to Gly m 5 was found to be significantly correlated (p<0.001) with Ara h 2-sIgE.
Further, a similar co-existing pattern of clinical peanut and soy allergy was observed in a study in Gothenburg, Sweden conducted on 47 severe peanut-allergic adults, 22 peanut-sensitized adults, and 22 healthy controls. Sensitization to soy-IgE was observed in 72.3% (34 out of 47) of severe peanut-allergic adults and 50% (11 out of 22) of peanut-sensitized adults. Further, it was observed that IgE reactivities to Gly m 5 or Gly m 6 were correlated with IgE, SPT, and BAT to soy, suggesting it to be a clinically relevant soy allergy in peanut-allergic patients. In a study on 10 soy and/or peanut-allergic patients, sIgE reactivity to Gly m 5 as well as corresponding 7S vicilin in peanut (Ara h 1) was observed in 9 patients.
This pattern of cross-reactivity was confirmed by a retrospective cohort study in 1057 food-allergic patients in Vienna. The study found that “peanut-soybean” is an important cluster, majorly due to cross-reactivity of peanut allergen Ara h 3 with soybean allergens, Gly m 5, and Gly m 6. Furthermore, peanut and soy allergy was found to be co-existing in 2 cases of FDEIA, which was attributed due to sensitivity to seed storage proteins of soy (Gly m 5 and Gly m 6).
Diagnostics
Disease Severity
Sensitization to Gly m 5-sIgE can serve as an indicator of developing severe allergic reactions to soy in children and can better identify soy allergy compared to IgE towards soy extract. Further, IgE reactivity to Gly m 5 and Gly m 6 could help to diagnose soy allergic patients who are at risk of developing severe reactions.
Exposure
The main route of exposure is through ingestion.
Cross-Reactivity
Nearly 50% amino acid sequence similarity has been observed between Gly m 5 and other legume proteins. Ara h 1 has been recognized as a homolog of Gly m 5. Immuno-cross-reactivity between peanut and soybean can be attributed to similarities between their allergens like Ara h 1 and Gly m 5 based on amino acid sequence, IgE epitope mapping, and molecular modeling.
Further, sequence homology has been shown in some in-vitro studies between common 7S vicilins of other allergenic foods. The sequence homology of soy 7S vicilin (Gly m 5) was found to be 40-49% with Peanut 7S (Ara h 1), 51-56% with Pea (Pis s 1), and 31-34% with Hazelnut 7S (Cor a 11).
Interestingly, cross-reactive IgE epitopes have been found between non-homologous allergens of soy and bovine casein. Such cross-reactive IgE epitopes were found between α-subunit of Gly m 5 (Gly m 5.0101), Bos d 8, and Bos d 9.0101 (bovine casein).
References
- Messina M, Venter C. Recent Surveys on Food Allergy Prevalence. Nutrition Today. 2020;55(1).
- Cabanillas B, Jappe U, Novak N. Allergy to Peanut, Soybean, and Other Legumes: Recent Advances in Allergen Characterization, Stability to Processing and IgE Cross-Reactivity. Mol Nutr Food Res. 2018;62(1):1700446.
- Ito K, Sjolander S, Sato S, Moverare R, Tanaka A, Soderstrom L, et al. IgE to Gly m 5 and Gly m 6 is associated with severe allergic reactions to soybean in Japanese children. J Allergy Clin Immunol. 2011;128(3):673-5.
- Ueberham E, Spiegel H, Havenith H, Rautenberger P, Lidzba N, Schillberg S, et al. Simplified Tracking of a Soy Allergen in Processed Food Using a Monoclonal Antibody-Based Sandwich ELISA Targeting the Soybean 2S Albumin Gly m 8. Journal of Agricultural and Food Chemistry. 2019;67(31):8660-7.
- Borres MP, Ebisawa M, Eigenmann PA. Use of allergen components begins a new era in pediatric allergology. Pediatr Allergy Immunol. 2011;22(5):454-61.
- Berneder M, Bublin M, Hoffmann-Sommergruber K, Hawranek T, Lang R. Allergen chip diagnosis for soy-allergic patients: Gly m 4 as a marker for severe food-allergic reactions to soy. Int Arch Allergy Immunol. 2013;161(3):229-33.
- Ito K. Grain and legume allergy. Chem Immunol Allergy. 2015;101:145-51.
- Maruyama N, Sato S, Cabanos C, Tanaka A, Ito K, Ebisawa M. Gly m 5/Gly m 8 fusion component as a potential novel candidate molecule for diagnosing soya bean allergy in Japanese children. Clin Exp Allergy. 2018;48(12):1726-34.
- Lu M, Jin Y, Cerny R, Ballmer-Weber B, Goodman RE. Combining 2-DE immunoblots and mass spectrometry to identify putative soybean (Glycine max) allergens. Food Chem Toxicol. 2018;116(Pt B):207-15.
- Holzhauser T, Wackermann O, Ballmer-Weber BK, Bindslev-Jensen C, Scibilia J, Perono-Garoffo L, et al. Soybean (Glycine max) allergy in Europe: Gly m 5 (beta-conglycinin) and Gly m 6 (glycinin) are potential diagnostic markers for severe allergic reactions to soy. J Allergy Clin Immunol. 2009;123(2):452-8.
- Matsuo A, Matsushita K, Fukuzumi A, Tokumasu N, Yano E, Zaima N, et al. Comparison of Various Soybean Allergen Levels in Genetically and Non-Genetically Modified Soybeans. Foods. 2020;9(4):522.
- Ramadan S, Marsh J, El-Sherbeny GA, El-Halawany EF, Luan F, Baumert JL, et al. Purification of soybean cupins and comparison of IgE binding with peanut allergens in a population of allergic subjects. Food Chem Toxicol. 2021;147:111866.
- Borres MP, Sato S, Ebisawa M. IgE-related examination in food allergy with focus on allergen components. Chem Immunol Allergy. 2015;101:68-78.
- Klemans RJ, Knol EF, Michelsen-Huisman A, Pasmans SG, de Kruijf-Broekman W, Bruijnzeel-Koomen CA, et al. Components in soy allergy diagnostics: Gly m 2S albumin has the best diagnostic value in adults. Allergy. 2013;68(11):1396-402.
- Hayashi M, Pawankar R, Yamanishi S, Itoh Y. Food-dependent exercise-induced anaphylaxis to soybean: Gly m 5 and Gly m 6 as causative allergen components. World Allergy Organ J. 2020;13(7):100439-.
- Ebisawa M, Brostedt P, Sjölander S, Sato S, Borres MP, Ito K. Gly m 2S albumin is a major allergen with a high diagnostic value in soybean-allergic children. J Allergy Clin Immunol. 2013;132(4):976-8.e1-5.
- Green BJ, Cummings KJ, Rittenour WR, Hettick JM, Bledsoe TA, Blachere FM, et al. Occupational sensitization to soy allergens in workers at a processing facility. Clin Exp Allergy. 2011;41(7):1022-30.
- Rentzos G, Lundberg V, Lundqvist C, Rodrigues R, van Odijk J, Lundell A-C, et al. Use of a basophil activation test as a complementary diagnostic tool in the diagnosis of severe peanut allergy in adults. Clin Transl Allergy. 2015;5:22-.
- Dezfouli SG, Mothes-Luksch N, Jensen AN, Untersmayr E, Kundi M, Jensen-Jarolim E. Linking cross-reactivity clusters of food and respiratory allergens in PAMD@ to asthma and duration of allergy. World Allergy Organization Journal. 2020;13(12):100483.
- Krishnan HB, Kim W-S, Jang S, Kerley MS. All Three Subunits of Soybean β-Conglycinin Are Potential Food Allergens. Journal of Agricultural and Food Chemistry. 2009;57(3):938-43.
- Zheng S, Qin G, Tian H, Zhang F. Three-dimensional structure of Gly m 5 (beta-conglycinin) plays an important role in its stability and overall allergenicity. Food Chem. 2017;234:381-8.
- WHO/IUIS. ALLERGEN NOMENCLATURE: WHO/IUIS Allergen Nomenclature Sub-Committee; 2019 [cited 2021 Jan 12]. Available from: http://www.allergen.org/viewallergen.php?aid=346.
- Kern K, Havenith H, Delaroque N, Rautenberger P, Lehmann J, Fischer M, et al. The immunome of soy bean allergy: Comprehensive identification and characterization of epitopes. Clin Exp Allergy. 2019;49(2):239-51.
- Kroghsbo S, Bogh KL, Rigby NM, Mills EN, Rogers A, Madsen CB. Sensitization with 7S globulins from peanut, hazelnut, soy or pea induces IgE with different biological activities which are modified by soy tolerance. Int Arch Allergy Immunol. 2011;155(3):212-24.
- Bublin M, Breiteneder H. Cross-reactivities of non-homologous allergens. Allergy. 2020;75(5):1019-22.
- Borres MP, Maruyama N, Sato S, Ebisawa M. Recent advances in component resolved diagnosis in food allergy. Allergology International. 2016;65(4):378-87.