Mal d 1
Summary
Mal d 1 is a 17.5 kDa, pathogenesis-related 10 protein (Bet v 1-like) recognized as one of the major allergens of apple. The prevalence of apple allergy is reported commonly in European countries, and Mal d 1 sensitization is observed majorly in the middle and northern parts of Europe and some parts of North America. Patients sensitized to Mal d 1 most commonly develop oral allergy syndrome and sometimes even systemic symptoms including urticaria and anaphylaxis. Mal d 1 is found in pulp as well as peel of the apple (majorly in peel) and is a heat-and proteolyze-sensitive protein. Thus, apple peeling, or consuming cooked form rather than raw form could be effective methods to reduce the exposure to Mal d 1. It is classified into four clusters of isoallergens namely, Mal d 1.01, Mal d 1.02, Mal d 1.03, and Mal d 1.04 which differ in their ability to elicit an allergenic reaction. A strong clinical and structural cross-reactivity has been observed between Mal d 1 and Bet v 1 (birch pollen allergen). However, Mal d 1-sensitization could not differentiate between patients with true apple allergy and patients with cross-reactivity with birch pollens.
Epidemiology
Worldwide distribution
Allergy to various fruits of the Rosaceae family is commonly seen. The European Community Respiratory Health Survey involving sera of 4522 individuals from 13 countries stated the overall prevalence of sensitization to apple was more common in European countries (Germany, Belgium, Italy, Norway, Sweden, France, and Spain) as compared to the United Kingdom, the United States and Australia. Presently, apple allergy due to Mal d 1 sensitization is mostly seen in the middle and northern parts of Europe and in some parts of North America.
Malus domestica 1 (Mal d 1) is a prominent allergen in apple belonging to pathogenesis-related (PR)-10 protein groups and a Bet v 1 (birch pollen allergen) homolog.
In a prospective cross-sectional study conducted in 389 apple-allergic patients from the Netherlands, Austria, Italy, and Spain, >90% of patients (except Spain) presented with oral symptoms due to sensitization to Mal d 1 and correlated with birch pollen allergy. Further, sensitization to Mal d 1 was found higher in the Netherlands, Austria, and Italy as compared to Spain. Interestingly, another study conducted among 81 apple-hypersensitive patients in Spain (birch-free region) demonstrated Mal d 1 sensitization in 27% of these patients.
Furthermore, in a retrospective explorative study conducted among 305 food-allergic Dutch patients, 74% (226 out of 305) of patients were found to possess one or more PR-10 protein sensitization. Among the PR-10 family, Mal d 1 sensitization was found in 67.9% of 305 subjects. Also, another study on 20 food-allergic children in Portugal found Mal d 1 sensitivity in 35% (7 out of 20) patients based on skin prick tests (SPT).
Clinical Relevance
Disease severity
Oral allergy syndrome
Mal d 1 sensitization in apple-allergic patients leads to majorly oral allergy syndrome (OAS), and a significant association was found between the history of OAS and Mal d 1 (p<0.03). The oral allergic symptoms like itching and swelling of the lips, throat, tongue occur within minutes of consuming apples. Also, significant variability between the patients has been observed for the allergic responses to Mal d 1.
In a study conducted among 37 birch-pollen allergic patients in Belgium, 20 patients reported OAS to apple, 17 reported birch-pollen allergy without apple-mediated OAS and 8 were healthy controls. The specific immunoglobulin (sIgE) to Mal d 1 was found in 19 of 20 patients with OAS to apple and 15 of 17 patients without OAS. In another study conducted on 30 birch pollen IgE-sensitized patients, 26 patients showed OAS to apple. Of these patients, 65.4% (17 out of 26) and 92.3% (24 out of 26) patients demonstrated specific IgE to apple and Mal d 1, respectively. Significantly higher Mal d 1-sIgE levels were observed as compared with apple extract IgE levels (p = 0.0016).
A prospective, cross-sectional study on 389 apple-allergic patients from the Netherlands, Austria, Italy, and Spain found Mal d 1 sensitization to be significantly associated with local symptoms (OAS) and protective against systemic symptoms (urticaria or anaphylaxis) (p<0.0001). Further, in a study among 81 apple-hypersensitive patients, OAS was observed in 43.2% (35/81) patients and generalized symptoms were observed in 46 patients. Specific IgE to Mal d 1 was found in 31% of 35 patients with OAS and 23% of 46 patients with generalized symptoms.
Furthermore, according to a questionnaire survey on 6824 people, 734 reported OAS symptoms due to allergies to different foods. Specific IgE was measured in 249 of 734 patients with OAS and found Mal d 1-sIgE in 69 individuals. However, clinical allergic symptoms after apple consumption were reported to be developed in 40% (28 of 69) of Mal d 1-sIgE positive individuals.
Anaphylaxis
Sensitization to Mal d 1 was considered as protective against severe systemic symptoms to apple. However, a case of anaphylaxis has been reported in a patient consuming an apple drink containing 60% fruit concentration due to Bet v 1 homolog (a PR-10 protein).
Cross-reactive molecules
Patients allergic to birch-pollen are found to exhibit an allergy to various birch pollen-related foods, including apples, because of high-level cross-reactivity between major birch pollen allergen, Bet v 1 and Mal d 1 in apples. Birch pollen sensitized individuals frequently develop apple allergy which may be attributed to cross-reaction between Mal d 1 and Bet v 1. This apple allergy in birch pollen allergic patients is termed birch-apple syndrome.
A similar pattern of birch pollen correlation was observed in a retrospective study in China conducted on 203 allergic subjects. Bet v 1 sensitization was found in 28 subjects, of which 27 subjects showed co-sensitization to Mal d 1 while none of the Bet v 1 negative patient showed Mal d 1 sensitivity.
A study conducted in Spain postulated that sensitivity to Bet v 1 in the study area, among apple-hypersensitive patients, may be due to cross-reactivity with Mal d 1, making Mal d 1 a primary sensitizer in non-birch areas.
Diagnostics
Disease Severity
Mal d 1 is heat-labile and thus patients show better tolerability to cooked than raw forms of apples.
Mal d 1 can be a dependable diagnostic tool in evaluating birch pollen-related apple allergy. A study among 21 patients with birch pollen allergy and apple-mediated OAS in Austria found significantly higher Mal d 1-sIgE levels (p<0.001) than commercial apple extract-sIgE levels. Thus, the use of Mal d 1-sIgE can increase the sensitivity of the serologic analysis. Further, the authors suggested that the use of Mal d 1 could help to standardize the double-blind placebo-controlled food challenges also.
In a study conducted on 37 birch-pollen allergic patients in Belgium, 20 showed apple allergy with OAS, 17 without apple-mediated OAS and 8 were healthy controls. The study demonstrated that the use of Mal d 1-sIgE levels could discriminate between birch-pollen related apple allergic patients with OAS and healthy controls. However, it does not have the differentiating ability between patients with true apple allergy and patients with cross-reactivity with birch pollens.
Cross-Reactivity
Different clinical studies have reported that the occurrence of apple allergy usually follows the onset of birch pollinosis. This may be due to cross-reactivity between Bet v 1-specific IgE antibodies and Mal d 1.
Exposure
The main exposure route for this allergen is through ingestion.
Prevention And Therapy
Experimental trails
Mal d 1 is majorly found in the peel, thus, apple peeling might be an effective strategy to remove most of the allergen.
Cross-Reactivity
A high structural similarity exists between Mal d 1 and the major birch pollen allergen, Bet v 1 which may be responsible for the immunologic cross-reactivity observed. It is reported that the difference in length between Mal d 1 and Bet v 1 is of single amino acid. The isoform Mal d 1.0101 shows 61% sequence identity with the corresponding Bet v 1.0101 isoform. Further, similar IgE epitope sharing have been observed between Mal d 1 and Bet v 1.
In a study conducted on 526 Italian PR-10 positive patients, cross-reactivity among various PR-10 proteins was assessed. The findings reported a significant Spearman correlation coefficient for Mal d 1 with Bet v 1 (birch), Aln g 1 (alder), Cor a 1.0101 and Cor a 1.0401 (hazel) and Pru p 1 (peach). Furthermore, the study also identified amino acid sequence homology between Mal 1 and other PR-10 proteins. It was found to be 38.1% for Api g 1 (celery), 49.3% for Ara h 8 (peanut), 50% for Act d 8 (kiwi), 50.6% for Gly m 4 (soybean), 55.6% for Aln g 1, 56.2% for Cor a 1.0101, 56.8% for Bet v 1, 62.1% for Cor a 1.0401 and 86.8% for Pru p 1
In a study including 9 patients with birch pollen and apple allergy, Mal d 1 showed 64.5% amino acid sequence identity and 55.6% nucleic acid sequence identity to Bet v 1.
Furthermore, another study demonstrated a 77% sequence similarity between Fra a 1 (strawberry) and Mal d 1. A sequence resemblance has also been observed between Rub i 1 (from raspberry) and Mal d 1.
References
- Fernandez-Rivas M, Bolhaar S, Gonzalez-Mancebo E, Asero R, van Leeuwen A, Bohle B, et al. Apple allergy across Europe: how allergen sensitization profiles determine the clinical expression of allergies to plant foods. J Allergy Clin Immunol. 2006;118(2):481-8.
- Burney P, Summers C, Chinn S, Hooper R, Van Ree R, Lidholm J. Prevalence and distribution of sensitization to foods in the European Community Respiratory Health Survey: a EuroPrevall analysis. Allergy. 2010;65(9):1182-8.
- Romer E, Chebib S, Bergmann KC, Plate K, Becker S, Ludwig C, et al. Tiered approach for the identification of Mal d 1 reduced, well tolerated apple genotypes. Sci Rep. 2020;10(1):9144.
- Ahammer L, Grutsch S, Kamenik AS, Liedl KR, Tollinger M. Structure of the Major Apple Allergen Mal d 1. J Agric Food Chem. 2017;65(8):1606-12.
- Gomez F, Aranda A, Campo P, Diaz-Perales A, Blanca-Lopez N, Perkins J, et al. High prevalence of lipid transfer protein sensitization in apple allergic patients with systemic symptoms. PLoS One. 2014;9(9):e107304.
- Blankestijn MA, Knulst AC, Knol EF, Le TM, Rockmann H, Otten HG, et al. Sensitization to PR-10 proteins is indicative of distinctive sensitization patterns in adults with a suspected food allergy. Clin Transl Allergy. 2017;7:42.
- Vieira T, Cunha L, Neves E, Falcao H. Diagnostic usefulness of component-resolved diagnosis by skin prick tests and specific IgE to single allergen components in children with allergy to fruits and vegetables. Allergol Immunopathol (Madr). 2014;42(2):127-35.
- Jun-Jun Liu AKME. The family 10 of plant pathogenesis-related proteins: Their structure, regulation, and function in response to biotic and abiotic stresses,. Physiological and Molecular Plant Pathology. 2006;68(1-3):3-13.
- Kaeswurm JAH, Nestl B, Richter SM, Emperle M, Buchweitz M. Purification and Characterization of Recombinant Expressed Apple Allergen Mal d 1. Methods Protoc. 2020;4(1).
- Gao Z, van de Weg EW, Matos CI, Arens P, Bolhaar ST, Knulst AC, et al. Assessment of allelic diversity in intron-containing Mal d 1 genes and their association to apple allergenicity. BMC Plant Biol. 2008;8:116.
- Scala E, Abeni D, Cecchi L, Guerra EC, Locanto M, Pirrotta L, et al. Molecular Recognition Profiles and Clinical Patterns of PR-10 Sensitization in a Birch-Free Mediterranean Area. Int Arch Allergy Immunol. 2017;173(3):138-46.
- Ebo DG, Bridts CH, Verweij MM, De Knop KJ, Hagendorens MM, De Clerck LS, et al. Sensitization profiles in birch pollen-allergic patients with and without oral allergy syndrome to apple: lessons from multiplexed component-resolved allergy diagnosis. Clin Exp Allergy. 2010;40(2):339-47.
- Shirasaki H, Yamamoto T, Abe S, Kanaizumi E, Kikuchi M, Himi T. Clinical benefit of component-resolved diagnosis in Japanese birch-allergic patients with a convincing history of apple or peach allergy. Auris Nasus Larynx. 2017;44(4):442-6.
- Osawa Y, Ito Y, Takahashi N, Sugimoto C, Kohno Y, Mori S, et al. Epidemiological study of oral allergy syndrome in birch pollen dispersal-free regions. Allergol Int. 2020;69(2):246-52.
- Roseler S, Balakirski G, Plange J, Wurpts G, Baron JM, Megahed M, et al. [Anaphylaxis to PR-10 proteins (Bet v1 homologues)]. Hautarzt. 2013;64(12):890-2.
- Schimek. Gastrointestinal digestion of Bet v 1- homologous food allergens destroy their mediator-releasing, but not T cell-activating, capacity. Journal of Investigational Allergology and Clinical Immunology. 2005;116(6):1327-33.
- Incorvaia C, Ridolo E, Mauro M, Russello M, Pastorello E. Allergen immunotherapy for birch-apple syndrome: what do we know? Immunotherapy. 2017;9(15):1271-8.
- Hao GD, Zheng YW, Wang ZX, Kong XA, Song ZJ, Lai XX, et al. High correlation of specific IgE sensitization between birch pollen, soy and apple allergens indicates pollen-food allergy syndrome among birch pollen allergic patients in northern China. J Zhejiang Univ Sci B. 2016;17(5):399-404.
- Pagliarani G, Paris R, Arens P, Tartarini S, Ricci G, Smulders MM, et al. A qRT-PCR assay for the expression of all Mal d 1 isoallergen genes. BMC Plant Biol. 2013;13:51.
- Aglas L, Soh WT, Kraiem A, Wenger M, Brandstetter H, Ferreira F. Ligand Binding of PR-10 Proteins with a Particular Focus on the Bet v 1 Allergen Family. Curr Allergy Asthma Rep. 2020;20(7):25.
- Gao ZS, Weg WE, Schaart JG, Arkel G, Breiteneder H, Hoffmann-Sommergruber K, et al. Genomic characterization and linkage mapping of the apple allergen genes Mal d 2 (thaumatin-like protein) and Mal d 4 (profilin). Theor Appl Genet. 2005;111(6):1087-97.
- WHO/IUIS. 2019 [20.01.21]. Available from: http://www.allergen.org/viewallergen.php?aid=425.
- Vanek-Krebitz M, Hoffmann-Sommergruber K, Laimer da Camara Machado M, Susani M, Ebner C, Kraft D, et al. Cloning and sequencing of Mal d 1, the major allergen from apple (Malus domestica), and its immunological relationship to Bet v 1, the major birch pollen allergen. Biochem Biophys Res Commun. 1995;214(2):538-51.
- Musidlowska-Persson A, Alm R, Emanuelsson C. Cloning and sequencing of the Bet v 1-homologous allergen Fra a 1 in strawberry (Fragaria ananassa) shows the presence of an intron and little variability in amino acid sequence. Mol Immunol. 2007;44(6):1245-52.
- Marzban G, Herndl A, Kolarich D, Maghuly F, Mansfeld A, Hemmer W, et al. Identification of four IgE-reactive proteins in raspberry (Rubus ideaeus L.). Mol Nutr Food Res. 2008;52(12):1497-506.
- Abrams EM, Sicherer SH. Diagnosis and management of food allergy. CMAJ. 2016;188(15):1087-93.
- Kollmann D, Geroldinger-Simic M, Kinaciyan T, Huber H, Ebner C, Lidholm J, et al. Recombinant Mal d 1 is a reliable diagnostic tool for birch pollen allergen-associated apple allergy. J Allergy Clin Immunol. 2013;132(4):1008-10.
- Asero R, Piantanida M, Pravettoni V. Allergy to LTP: to eat or not to eat sensitizing foods? A follow-up study. Eur Ann Allergy Clin Immunol. 2018;50(4):156-62.