Emergence and significance of carbohydrate-specific antibodies

Abstract

Carbohydrate-specific antibodies are widespread among all classes of immunoglobulins. Despite their broad occurrence, little is known about their formation and biological significance. Carbohydrate-specific antibodies are often classified as natural antibodies under the assumption that they arise without prior exposure to exogenous antigens. On the other hand, various carbohydrate-specific antibodies, including antibodies to ABO blood group antigens, emerge after the contact of immune cells with the intestinal microbiota, which expresses a vast diversity of carbohydrate antigens. Here we explore the development of carbohydrate-specific antibodies in humans, addressing the definition of natural antibodies and the production of carbohydrate-specific antibodies upon antigen stimulation. We focus on the significance of the intestinal microbiota in shaping carbohydrate-specific antibodies not just in the gut, but also in the blood circulation. The structural similarity between bacterial carbohydrate antigens and surface glycoconjugates of protists, fungi and animals leads to the production of carbohydrate-specific antibodies protective against a broad range of pathogens. Mimicry between bacterial and human glycoconjugates, however, can also lead to the generation of carbohydrate-specific antibodies that cross-react with human antigens, thereby contributing to the development of autoimmune disorders.

Fig. 1. Commonly recognized glycan epitopes by human antibodies.

a N-acetyl-neuraminic acid (NeuAc) and N-glycolyl-neuraminic acid (NeuGc) differ only by the occurrence of an additional hydroxyl group in NeuGc. b Schematic structure of Forssman and Galili antigen. Glycosidic linkages are marked using the minimal nomenclature; α3 for α1–3, β3 for β1–3 and β4 for β1–4. c Schematic structure of ABO blood group antigens. d Chemical composition of galactose (Gal) and N-acetylgalactosamine (GalNAc) with highlighted acetamido group at C2. e Schematic structure of Lewis antigens Lewis A, B, X, and Y. f Structure of the P blood group antigens Pk, P, and P1.

Fig. 2. Antigen processing and presentation for different types of carbohydrate structures.

Extracellular glycoproteins are engulfed in endocytic or phagocytic vesicles, broken down in phagolysosomes and fragments of the glycopeptide are loaded on major histocompatibility complex II (MHC-II) to be presented at the cell surface. A similar mechanism is applied for zwitterionic polysaccharides, however, with a different processing mechanism depending on nitric oxide (NO). Glycolipids are presented on CD1-type proteins that are similar to MHC-I after being captured by lipid transfer proteins, such as saposins. The mechanisms underlying the processing and presentation of soluble oligo- and polysaccharides are unknown but are likely to involve binding through C-type lectins expressed at the surface of antigen-presenting cells.

Fig. 3. T-cell-dependent and -independent activation of B-cells.

T cells activate B-cells and promote antibody class switching through multiple interactions involving antigen-bound MHC-II with the T-cell receptor (TCR), and activation though the co-receptor systems CD40-CD40L, ICOS-ICOSL, PD1/PD1L, and CD28-CD80/86. In the absence MHC-II presentation of antigens to T cells, B-cell activation and immunoglobulin class-switching can be mediated through binding to the activating proteins BAFF and APRIL secreted by myeloid cells, such as dendritic cells (Dc). APRIL binds to its receptor TAC1 on B cells after docking to heparan sulfate proteoglycans (HSPG).

Fig. 4. Molecular mimicry between animal glycan epitopes and bacterial glycans.

a Schematic structure of the Galili xenoantigen and Escherichia coli O86 O-antigen expressed on lipopolysaccharide (LPS). The conserved Gal(α1–3)Gal motif is highlighted in blue. b Structures of lipooligosaccharides (LOS) of Neisseria meningitidis and Haemophilus ducreyi including the lacto-N-neotetraose (LNnT) epitope found in human milk oligosaccharides and on glycosphingolipids. c Similarity between the Lewis Y epitope and the LPS of Helicobacter pylori M019. d Schematic structure of the ganglioside GM1 and the LOS epitope of Campylobacter jejuni.