Histone deacetylase inhibitors dampen antibody and autoantibody responses by upregulating selected B cell microRNAs that silence AID and Blimp-1 expression (IRM10P.603)

Abstract

Class-switch DNA recombination (CSR) and somatic hypermutation (SHM), which require AID, and plasma cell differentiation, which requires Blimp-1, are critical for the generation of class-switched and hypermutated (mature) antibody and autoantibody responses. We show that histone deacetylase inhibitors (HDIs) valproic acid (VPA) and butyrate upregulated miR-155, miR-181b and miR-361 to silence AICDA/Aicda, and miR-23b, miR-30a and miR-125b to silence PRDM1/Prdm1, in human and mouse B cells. This led to downregulation of AID, Blimp-1 and Xbp-1, thereby inhibiting CSR, SHM and plasma cell differentiation. The selectivity of HDI-mediated silencing of AICDA/Aicda and PRDM1/Prdm1 was emphasized by unchanged expression of HoxC4 and Irf4 (important AICDA/Aicda inducer/modulators), Rev1 and Ung (central elements for CSR/SHM), and Bcl6, Bach2 or Pax5 (repressors of PRDM1/Prdm1 expression), as well as unchanged expression of miR-19a/b, miR-20a and miR-25, which are not known to regulate AICDA/Aicda or PRDM1/Prdm1. Through these B cell intrinsic epigenetic mechanisms, VPA blunted class-switched and hypermutated T-dependent and T-independent antibody responses in C57BL/6 mice. It also decreased class-switched and hypermutated autoantibodies, ameliorated disease and extended survival in lupus MRL/Faslpr/lpr mice. Our findings outline important epigenetic mechanisms of modulation of antibody responses and providing proof-of-principle therapeutics in autoantibody-mediated autoimmunity.