REGULATION OF AUTOANTIBODIES TO RIBOSOMAL P PROTEINS

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Autoantibodies to ribosomal P proteins (anti-P) are highly specific for systemic lupus erythematosus (SLE), and are potentially pathogenic. We serendipitously observed that virtually all healthy adults also possess anti-P. These anti-P, however, are masked by anti-idiotypic antibodies (anti-Ids). We hypothesize that anti-Ids to anti-P prevent recognition of autologous ribosomal P proteins by anti-P antibodies in healthy adults, and that their dysfunction allows anti-P to recognize these self proteins, and thereby, promote tissue injury in SLE patients. The goals of this proposal are to characterize the idiotype network for anti-P in healthy adults, patients, and their relatives, and to generate recombinant anti-Ids to anti-P. The specific aims are to: 1) isolate and characterize the anti-Ids to anti-P in a cohort of healthy adults; 2) compare the idiotypes of anti-P antibodies from SLE patients and healthy controls; 3) generate recombinant anti-Ids to anti-P; and 4) determine if anti-Ids to anti-P exist in SLE patients and their relatives. IgG anti-Ids to anti-P from ten healthy adults will be purified and analyzed for idiotope specificity, heterogeneity, and binding properties. These anti-Ids will be used to evaluate idiotypic similarities among anti-P antibodies from SLE patients and healthy controls. The recombinant phage antibody system (Pharmacia) will be used to generate recombinant anti-Ids to anti-P. SLE patients with anti-P and their consanguineous relatives will be evaluated for anti-Ids to anti-P. Results from the proposed investigations should provide insights into the regulation of anti-P by anti-Id antibodies in health and disease. This knowledge will allow new strategies to be developed that will prevent self-recognition by anti-P autoantibodies in anti-P autoimmunity. Important tools will be generated that will allow future mechanistic and molecular immunologic studies to be devised. Furthermore, the results may have general applicability to their autoantibody systems as well. If anti-Ids from healthy adults react with anti-P from patients, and recombinant anti-Ids are generated that mask anti-P, then these anti-Ids may be useful therapeutically to control the expression, and thereby, the clinical sequelae of anti-P in patients.