Allergen

Summary

Many allergens are glycoproteins, i.e. they contain one or several oligosaccharide moieties linked to the peptide backbone of the protein. These may be complex, branched structures linked to asparagine residues (N-linked) or smaller and less complex, linked to serine or threonin residues (O-linked). While also many human proteins are glycoproteins, their carbohydrate structures lack some specific parts that are present in plants and insects which are therefore recognized as non-self and are immunogenic. Each of these particular glyco-epitopes, α1,3-fucose and β1,2-xylose, may be displayed identically on glycoproteins from any plant species and beyond the limits of protein families, making them highly cross-reactive for human IgE antibodies. Glycans of insect glycoproteins contain the α1,3-fucose but not the β1,2-xylose moiety. Glycan structures comprising one or both of these determinants are commonly referred to as Cross-reactive Carbohydrate Determinants or CCDs. The clinical relevance of CCD is considered negligible as no significant allergic responses associated with IgE to this epitope have been observed.

MUXF3 is a CCD structure present in the single glycan moiety of bromelain, a glycoprotein from pineapple. The glycan structure includes α1,3-fucose, β1,2-xylose and mannose. As a suitable reagent for detection of CCD-reactive IgE, a short glycopeptide carrying the glycan structure can be isolated from a proteolytic digest of bromelain.

Epidemiology

Worldwide distribution

MUXF3 is a carbohydrate structure comprising a cross-reacting carbohydrate determinant (CCD) found in a glycoprotein from pineapple, known as bromelain. MUXF3 contains α1,3-fucose and β1,2-xylose along with mannose. Primary bromelain sensitization is an uncommon occurrence, and hence, bromelain-specific IgE levels are suggestive of a CCD-sensitization.

Route Of Exposure

Exposure and sensitization to CCDs may take place via the airways (inhalation of pollen), the gastrointestinal tract (ingestion of food) or percutaneously (insect stings).

Clinical Relevance

Disease severity

Evidence suggests that MUXF3 is of negligible clinical significance, with no observed allergic reactions associated with IgE responses to this epitope alone.

Cross-reactive molecules

Allergen glyco-proteins with cross-reacting carbohydrate moieties represented by MUXF3 are present in pollens, insect venoms, latex and foods of plant origin, mainly vegetables and fruits, but also seeds such as peanuts and tree nuts.

Diagnostics

A CCD test comprising the defined MUXF3 carbohydrate epitope can be helpful when in vitro IgE results do not match the clinical picture (symptoms, skin tests), especially in cases of polysensitization in the absence of obvious clinical symptoms to some or many of the allergens tested, or in cases of IgE positivity to multiple insect venoms.

Cross-reactivity

IgE to CCDs can cross-react with CCD-type carbohydrates from a wide variety of plant-derived aeroallergens, food allergens and latex, as well insect venom allergens.

Explained Results

Allergen Information

MUXF3 is a cross-reactive carbohydrate structure present in a glycopeptide isolated from the glycoprotein bromelain from pineapple stem. It represents CCDs found across the plant kingdom and in insect venoms.

Clinical relevance

The clinical relevance of MUXF3 is considered negligible as no significant allergic responses associated with IgE to this epitope alone have been observed.

Cross-reactivity

MUXF3 IgE has been shown to exhibit cross-reactivity with several plant-derived aeroallergens, food allergens, and allergens from venom and latex.

Author: Turacoz

Reviewer: Dr. Jonas Lidholm

Aalberse RC, Koshte V, Clemens JG. (1981) “Immunoglobulin E antibodies that crossreact with vegetable foods, pollen, and Hymenoptera venom”. J Allergy Clin Immunol. 68:356-64.

Altmann F. (1992) "Determination of amino sugars and amino acids in glycoconjugates using precolumn derivatization with o-phthalaldehyde". Anal Biochem. 204:215-9

Altmann F. The role of protein glycosylation in allergy. Int Arch Allergy Immunol. 2007;142:99-115.

Alvela-Suarez, L., Campos, J., Carballo, I., Gomez-Rial, J., Vidal, C., Lombardero, M., Linneberg, A. and Gonzalez-Quintela, A. (2019). "False-Positive Results of Serological Tests for Allergy in Alcoholic Patients." J Investig Allergol Clin Immunol 29: 213-221.

Amoah AS, Obeng BB, Larbi IA, Versteeg SA, Aryeetey Y, Akkerdaas JH, Zuidmeer L, Lidholm J, Fernández-Rivas M, Hartgers FC, Boakye DA, van Ree R, Yazdanbakhsh M. Peanut-specific IgE antibodies in asymptomatic Ghanaian children possibly caused by carbohydrate determinant cross-reactivity. J Allergy Clin Immunol. 2013 Sep;132:639-647.

Beitia, J. M., Lopez-Matas, M. A., Alonso, A., Vega, A., Mateo, B., Cardenas, R. and Carnes, J. (2014). "Allergenic profile to Phleum pratense and immunological changes induced after grass allergen-specific immunotherapy." Int Arch Allergy Immunol 165: 9-17.

Chen, J. K., Shen, C. R. and Liu, C. L. (2010). "N-acetylglucosamine: production and applications." Mar Drugs 8: 2493-2516.

Falak, R., Sankian, M., Ketabdar, H., Moghadam, M. and Varasteh, A. R. (2013). "The role of anti-CCD antibodies in grape allergy diagnosis." Rep Biochem Mol Biol 1: 74-82.

Ferrari, E., Breda, D., Spisni, A. and Burastero, S. E. (2023). "Component-Resolved Diagnosis Based on a Recombinant Variant of Mus m 1 Lipocalin Allergen." Int J Mol Sci 24.

Ishihara H, Takahashi N, Oguri S, Tejima S. (1979) "Complete structure of the carbohydrate moiety of stem bromelain. An application of the almond glycopeptidase for structural studies of glycopeptides". J Biol Chem. 254:10715-10719.

Kamath, S. D., Bublin, M., Kitamura, K., Matsui, T., Ito, K. and Lopata, A. L. (2023). "Cross-reactive epitopes and their role in food allergy." J Allergy Clin Immunol 151: 1178-1190

Mari A, Ooievaar-de Heer P, Scala E, Giani M, Pirrotta L, Zuidmeer L, Bethell D, van Ree R. (2008) "Evaluation by double-blind placebo-controlled oral challenge of the clinical relevance of IgE antibodies against plant glycans". Allergy. 63:891-6.

Platts-Mills, T. A., Hilger, C., Jappe, U., van Hage, M., Gadermaier, G., Spillner, E., Lidholm, J., Keshavarz, B., Aalberse, R. C., van Ree, R., Goodman, R. E. and Pomes, A. (2021). "Carbohydrate epitopes currently recognized as targets for IgE antibodies." Allergy 76: 2383-2394.

Roman-Carrasco, P., Hemmer, W., Klug, C., Friedrich, A., Stoll, P., Focke-Tejkl, M., Altmann, F., Quirce, S. and Swoboda, I. (2020). "Individuals with IgE antibodies to alpha-Gal and CCD show specific IgG subclass responses different from subjects non-sensitized to oligosaccharides." Clin Exp Allergy 50:1107-1110.

Takahashi N, Yasuda Y, Kuzuya M, Murachi T. (1969) “The amino acid sequence of glycopeptides isolated from stem bromelain”. J Biochem. 66:659-67.