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.
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