The objectives of this proposal are to more precisely define the characteristics of pathogenic autoantibodies (autoAb) and the mechanisms by which they form immune deposits and to identify the immunologic pathways leading to the production of these pathogenic autoAb in Systemic Lupus Erythematosus. For this purpose, monoclonal antibodies derived from MRL-lpr/lpr mice that share either antigen binding or idiotypic properties with nephritogenic Ig will be characterized according to subclass, isotype, idiotype, charge and antigen binding properties, and the capacity of these antibodies to form glomerular immune deposits in vivo, in normal mice, will be determined by both direct binding to glomerular antigens and in situ immune complex formation with circulating antigens. In separate studies the capacity of monoclonal autoAb to bind directly to normal mesangial cells will be evaluated. In addition, the ability of glomerular binding autoAb to induce the production of Ab with similar binding properties through idiotype-network interactions will be investigated. The origin and mechanism of production of Ab with nephritogenic properties will be examined in an attempt to identify the immunologic pathways leading to the production of pathogenic autoAb. Two experimental approaches will be utilized. In the first, unstimulated B cells from lupus and normal animals will be examined. In the second, the capacity of auto- reactive T cells cloned from MRL-lpr/lpr mice to induce B cells from lupus and normal mice to produce pathogenic autoAb will be evaluated. In both cases B cell hybridomas from MRL-lpr/lpr and normal mice at various ages and their Ab products will be evaluated. The usage of VH gene families and of a germline gene that encodes a prototypic autoAb associated with a high frequency idiotype, will be examined by hybridization. These studies should provide information regarding: the nephritogenic properties of lupus autoAb and the genes that encode them; the immunologic pathways that lead to the production of these immunoglobulins; and whether similar pathways are present in normal mice. In addition, these studies should determine whether the properties of these pathogenic autoAb or the genes that encode them change during the lifespan of autoimmune mice, and whether they differ in normal and autoimmune strains. Ultimately through this understanding a more rational approach to alter these events in individuals with lupus can be planned.
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