Structural changes of Q. saponins linked to their immunological properties (IMAGE)
Caption
The adjuvanticity of Q. saponins, like QS-21, depends on several chemical groups to induce pro-inflammatory Th1 immune responses. (a) Q. saponins have two groups critical for their Th1 adjuvanticity: the C4-aldehyde group (red) on the triterpene nucleus and the fatty acid side-chain with terminal arabinose (fuchsia) bound to the fucose residue (blue). Reduction of the aldehyde group to alcohol results in a loss of adjuvanticity due to the inability to deliver the co-stimulatory signal required for T-cell activation. The fatty acid side-chain bound to the fucose’s 3 or 4-hydroxyl groups (*), most likely interferes with the binding of this sugar to the DC-SIGN receptor on dendritic cells (DCs), preventing polarization of DCs towards a Th2 phenotype. It has been claimed that for adjuvanticity, the C4-aldehyde group is irrelevant, while the C16-hydroxyl group (yellow) of the triterpene group is essential, an assumption that ignores the fact that the inactive reduced QS-21, while lacking the C4-aldehyde group, still has the C16-hydroxyl group. Hence, this hydroxyl is practically unnecessary for adjuvanticity. b) Removal of the fatty acid side-chain from the fucose’s 3 or 4-hydroxyl groups (*) yields deacylated Q. saponins, QT-0101. This product stimulates solely Th2 anti-inflammatory immunity, likely because the deacylated fucose residue (blue) can bind to DC-SIGN and bias DCs towards a Th2 phenotype. This underscores the critical roles of the fucose’s 3 and 4-hydroxyl groups (*) in determining the type of elicited immunity, i.e., Th1 or Th2. c) N-acylation of the Q. saponins’ single glucuronic acid residue (orange) by alkyl chains with n = 1 to 14 carbons (green) reverses the capacity of deacylated saponins to elicit Th2 to Th1 immunity; i.e., Th2 → Th1 → Th2. This transition depends on the length of the alkyl chain, with analogs carrying larger alkyl chains reverting to inducing Th2 immunity. This transition is also dependent on the hydrophilic-lipophilic balance value of each saponin derivative. Changes in adjuvanticity are likely due to alterations in both conformational and associative properties of alkylated saponis. DC-SIGN, dendritic cell-specific ICAM-grabbing non-integrin.
Credit
Dante J. Marciani
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