Exploring the Drug Repurposing Versatility of Valproic Acid as a Multifunctional Regulator of Innate and Adaptive Immune Cells

Figure 10

VPA impacts the B cell differentiation into plasma cells and in the isotype switch and maturation affinity of immunoglobulins. There are various signals by which B lymphocytes can differentiate into plasma cells that produce one or another immunoglobulin. CD40L+IL-21 promote IgM production and isotype switch into IgG and IgA; LPS+IL-4 induce isotype switch into IgG1; CD40L and IL-4 enable isotype switch into IgE; and IL-4+IL-5+LPS+TGF-β+dextran-conjugated anti IgD (not shown) prompt isotype switch into IgA. Isotype switch is mainly mediated by AID expression, while the naïve B lymphocyte differentiation into a plasma cell is governed by Blimp-1. VPA interferes with those mechanisms by inhibiting several HDACs, which promotes an increase in acetylation of the H3 that is next to the codifying genes for multiple miRNAs, which then block mRNA for AID (Aicda) and for Blimp-1 (Prdm1). Besides, VPA inhibits the expression of the early activation molecule CD69 and of MHC-II. Furthermore, this effect could be employed to reduce the generation of autoantibodies in mouse experimental lupus models. Green arrows indicate the processes, molecules, or mediators in the signaling pathway that are augmented and/or promoted by VPA. Red arrows indicate processes, molecules, or mediators in the signaling pathway that are inhibited by VPA. Figure based on [147].