Epigenetic downregulation of the antibody response and inhibition of autoimmunity

Summary

Principal Investigator: Paolo Casali
Abstract: 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. !
Funding Period: 2013-06-14 - 2014-01-31
more information: NIH RePORT

Top Publications

  1. pmc Induction of activation-induced cytidine deaminase-targeting adaptor 14-3-3γ is mediated by NF-κB-dependent recruitment of CFP1 to the 5'-CpG-3'-rich 14-3-3γ promoter and is sustained by E2A
    Thach Mai
    Institute for Immunology, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA
    J Immunol 191:1895-906. 2013
  2. pmc Combinatorial H3K9acS10ph histone modification in IgH locus S regions targets 14-3-3 adaptors and AID to specify antibody class-switch DNA recombination
    Guideng Li
    Institute for immunology and School of Medicine, University of California, Irvine, 3028 Hewitt Hall, Irvine, CA 92697 4120, USA
    Cell Rep 5:702-14. 2013

Research Grants

Detail Information

Publications2

  1. pmc Induction of activation-induced cytidine deaminase-targeting adaptor 14-3-3γ is mediated by NF-κB-dependent recruitment of CFP1 to the 5'-CpG-3'-rich 14-3-3γ promoter and is sustained by E2A
    Thach Mai
    Institute for Immunology, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA
    J Immunol 191:1895-906. 2013
    ..Thus, 14-3-3γ induction in CSR is enabled by the CFP1-mediated H3K4me3 enrichment in the promoter, dependent on NF-κB and sustained by E2A...
  2. pmc Combinatorial H3K9acS10ph histone modification in IgH locus S regions targets 14-3-3 adaptors and AID to specify antibody class-switch DNA recombination
    Guideng Li
    Institute for immunology and School of Medicine, University of California, Irvine, 3028 Hewitt Hall, Irvine, CA 92697 4120, USA
    Cell Rep 5:702-14. 2013
    ..Thus, H3K9acS10ph is a histone code that is "written" specifically in S regions and is "read" by 14-3-3 adaptors to target AID for CSR as an important biological outcome. ..

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. "Perturbation of peripheral B cell tolerance by the lupus susceptibility loci"
    Ziaur S M Rahman; Fiscal Year: 2013
    ..Data generated from these studies will reveal how these two mechanisms permit autoantibody production in lupus and thus have both diagnostic and therapeutic implications. ..
  3. Influenza Immunity: Protective Mechanisms Against Pandemic Respiratory Virus
    MARK MORRIS DAVIS; Fiscal Year: 2013
    ..It will also provide important information regarding the mechanisms responsible for the generation of protective B cell immunity against a wide array of other important human pathogens and bioterrorism agents. ..
  4. B-cell Biology of Mucosal Immune Protection from SIV Challenge
    Eric Hunter; Fiscal Year: 2013
    ....
  5. Experimental Therapeutics of Leukemia
    John C Byrd; Fiscal Year: 2013
    ..We believe that this SPORE group, as a multidisciplinary, highly interactive and accomplished team, will have a substantial impact on improving the clinical outcome of leukemia patients. ..
  6. Cellular &Molecular Defects in Human B Cell Development
    Charlotte Cunningham-Rundles; Fiscal Year: 2013
    ..We hypothesize that mutations in this receptor and its isoforms can be used to elucidate the complex functions of this receptor in a human system. ..
  7. Wisconsin Center of Excellence in Genomics Science
    Michael Olivier; Fiscal Year: 2013
    ..Data, technology, and software will be widely disseminated by multiple mechanisms including licensing and commercialization activities. ..
  8. NK Cells, Their Receptors and Unrelated Donor Transplant
    Jeffrey S Miller; Fiscal Year: 2013
    ..The program also promises to change practice of allogeneic transplantation, to the greater benefit of patients with advanced leukemia. ..
  9. CCR5 Regulation and Promoter Variants in HIV-1
    Srinivas Mummidi; Fiscal Year: 2013
    ..These studies may result in advancing our knowledge about factors that influence HIV-AIDS susceptibility. ..
  10. Signaling in Airway Inflammation
    Roberto P Garofalo; Fiscal Year: 2013
    ..Our work will lay the foundation for future studies aimed at translating the findings from this project period into novel treatments for asthma. ..
  11. M D Anderson Cancer Center Prosate SPORE
    Christopher J Logothetis; Fiscal Year: 2013
    ..We are optimistic that our research efforts will contribute to reductions in the incidence of, and morbidity and mortality from, this devastating disease by translating basic research into clinical practice. ..
  12. Structural Cell Biology of DNA Repair Machines
    John A Tainer; Fiscal Year: 2013
    ..abstract_text> ..
  13. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  14. Tissue compartmentalization of human lymphocytes
    Donna L Farber; Fiscal Year: 2013
    ..The results obtained will lead to new strategies for tissue targeting of T cell responses in vaccines and immunotherapies. ..
  15. Toll-Like Receptors in Systemic Autoimmune Disease
    Ann Marshak-Rothstein; Fiscal Year: 2013
    ....
  16. HDAC inhibition for the chemoprevention of lung cancer
    Johann Christoph Brandes; Fiscal Year: 2013
    ..With a 37% absolute risk reduction for lung cancer incidence, this would translate into 55,000 lives saved per year. ..
  17. B Cell Development Defects in Murine Lupus
    Laurence Morel; Fiscal Year: 2013
    ..The results from these studies will provide a better understanding of the defining features of autoreactive B cells and will help to target therapies toward these autoreactive B cells. ..
  18. Effects of miR-21 and miR-155 inhibition in SLE
    Marianthi Kiriakidou; Fiscal Year: 2013
    ..To our knowledge HITS-CLIP has not been previously performed in SLE and the combined results of HITS-CLIP and RNAseq will offer a panoramic view of all genes directly regulated by miRNAs in cells of the immune system in mouse lupus. ..
  19. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  20. Autoimmunity Center of Excellence (ACE) at Stanford
    CHARLES GARRISON FATHMAN; Fiscal Year: 2013
    ..The Stanford ACE proposes clinical research projects that encompass three different autoimmune diseases (SSc, psoriatic arthritis and SJIA), and proposes to study the MoA of therapeutics for preventing or treating different Al diseases. ..
  21. DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM
    Christopher B Newgard; Fiscal Year: 2013
    ..abstract_text> ..
  22. VACCINE INDUCED IMMUNITY IN THE YOUNG AND AGED
    Rafi Ahmed; Fiscal Year: 2013
    ....
  23. FAIM in Immunity and Autoimmunity
    Thomas L Rothstein; Fiscal Year: 2013
    ....
  24. The effect of innate immunity on B cell tolerance
    Thereza Imanishi-Kari; Fiscal Year: 2013
    ..These experiments will help unravel the mechanisms by which RNA-specific B cells become activated and produce pathogenic autoantibodies in SLE. ..
  25. Systems Biological Analysis of Innate and Adaptive Responses to Vaccination
    Bali Pulendran; Fiscal Year: 2013
    ..The successful completion of this program may provide insights into the defects that underlie poor vaccine efficacy in the elderly, and establish the broad utility of systems biology in predicting vaccine immunogenicity. ..
  26. Defining signatures for immune responsiveness by functional systems immunology
    David A Hafler; Fiscal Year: 2013
    ..abstract_text> ..
  27. Somatic hypermutation and class switching in autoimmunity
    Paolo Casali; Fiscal Year: 2013
    ....