The History of Carbohydrates in Type I Allergy

Abstract

Although first described decades ago, the relevance of carbohydrate specific antibodies as mediators of type I allergy had not been recognized until recently. Previously, allergen specific IgE antibodies binding to carbohydrate epitopes were considered to demonstrate a clinically irrelevant cross-reactivity. However, this changed following the discovery of type I allergies specifically mediated by oligosaccharide structures. Especially the emerging understanding of red meat allergy characterized by IgE directed to the oligosaccharide alpha-gal showed that carbohydrate-mediated reactions can result in life threatening systemic anaphylaxis which in contrast to former assumptions proves a high clinical relevance of some carbohydrate allergens. Within the scope of this review article, we illustrate the historical development of carbohydrate-allergen-research, reaching from only diagnostically relevant crossreactive-carbohydrate-determinants to clinically important antigens mediating type I allergy. Focusing on clinical and immunological features of the alpha-gal syndrome, we highlight the discovery of oligosaccharides as potentially highly immunogenic antigens and mediators of type I allergy, report what is known about the route of sensitization and the immunological mechanisms involved in sensitization and elicitation phase of allergic responses as well as currently available diagnostic and therapeutic tools. Finally, we briefly report on carbohydrates being involved in type I allergies different from alpha-gal.

Keywords: IgE; allergen; alpha-gal; carbohydrate; crossreactive carbohydrate determinants; glycolipid; glycoprotein; type I allergy.

Figure 1

Timeline showing relevant milestones in understanding the role of carbohydrates in allergology.

Figure 2

Structure of the most relevant carbohydrate allergenic structures. (A,B) Structure of the CCDs MMXF and MUXF. (C) Structure of the allergen alpha-gal and (D) shows in comparison the difference to the blood group B antigen.

Figure 3

The alpha-gal syndrome. All individuals initially develop tolerance to alpha-gal mediated by constant exposure through bacterial colonization of the intestine and potentially also to food, associated with alpha-gal specific IgG and IgM antibodies (1). However, in some individuals, repetitive tick bites can result in a break of tolerance by induction of alpha-gal specific IgE (2). Upon consumption of red meat and innards as well as administration of alpha-gal containing drugs such as the therapeutic monoclonal antibody cetuximab, these individuals experience symptoms up to fatal anaphylaxis. While symptoms in response to cetuximab occur immediately after administration, anaphylaxis in response to red meat or innards occurs in a delayed fashion 3–6 h after consumption (3).

Figure 4

Immune response to carbohydrate antigens. (A) Dendritic cells sense carbohydrate constituents on allergens via pathogen recognition receptors (PRR) such as C-type lectin receptors, leading to their activation. Allergens are taken up by receptor mediated endocytosis or phagocytosis, processed and presented on MHCII (glycoproteins, defined polysaccharides) or CD1 (glycolipids) to specifically activate CD4⁺ T cells or NKT cells, respectively. Activated dendritic cells additionally secrete different cytokines and chemokines and express co-stimulatory molecules which initiate and modulate the adaptive immune response. (B) Activated CD4⁺ T cells in turn activate naïve B cells recognizing and presenting the same allergen on MHCII via co-stimulatory signals and secretion of specific cytokines resulting in affinity maturation, class switch recombination, memory B cell and plasma cell differentiation and antibody secretion. (C) Specific B cell subsets, mainly B1 cells, can be activated in a T cell independent fashion via extensive cross-linking of the B cell receptors by repetitive epitopes, resulting in the secretion of so-called natural antibodies characterized by only low antigen affinity and mainly IgM isotype.