Epigenetic downregulation of the antibody response and inhibition of autoimmunity

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DESCRIPTION (provided by applicant): Epigenetic downregulation of the antibody response and inhibition of autoimmunity Epigenetic marks (including histone modifications, DNA methylation and microRNAs) "interact" with genetic programs to regulate B cell functions, such as class switch DNA recombination (CSR), somatic hypermutation (SHM) and plasma cell differentiation, thereby informing the antibody response. Epigenetic dysregulation can result in aberrant antibody responses, and compound genetic susceptibility to mediate autoimmunity, including systemic lupus (SLE), in which heavily mutated and class-switched (mainly IgG) autoantibodies to nuclear antigens, as secreted by large numbers of plasma cells, produce widespread tissue and organ injury. Prompted by our compelling preliminary findings in human and mouse B cells in vitro, and in normal and lupus-prone mice, we hypothesize that the epigenetic modulators histone deacetylase inhibitors (HDIs) inhibit CSR/SHM, plasma cell differentiation and, therefore, specific antibody and autoantibody responses, and prevent autoimmunity and "cure" mice in an advanced stage of lupus. We also argue that HDIs inhibit antibody and autoantibody responses by upregulating expression of selected microRNAs through enhanced acetylation and transcription of those microRNA host genes. As suggested by our preliminary data, we contend that HDIs upregulate miR-155, miR-181b, miR-93 to downregulate AID (central to CSR/SHM), miR- 146a to downregulate transcription factors Irf5 and (through Stat1) T-bet (important in CSR to IgG2a and lupus), miR-127 and miR-125b to downregulate Blimp1/Xbp1 (critical for plasma cell differentiation). The Casali lab is uniquely poised to test these novel hypotheses, owing to its record of accomplishment in B cell biology, molecular CSR/SHM and autoimmunity over the last 25 years, and the recently established cutting-edge epigenetic approaches. We will analyze the impact of HDIs (valproic acid, butyrate, suberoylanilide hydroxamic acid) on T-dependent and T-independent antibody responses in normal C57BL/6 and Balb/c mice, and autoantibody responses and autoimmunity in lupus-prone MRL/Faslpr/lpr and B6.NZM/Sle1.Sle2.Sle3 mice (Aim 1). We will address the downregulation of AID, Irf5, T-bet, Blimp1 and Xbp1, as targeted by (HDI-mediated) upregulation of miR-155, miR-181b, miR-93, miR-146a, miR-127 and miR-125b through enhanced acetylation of these microRNA "host genes" (Aim 2). Finally, we will define the role of microRNAs in mediating HDI inhibition of autoimmunity using lupus-prone mice lacking Dicer or Drosha in AID+ B cells or lacking microRNA targeting sites in Aicda and Prdm1 mRNAs, and identify genome-wide HDI-susceptible microRNA/target mRNA pairs in lupus mice (Aim 3). Our proposal is highly significant and innovative, as it addresses core epigenetic mechanisms of lupus and will have sustained impact on the fields of epigenetics, immunoregulation and autoimmunity. Finally, it is exquisitely translational, as (at the time when expensive biologics enter clinical trials) it provies a sound mechanistic basis for use of inexpensive and available epigenetic modulators as therapeutics in autoimmune diseases. !