Glycosylation: An intrinsic sign of "danger"

The "danger" model of immunity posits that the immune system is triggered by endogenous danger signals, rather than exogenous non-self signals per se. It has been proposed that danger signals may consist of both intracellular "pre-packed" molecules released from damaged cells and stress-induced proteins. Here we focus on glycosylation aberrancies as a unifying concept for danger signaling. According to this proposition glycosylation patterns reliably reflect cellular phenotypic state and appearance of altered carbohydrate structures may constitute a pivotal phenotypic alteration that alarms the immune system to danger and initiates immunity. Viewed from this vantage point, healthy cells avert immune recognition by virtue of their normal terminal glycosylation patterns. By contrast, abnormal cells display and release glycoproteins and glycolipids with aberrant terminal glycosylation trees, which in turn immunologically flag these cells. Diverse carbohydrate-binding receptors are expressed on immune cells and are used to detect these phenotypic changes. Thus, in addition to the "pre-packed" and stress-induced signals this glycosylation-based signal represents an endogenous signal reliably reflecting the cell phenotypic status, enabling the immune system to monitor the tissue/cell's physical condition and to respond accordingly.