There is considerable circumstantial and now direct evidence that the complement system is involved in the pathogenesis of lupus nephritis. The work proposed in this application will examine the role of the complement system in renal disease occurring in the accurate MRL/lpr mouse model of human systemic lupus erythematosus. To accomplish this, gene targeted mice will be used in a breeding strategy so that MRL/lpr mice acquire deficiencies of particular complement proteins. Studied will be receptors for the anaphylatoxins, C3a and C5a, which are present on circulating leukocytes and renal glomerular and tubular cells, and likely to be involved in inflammatory cell recruitment to the kidney as well as the progressive fibrosis occurring over time; CR3, a receptor on a variety of cells of hematopoeitic lineage which binds iC3b in immune complexes, leading to their processing by hepatic macrophages and inflammatory cell accumulation in kidney; and, factor H, a versatile C3b-binding protein present in plasma as a complement regulator, on platelets as the immune adherence receptor and in intrinsic renal cells, where its function is undetermined. In addition to examining renal phenotype through the measurement of albuminuria and glomerular filtration, additional complement dependent phenotypic changes that will be studied include immune complex handling, inflammatory gene expression, assessment of signaling cascades, and pro-fibrotic gene and protein accumulation. To determine the particular cell(s) involved in phenotypic changes brought about by these complement deficiencies, transplantation of kidney and bone marrow cells will be performed between knockout and wild-type animals. Because of certain limitations inherent in using knockout animals, parallel studies will be performed using specific inhibitors of these complement proteins. These studies will allow conclusive determination of the role of the complement system in lupus nephritis, including what the relevant complement protein/receptors are, on which cells these are active, and pinpointing their involvement to a particular limb of the pathogenic cascade. Understanding the pathogenesis of a complex disease like lupus nephritis offers the potential to design rationale therapy. Specific manipulation of the complement system at each of the sites studied in this application is now possible and can be applied in a clinical setting if supported by work in the experimental animal.
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