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Glycans – the third revolution in evolution

Autoimmunity: Altered self-N-glycans trigger innate-mediated autoimmunity

Steven J Van Dyken and Richard M Locksley

According to the one origin of life theory, called glyco-world, carbohydrates are thought to be the original molecules of life, which provided molecular basis for the evolution of all living things.

The most abundant monosaccharides that can be found in animal glycan are: fucose (Fuc), galactose (Gal), glucose (Glu), mannose (Man),-acetylgalactosamine (GalNAc),=-acetylglucosamine (GlcNAc), sialic acid (Sia) and xylose (Xyl).

Glycans enable adaptive response to environmental changes and, unlike other epiproteomic modifications, which act as off/on switches, glycosylation significantly contributes to protein structure and enables novel functions. The importance of glycosylation is evident from the fact that nearly all proteins invented after the appearance of multicellular life are composed of both polypeptide and glycan parts.

A new theory to explain autoimmunity: The Altered Glycan Theory of Autoimmunity

The biggest evolutionary advantage that glycans confer to higher eukaryotes is the ability to create new structures without introducing changes into the precious genetic heritage

All cells of the body are made of four classes of molecules: nucleic acids, proteins, lipids and glycans. Of the four, glycans have been least studied and ignored in the intrinsic role they play in immune responses and in particular autoimmunity.

In the Journal of Autoimmunity,  Maverakis et el collate the mounting evidence for the role of glycan structures in the pathology of autoimmunity. Autoimmune diseases have been strongly linked to a particular antibody class or subclass. For example, IgG4 is associated with pemphigus foliaceus and autoimmune pancreatitis. The authors review and propose that whilst the antigen specificity of theantibody will determine the “site of attack”, the glycan/antibody isotype combination “will dictate the physical nature of the attack”.

Based on these fundamental principles, the authors propose “The Altered Glycan Theory of Autoimmunity”, where they state “that each autoimmune disease will have a unique glycan signature characterized by the site-specific relative abundances of individual glycan structures present on immune cells and extracellular proteins, especially the site-specific glycosylation patterns of the different Ig classes and subclasses.” This theory would then explain that changes in glycan recognition patterns by antibodies of a specific class would lead to aberrant (or self) recognition and precipitating membrane attack complexes and inflammation leading to pathophysiology.

Maverakis, E. et al. 2015. Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: A critical review.Journal of Autoimmunity.