Compelling evidence indicates that chemokines play a key role in the development of renal inflammation. The regulation of chemokine expression in human renal disease is poorly understood. This investigation will examine molecular, cellular, and genetic aspects of chemokine regulation in the context of a clinically relevant mechanism of immune injury, immune complex (IC)-mediated renal inflammation.
In Aim 1 the hypothesis that IC-induced chemokine expression in the kidney is mediated by FCgamma- receptor III-bearing lymphocytes that have been activated by IC will be tested. A cell culture model of pathogenic IC interaction with leukocytes and renal parenchymal cells will be used for this evaluation. In vivo correlates to support the model will be sought in a patient population with systemic lupus erythematosus (SLE) nephritis, a classical IC-dependent renal lesion. Because polymorphisms of Fc receptors have been described that alter Fc receptor function, it is conceivable that Fc-receptor mediated chemokine expression is influenced by Fc receptor phenotype. Therefore, the effect of Fc receptor polymorphisms on IC-induced leukocyte chemokine production will be assessed.
In Aim 2, the theme of genetic regulation of chemokine expression will be expanded by testing the hypothesis that polymorphisms in the regulatory regions of chemokine genes affect the level of chemokine production, and consequently the degree of tissue inflammation in response to IC or pro- inflammatory cytokines. Genomic DNA from a normal population will be sequenced to identify polymorphisms in the regulatory elements of chemokine genes. Polymorphic variants of these regulatory regions will be inserted into reporter vectors for functional evaluation. The prevalence of functional regulatory region polymorphisms will be assessed in the SLE nephritis patient population, and correlated to severity of renal injury. These studies are expected to offer novel insights into the molecular and cellular mechanisms that initiate inflammation and determine the severity of inflammation in IC renal disease. This information will likely suggest new directions for interventions to control renal inflammation.
