Fig. 4

HCQ interference in the T-cell activation pathway and transcription of CD 154: When T-cell receptor (TCR) is stimulated by antigen via MHC, a series of events leads to the activation of the Phospholipase C, which then generates Inositol triphosphate (IP3). IP3 induces the release of calcium from the endoplasmic reticulum (ER). Calcium acts as a secondary messenger to activate Calcium-release-activated Calcium channel (CRAC) for a steady influx of extracellular calcium. Intracellular calcium binds to calmodulin and activates the phosphatase calcineurin (not shown in the diagram). Calcineurin dephosphorylates and activates transcription factor NFATc2. NFATc2 migrates the nucleus and triggers the transcription of NFATc1. NFATc1 mRNA is exported outside the nucleus where de novo synthesis of transcription factor NFATc1 occurs. NFATc1 then migrates back into the nucleus to triggers the transcription of CD 154. HCQ can potentially interfere with intracellular calcium signaling and prevent dephosphorylation and activation of the transcription factor NFAT. This is one of the mechanisms by which HCQ interfere in T-cell activation and CD 154 transcription