Carbohydrate epitopes currently recognized as targets for IgE antibodies

Abstract

Until recently, glycan epitopes have not been documented by the WHO/IUIS Allergen Nomenclature Sub-Committee. This was in part due to scarce or incomplete information on these oligosaccharides, but also due to the widely held opinion that IgE to these epitopes had little or no relevance to allergic symptoms. Most IgE-binding glycans recognized up to 2008 were considered to be "classical" cross-reactive carbohydrate determinants (CCD) that occur in insects, some helminths and throughout the plant kingdom. Since 2008, the prevailing opinion on lack of clinical relevance of IgE-binding glycans has been subject to a reevaluation. This was because IgE specific for the mammalian disaccharide galactose-alpha-1,3-galactose (alpha-gal) was identified as a cause of delayed anaphylaxis to mammalian meat in the United States, an observation that has been confirmed by allergists in many parts of the world. Several experimental studies have shown that oligosaccharides with one or more terminal alpha-gal epitopes can be attached as a hapten to many different mammalian proteins or lipids. The classical CCDs also behave like haptens since they can be expressed on proteins from multiple species. This is the explanation for extensive in vitro cross-reactivity related to CCDs. Because of these developments, the Allergen Nomenclature Sub-Committee recently decided to include glycans as potentially allergenic epitopes in an adjunct section of its website (www.allergen.org). In this article, the features of the main glycan groups known to be involved in IgE recognition are revisited, and their characteristic structural, functional, and clinical features are discussed.

Keywords: MMXF; MUXF3; O-glycans; alpha-gal; clinical relevance; cross-reactive carbohydrate determinants; hapten.

FIGURE 1

Each monosaccharide is indicated with the standard abbreviation first and the letter codes in parenthesis after the names are those used in Proglycan nomenclature (www.proglycan.com). The letter code MM indicates the primary core with two terminal mannose sugars. X indicates xylose which is only ever linked to the core as a beta 1–2 linkage on the proximal mannose. The letter F indicates a fucose and that is only linked to the proximal GlcNAc but should be labeled F3 to indicate the 1–3 linkage

FIGURE 2

(A) Formal depiction of N-linkage to asparagine and O-linkage to serine or threonine. The proximal monosaccharides are GlcNAc and GalNAc, respectively. (B) Common forms of O-linked oligosaccharides linked through mannose to GlcNAc and through GalNAc to GlcNAc. (C) The arabinose saccharides are linked to hydroxyproline and known to be a significant target of IgE antibodies on Art v 1 from Mugwort

FIGURE 3

The term MU in MUXF3 indicates that the terminal mannose deletion is of the 1–3 linkage; the X indicates a xylose linked beta 1–2 to the proximal mannose, and F3 indicates a fucose linked alpha 1–3 on the proximal GlcNAc. In each case, these changes are of a unique form not seen at other sites in the core

FIGURE 4

(A) The alpha 1–3 galactosyltransferase that establishes the alpha-gal linkage is different from the alpha 1–3 galactosyltransferase that can make a very similar linkage to a substituted galactose on blood group B. The alpha-gal hapten as well as the A and B blood group oligosaccharides can be linked either to asparagine or O-linked to the sphingolipid ceramide. (B) Despite abundant evidence that oligosaccharides with terminal Neu5Gc can be antigenic there is little evidence that they are target of human IgE. (C) GOS are galacto-oligosaccharides of various lengths produced as prebiotics from cow’s milk (see group E)

FIGURE 5

Many different oligosaccharides are expressed on helminth proteins and can be the target of IgE antibodies. The oligosaccharides shown for schistosomes are very similar to classical CCD. By contrast, the oligosaccharide shown for Echinococcus is O-linked and has a very different structure. *An is the Proglycan form for N-acetyl galactosamine and the X is for xylose which is only found attached 1 → 2 to the proximal mannose of the core