Anaphylaxis syndromes related to a new mammalian cross-reactive carbohydrate determinant

Abstract

Anaphylaxis is a severe allergic reaction that can rapidly progress and occasionally be fatal. In instances in which the triggering allergen is not obvious, establishing the cause of anaphylaxis is pivotal to long-term management. Assigning cause is limited, however, by the number of known exposures associated with anaphylaxis. Therefore identification of novel causative agents can provide an important step forward in facilitating new, allergen-specific approaches to management. In contrast to the view that carbohydrate-directed IgE has minimal, if any, clinical significance, recent data suggest that IgE antibodies to carbohydrate epitopes can be an important factor in anaphylaxis that might otherwise appear to be idiopathic. Here we review the evidence relating to carbohydrates in food allergy and anaphylaxis and discuss the implications of a new mammalian cross-reactive carbohydrate determinant.

Fig. 1

Plant and mammalian glycans. A) Structure of MUXF (bromelain), which contains the structural features of xylose and core α1,3-fucose. Xylose and core α1,3-fucose are the main motifs for CCD-directed IgE and are the essential part of two independent epitopes. B) Structure of the galactose-α-1,3-galactose (alpha-gal) epitope found in lower mammals and depiction of the important α(1→3) linkage. C) Structure of N-glycol neuraminic acid that, like alpha-gal, is found in lower mammals but not humans.

Fig. 2

Comparison of representative glycans referenced in the text. The oligosaccharide structures are shown in the symbolic depiction suggested by the Consortium of Functional Glycomics. Note that the lack of a core fucose residue separates the structure of blood group B antigen from alpha-gal.

Fig. 3

Structure of IgG antibody molecule showing potential sites of glycosylation. The IgG-Fc region contains C_H2 domains that are glycosylated through covalent attachment of oligosaccharide at asparagine 297 (Asn 297, indicated by black asterisks). The oligosacharide at Asn 297 is integral to the IgG-Fc structure, forms multiple noncovalent interactions with the protein surface of the C_H2 domain and is important to the function of the molecule; therefore, the site cannot engineered out. In addition to the conserved glycosylation site at Asn 297, 15-20% of polyclonal human IgG molecules bear N-linked glycosylation within the IgG-Fab region. While there is no consensus sequence for N-linked oligosaccharide within the constant domain of the light chain or the C_H1 domain of the heavy chain, glycosylation can be present in the variable regions of the kappa and lambda (V_L, green asterisks) or heavy chains (V_H, blue asterisks), and sometimes both. For example, the amino acid sequence of cetuximab has potential glycosylation sites at Asn43 of the light chain and at Asn88 and Asn299 of the heavy chain but the glycosylation site at Asn43 is not glycosylated. The biopharmaceutical industry and others have shown that differences in glycosylation products and manipulation of oligosaccharide placement (or deletion) can have significant effects on therapeutic efficacy for recombinant monoclonal antibodies. S–S denotes a disulfide bond.