Antibody Mediated Autoimmunity in Neuromyelitis Optica

Summary

Principal Investigator: HANS CHRISTIAN VON BUEDINGEN
Abstract: DESCRIPTION (provided by applicant): There is increasing appreciation that B cells and antibodies are important players in the immunopathogenesis of autoimmune demyelinating disorders of the central nervous system (CNS) such as neuromyelitis optica (NMO) and multiple sclerosis (MS). NMO is a severe inflammatory demyelinating disease affecting the optic nerves and spinal cord. Aquaporin-4 (AQP4) has been identified as a target of pathogenic autoantibody responses in NMO. Thus, NMO can be considered a model disease for CNS directed B cell and antibody autoimmunity. AQP4 is a water channel protein, which is expressed in astrocytes of the CNS. Anti- AQP4 antibodies have been proposed to exert neuropathological effects by a number of different mechanisms in NMO, including complement activation, antibody-dependent cell-mediated cytotoxicity, and downregulation of AQP4 and associated proteins. However, the exact epitope specificities of pathogenic anti-AQP4 antibodies remain unknown. It is unclear whether antigens other than AQP4 are also targets of pathologically relevant autoantibodies and no information is available regarding epitope targets of pathogenic autoantibodies in anti- AQP4 seronegative patients. However, there is evidence for extensive B cell-dependent autoimmunity in NMO, which likely translates into a diverse, pathogenic, CNS-directed autoantibody repertoire. We hypothesize that the AQP4-specific antibody repertoire is diverse, both in regards to AQP4 epitope recognition and with respect to pathological effects on CNS tissue. To address this hypothesis, we will first delineate the repertoire of AQP4 epitopes recognized by a.) recombinant monoclonal antibodies (rAbs) generated from CSF plasma cells, and by b.) purified soluble immunoglobulins from serum and CSF from anti- AQP4 seropositive NMO patients. Subsequently, monoclonal anti-AQP4 antibodies representative of individual AQP4-epitopes will be further characterized regarding their potential to damage AQP4 expressing cells. To establish an in vitro experimental system as close to in vivo as possible, we will also study pathological effects of anti-AQP4 antibodies on astrocytes derived from induced pluripotent stem cells (iPSC) from NMO patients. We also hypothesize, that antibody mediated immunity against targets other than AQP4 may play a role in AQP4-seronegative and possibly even AQP4-seropositive NMO patients. To address this hypothesis, we propose to identify targets of AQP4 non-reactive antibodies from AQP4-seronegative and -seropositive NMO patients. To achieve this goal, we will determine the reactivity of AQP4 non-reactive antibodies with iPSC-derived CNS cells (e.g. astrocytes, oligodendrocytes or neurons) and study pathological effects resulting from this autoantibody binding. These studies will elucidate pathologically relevant antibody-antigen interactions and are expected to serve as an important foundation for the development of disease-specific therapies and novel biomarkers.
Funding Period: 2011-06-15 - 2016-05-31
more information: NIH RePORT

Top Publications

  1. pmc B cell exchange across the blood-brain barrier in multiple sclerosis
    H Christian von Büdingen
    Department of Neurology, UCSF, San Francisco, California 94158, USA
    J Clin Invest 122:4533-43. 2012
  2. pmc In multiple sclerosis, oligoclonal bands connect to peripheral B-cell responses
    Jaishree Bankoti
    Departments of Neurology, University of California, San Francisco, San Francisco, CA
    Ann Neurol 75:266-76. 2014
  3. pmc Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients
    Arumugam Palanichamy
    Department of Neurology, University of California, San Francisco, San Francisco, CA 94158 and
    J Immunol 193:580-6. 2014

Detail Information

Publications3

  1. pmc B cell exchange across the blood-brain barrier in multiple sclerosis
    H Christian von Büdingen
    Department of Neurology, UCSF, San Francisco, California 94158, USA
    J Clin Invest 122:4533-43. 2012
    ..These data also provide a powerful approach to identify and monitor B cells in the PB that correspond to clonally amplified populations in the CNS in MS and other inflammatory states...
  2. pmc In multiple sclerosis, oligoclonal bands connect to peripheral B-cell responses
    Jaishree Bankoti
    Departments of Neurology, University of California, San Francisco, San Francisco, CA
    Ann Neurol 75:266-76. 2014
    ..To determine to what extent oligoclonal band (OCB) specificities are clonally interrelated and to what degree they are associated with corresponding B-cell responses in the peripheral blood (PB) of multiple sclerosis (MS) patients...
  3. pmc Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients
    Arumugam Palanichamy
    Department of Neurology, University of California, San Francisco, San Francisco, CA 94158 and
    J Immunol 193:580-6. 2014
    ..However, given their potential proinflammatory functionality, depletion of CD20-expressing T cells may also contribute to the therapeutic effect of RTX and other mAbs targeting CD20. ..

Research Grants30

  1. Humoral Immunity, Astrocyte Injury, and Demyelination in Neuromyelitis Optica
    Jeffrey L Bennett; Fiscal Year: 2013
    ....
  2. Aquaporin-4 in NMO Optic Neuritis: Pathogenesis and New Therapies
    Alan S Verkman; Fiscal Year: 2013
    ..We have developed both monoclonal antibody and small-molecule approaches, which will be optimized and used in mouse models to obtain proof-of-concept that blocking NMO-IgG binding to AQP4 can reduce ocular pathology in NMO. ..
  3. Does chronic Theiler's demyelination require viral persistence?
    HOWARD LEE LIPTON; Fiscal Year: 2013
    ....
  4. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  5. New England Regional Center of Excellence in Biodefense and Emerging Infectious D
    Dennis L Kasper; Fiscal Year: 2013
    ..NERCE will also continue its Developmental Projects program and Career Development in Biodefense program in an effort to initiate new research efforts and to attract new investigators to this field. ..
  6. Therapeutic Opportunities for Pediatric Astrocytoma
    Rosalind A Segal; Fiscal Year: 2013
    ..The three projects interact with one another and are further unified by economies of scale enabled by an Innovative Neuropathology (INP) core. ..
  7. Immune Mechanisms That Control Ectromelia Virus Infection
    Luis J Sigal; Fiscal Year: 2013
    ..The results from this Project will provide a comprehensive picture of the innate response to a peripheral virus infection. ..
  8. 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. ..
  9. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  10. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  11. DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM
    Christopher B Newgard; Fiscal Year: 2013
    ..abstract_text> ..
  12. 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. ..
  13. VACCINE INDUCED IMMUNITY IN THE YOUNG AND AGED
    Rafi Ahmed; Fiscal Year: 2013
    ....