CELL SURFACE DNA - AN ANALYSIS OF SPECIFIC RECEPTORS

  • Bennett, Robert (Rob), (PI)

    Project: Research project

    Description

    Systemic lupus erythematosus (SLE) is the prototypical
    autoimmune systemic disease. The autoantibody response is
    directed towards two major classes of antigens: nuclear
    constitutents and cell surface molecules. Autoimmunity to
    nuclear antigens presents a puzzling enigma, as they exist in a
    "protected" location and are relatively non-immunogenic; the
    current proposal offers a novel explanation of this paradox which
    can be experimentally tested. We have presented evidence for
    the existence of a receptor for DNA on human leukocytes, and
    described dysfunction of this receptor in patients with SLE. It is
    hypothesized that autoimmunity to the DNA receptor is a
    common occurrence in patients with connective tissue disorders
    (CTD), and that under certain circumstances (?genetic,
    ?infective) a regulatory idiotypic network gains ascendency;
    according to Jerne's hypothesis this anti-iudiotypic response will
    contain antibodies to DNA. This hypothesis will be tested by
    experiments to: (i) determine the prevalence of antibodies to the
    DNA receptor in SLE, other CTD, chronic inflammatory disorders
    and a "normal" population; (ii) test Jerne's hypothesis predicting
    that antibodies to idiotypes in the DNA binding domain of anti-
    DNA antibodies, will exhibit anti-receptor activity, and vice
    versa; (iii) measure the fluctuation of antibodies to DNA, the
    DNA receptor and anti-DNA idiotypes in SLE, and determine
    whether anti-receptor antibody levels are inversely proportional
    to anti-DNA activity - as would be expected if anti-DNA
    antibodies arose as an idiotypic response to anti-receptor
    antibodies; (iv) use monoclonal antibodies (MAB) to the DNA
    binding domain of the DNA receptor to detect highly conserved
    idiotype(s) on anti-DNA antibodies; (v) use the same MAB to
    develop a rabbit model for the generation of anti-DNA antibodies;
    and (vi) clone and sequence the gene for the DNA receptor as a
    prelude to exploring critical amino acid sequences that may be
    involved in automimmunity in SLE. Accomplishment of these
    goals would have several implications for future research into the
    etiopathogenesis of SLE, and may provide insights into a
    regulatory idiotypic network which could be manipulated in the
    treatment of patients with SLE.
    StatusFinished
    Effective start/end date9/20/858/31/93

    Funding

    • National Institutes of Health
    • National Institutes of Health: $146,759.00
    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health

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    Systemic Lupus Erythematosus
    DNA
    Antinuclear Antibodies
    Connective Tissue
    Autoimmunity
    Antibodies
    Monoclonal Antibodies
    Leukocytes
    Surface Antigens
    DNA Probes
    Autoantibodies
    Antibody Formation
    DNA receptor
    Anti-Idiotypic Antibodies
    Amino Acid Sequence
    Clone Cells
    Rabbits
    Antigens
    Biotin
    Population

    ASJC

    • Medicine(all)