Gangliosides in the Immune System: Role of Glycosphingolipids and Glycosphingolipid-Enriched Lipid Rafts in Immunological Functions.

Although individuals are constantly exposed to infectious agents, these agents are generally resisted by the innate and acquired immune systems. Both the innate and acquired immune systems protect against invading organisms, but they differ functionally in several ways. The innate immune system is the body's inborn defense mechanism and the first line of defense against invading organisms, such as bacteria, fungi, and viruses. Glycosphingolipids (GSLs), which are expressed on the outer leaflet of plasma membranes (Murate et al., J Cell Sci 128(8):1627-1638, 2015), are involved in both innate and acquired immunity (Inokuchi et al., Biochim Biophys Acta 1851(1):98-106, 2015; Nakayama et al., Arch Immunol Ther Exp (Warsz) 61(3):217-228, 2013; Rueda, Br J Nutr 98(Suppl 1):S68-73, 2007; Popa and Portoukalian, Pathol Biol (Paris) 51(5):253-255, 2003).Recent studies have indicated that innate immunity is not a "nonspecific" immune system. Large numbers of viruses, bacteria, and bacterial toxins have been reported to bind to host surface carbohydrates, a number of which are components of GSLs (Schengrund, Biochem Pharmacol 65(5):699-707, 2003). Binding studies have also demonstrated that some glycolipids function as receptors for microorganisms and bacterial toxins (Yates and Rampersaud, Ann N Y Acad Sci 845:57-71, 1998). These findings clearly indicate that GSLs are involved in host-pathogen interactions.GSLs are composed of hydrophobic ceramide and hydrophilic sugar moieties (Hakomori, Annu Rev Biochem 50:733-764, 1980). The ceramide moiety of sphingolipids and the cholesterol sterol-ring system are thought to interact via hydrogen bonds and hydrophobic van der Waal's forces (Mukherjee and Maxfield, Annu Rev Cell Dev Biol 20:839-866, 2004). Additional hydrophilic cis interactions among GSL headgroups have been found to promote their lateral associations with surrounding lipid and protein membrane components. These interactions result in the separation in cell membranes of lipid rafts, which are lipid domains rich in GSLs, cholesterol, glycosylphosphatidylinositol (GPI)-anchored proteins and membrane-anchored signaling molecules (Pike, J Lipid Res 47(7):1597-1598, 2006). These GSL-enriched lipid rafts play important roles in immunological functions (Inokuchi et al., Biochim Biophys Acta 1851(1):98-106, 2015; Iwabuchi et al., Mediators Inflamm 2015:120748, 2015; Anderson and Roche, Biochim Biophys Acta 1853(4):775-780, 2015; Zuidscherwoude et al., J Leukoc Biol 95(2):251-263, 2014; Dykstra et al., Annu Rev Immunol 21:457-481, 2003). This introductory chapter describes the roles of GSLs and their lipid rafts in the immune system.