CELL SURFACE DNA - AN ANALYSIS OF SPECIFIC RECEPTORS

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.