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 (Platts-Mills 2021). Glycan structures comprising one or both of these determinants are commonly referred to as Cross-reactive Carbohydrate Determinants or CCDs (Aalberse 1981). The clinical relevance of CCD is considered negligible as no significant allergic responses associated with IgE to this epitope have been observed (Altmann 2007, Mari 2008, Amoah 2013).

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 (Takahashi 1969, Ishihara 1979, Altmann 1992).

Epidemiology

Worldwide distribution

MUXF3 is a carbohydrate structure comprising a cross-reacting carbohydrate determinant (CCD) found in a glycoprotein from pineapple, known as bromelain (Beitia 2014). MUXF3 contains α1,3-fucose and β1,2-xylose along with mannose (Alvela-Suarez 2019). Primary bromelain sensitization is an uncommon occurrence, and hence, bromelain-specific IgE levels are suggestive of a CCD-sensitization (Alvela-Suarez 2019, Kamath 2023).

Environmental characteristics

Source and tissue

MUXF3 is part of a glycan carried by a glycopeptide purified from bromelain, a glycoprotein of pineapple (Ananas comosus) stem (Takahashi 1969, Ishihara 1979).

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 (Altmann 2007, Mari 2008, Amoah 2013).

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.

Molecular aspects    

Biochemistry

Glycan moieties of glycoproteins may impact protein function, stability, solubility, and transport. Since α1,3-fucose and β1,2-xylose residues of many plant- and/or insect-derived glycans are absent in humans, these structures are  immunogenic and can trigger immune responses in humans (Kamath 2023). The α1–3-linked fucose is considered the most common target for anti-CCD antibodies (Wilson 1998, Platts-Mills 2021).

The MU from MUXF3 denotes the 1–3 linkage of the terminal mannose deletion, X represents a β1-2-linked xylose to the proximal mannose, and F3 signifies an α1–3-linked fucose on the proximal N-Acetylglucosamine or GlcNAc (an amide derivative of monosaccharide glucose) (Chen 2010, Platts-Mills 2021).

The monovalent structure of CCD is thought incapable of cross-linking with IgE antibodies bound to mast cells, thereby being unable of inducing mast cell degranulation and the release of inflammatory mediators.

Isoforms, epitopes, antibodies

Many plant- and insect-derived proteins are glycoproteins, i.e. they contain one or several complex oligosaccharide chains linked to the peptide structure of the protein which may be immunogenic (glyco-epitopes).

Cross-reactivity due to structural similarity

Allergen oligosaccharide glyco-epitopes can share significant structural similarity, beyond the limits of taxonomic relationships and protein families, making them prone to extensive IgE cross-reactivity.

Diagnostic relevance

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.

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) (Platts-Mills 2021).

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 (Kamath 2023).

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 (Altmann 2007, Mari 2008, Amoah 2013).

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