Glycosylation in the Pathophysiology of Heritable and Acquired Disease (Keynote)

JAMEY MARTH; PRABHJIT GREWAL; RICARDO LARDONE

Viena

Congreso; XXI International Symposium on Glycoconjugates; 2011

Of the 34 monosaccharides thus far identified that are used in the enzymatic process of glycosylation among all cells and organisms, mammalian glycans are produced from only 9 of these monosaccharides. With this limitation of monosaccharides and the glycosidic linkages that can be formed, a diverse repertoire of glycan linkages is nevertheless constructed. The resulting glycome of mammals has characteristic features that structurally differentiate it from the glycomes of prokaryotes, early eukaryotes, invertebrates, and even some other vertebrates. We are studying the outcomes of heritable and acquired changes in the mammalian glycome that expose cryptic and phylogenically more primitive glycan linkages. These abnormal glycans are detected by endogenous lectin receptors. Heritable, and possibly acquired, exposure of cryptic glycan linkages can promote chronic inflammatory conditions that evolve into autoimmune disease by a novel mechanism in which pathogenesis is independent of the adaptive immune system. This mechanism of autoimmune disease onset cannot be easily detected at present in clinical settings as diagnostics are still lacking, yet this mechanism may play a signifi cant role in the pathophysiology of common grievous diseases that include inflammatory, autoimmune, and degenerative syndromes that are of mysterious origin and which continue to escalate in the human population. We have further found that pathogen induced glycan re-modeling in mammals can also result in the exposure of phylogenically-primitive glycan linkages that are then recognized by phagocytic lectin receptors. In this case, lectin-ligand binding results in receptor-mediated endocytosis and clearance of deleterious glycoproteins from blood circulation, reflecting a protective mechanism that lessens the severity and improves the outcome of systemic infection.