IMMUNOLOGICAL MECHANISMS OF NEPHRITIS IN CHILDHOOD

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Childhood systemic lupus erythematosus (SLE) differs from the disease in adults by a higher prevalence of nephritis. We hypothesize that this higher prevalence of nephritis is due to several types of nephritogenic autoantibodies that occur concurrently in the childhood form of SLE. Our two major candidates for these autoantibodies are those directed against dsDNA which have long been recognized to play a role in adult lupus nephritis and autoantibodies to ribosomal "P" protein which have not been reported previously to be associated with either adult or pediatric lupus nephritis. We propose that in some patients antibodies to Ro/SSA may also play a nephritogenic role. Aside from recent preliminary clinical and animal data that support a role for anti-P in lupus nephritis, both anti- dsDNA and anti-ribosomal "P" antibodies have recently been found to contain subpopulations of antibodies that directly bind and injure cells in culture. This in vitro cell injury is hypothesized to be a surrogate for their immunopathogenic potential in vivo. We propose to define the pathogenic potential of these autoantibodies in individual patients by affinity purifying their autoantibodies and by studying their interaction with renal cells in culture. We will characterize the pattern of intracellular localization and the effects on cell function and viability. We will also characterize the diverse pathogenic mechanism of anti-dsDNA from individual patients as preliminary studies already have shown that some human antibodies injure cells by a complement dependent mechanism at the cell surface and others penetrate the cell, localize in either the nucleus or the cytoplasm, and affect cellular function over a longer period of time. We will correlate these immunopathogenetic properties in vitro with the patients clinical status. We believe such studies may generate data which will foster a new perspective on the mechanism of lupus nephritis in children and may suggest new strategies and interventions for the management of this serious complication.