FAIM in Immunity and Autoimmunity

Summary

Principal Investigator: Thomas L Rothstein
Abstract: DESCRIPTION (provided by applicant): Like the two faces of Janus, antibodies can be a gateway to anti-microbial immunity or to autoantibody- associated disease. The recent successful use of anti-CD20 to treat patients with autoimmune dyscrasias has re-focused attention on the role of B cells as therapeutic targets. Mature B cells become antibody secreting plasma cells through a complex process that begins in the germinal center and involves alterations in multiple transcription factors. Work from this laboratory has identified a new player in B cell activation and differentiation, namely the novel gene, Faim. FAIM is unique;it is highly evolutionarily conserved, yet does not contain sequence homology, or structural homology, with any other protein. In B cells FAIM acts as a force multiplier. It boosts CD40 signaling by enhancing CD40L-stimulated increases in NF-:B and IRF4, and, it enhances the CD40L-stimulated decline in BCL-6. As expected from the extra increase in IRF4 and decline in BCL-6 (as well as its location in the germinal center) FAIM overexpression augments the plasma cell compartment in chimeric mice. FAIM expression is stimulated by IRF4 and so once triggered FAIM is involved in a "feed-forward" positive re-inforcing mechanism. The long term objective of this proposal is two-fold: to understand normal B cell biology focusing on how "resting" B cells become effectors, and to determine the points at which these processes go awry resulting in autoantibody production and autoimmunity. The near term objective of this work is to define the role of FAIM in facilitating immunity and regulating autoimmunity, with the goal of identifying a new therapeutic target. The specific aims of this proposal are to: 1) conduct a careful molecular structure/function analysis to identify and characterize the unique FAIM effector motif;and, 2) evaluate the influence of FAIM on the quality and selection of antibody produced in a model normal immune response, and on checkpoint integrity in a model system of spontaneous autoantibody production, and elucidate the physiology of FAIM expression in the germinal center. The results of this work are highly likely to provide completely new and fundamental information about how signaling in B cells is promoted, and about how plasma cell differentiation is regulated. Moreover, the recent finding by other investigators (unpublished) that SNPs proximal to, and within, the FAIM sequence are strongly associated with human lupus disease indicates that the mechanisms revealed by this study are highly likely to be relevant to understanding clinical autoimmunity and may provide a new target for therapeutic manipulation.
Funding Period: 2010-07-01 - 2015-06-30
more information: NIH RePORT

Research Grants

  1. Infectious Agents and B Cell Anergy
    John C Cambier; Fiscal Year: 2013
  2. Somatic hypermutation and class switching in autoimmunity
    Paolo Casali; Fiscal Year: 2013
  3. B Cell Development Defects in Murine Lupus
    Laurence Morel; Fiscal Year: 2013
  4. A Novel B Cell Marker and Therapeutic Target in Lupus
    Joseph Craft; Fiscal Year: 2013
  5. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
  6. Citrullinated Antigens Bridge Innate and Adaptive Immunity in RA
    Jeremy Sokolove; Fiscal Year: 2013
  7. Effects of miR-21 and miR-155 inhibition in SLE
    Marianthi Kiriakidou; Fiscal Year: 2013
  8. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
  9. Autoimmunity Center of Excellence (ACE) at Stanford
    CHARLES GARRISON FATHMAN; Fiscal Year: 2013
  10. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013

Detail Information

Research Grants30

  1. Infectious Agents and B Cell Anergy
    John C Cambier; Fiscal Year: 2013
    ..g. EBV in human and gHV68 in mouse, re-awaken anergic B cells thereby leading to autoimmunity. Results of these studies may provide new strategies for prevention, diagnosis and treatment of autoimmunity. ..
  2. Somatic hypermutation and class switching in autoimmunity
    Paolo Casali; Fiscal Year: 2013
    ....
  3. 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. ..
  4. A Novel B Cell Marker and Therapeutic Target in Lupus
    Joseph Craft; Fiscal Year: 2013
    ..Finally, PSGL- 1+CD38hi PC will be characterized in the peripheral blood of lupus patients, correlating their numbers with disease activity in an effort to support the idea that PSGL-1 on PC is an appropriate therapeutic target in SLE. ..
  5. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  6. Citrullinated Antigens Bridge Innate and Adaptive Immunity in RA
    Jeremy Sokolove; Fiscal Year: 2013
    ....
  7. 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. ..
  8. 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. ..
  9. 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. ..
  10. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  11. Philadelphia Autoimmunity Center of Excellence
    A M Rostami; Fiscal Year: 2013
    ..The Clinical Component proposes novel clinical trial concepts and studies to understand the mechanisms of action of the therapeutics being tested. As such, they are an integral part of this ACE. ..
  12. VACCINE INDUCED IMMUNITY IN THE YOUNG AND AGED
    Rafi Ahmed; Fiscal Year: 2013
    ....