Nephritis is a frequent and severe manifestation of human SLE. Long- term immunosuppression is usually necessary. Relapse is common. SLE nephritis is the result of glomerular accumulation of immune complexes (IC). The risk factors for renal involvement, as well as the determinants of relapse and severity, are poorly understood. We postulate that 1) The dominant mechanism for glomerular IC accumulation is genetic and/or acquired defects of IC clearance proteins. Furthermore, the concurrence of 2 or more defective/deficient IC clearance proteins predisposes to severe nephritis. 2) IC mediate renal inflammation by regulating the local expression of chemotactic cytokines (chemokines). 3) Specific, quantifiable clinical events are triggers for SLE nephritis relapse, and influence disease severity. These hypotheses will be tested by 4 interrelated projects. Projects 1 and 2 analyze genetic polymorphisms of key IC clearance proteins (C2, C4, CR1, FcgammaRIIa, and FcgammaRIIIa), to determine which are susceptibility genes for human SLE nephritis. Project 3 examines genetic, molecular, and cellular mechanisms that regulate chemokine activity in human SLE nephritis. Project 3 examines genetic, molecular, and cellular mechanisms that regulate chemokine activity in human SLE nephritis. The genetic testing of Projects 1, 2, and 3 will involve 250 SLE nephritis patients (biopsy proven), 250 SLE patients who have never had nephritis, and 250 matched normals. Patients and siblings of the SLE patients will also be used for transmission disequilibrium testing (TDT). Project 4 is a meticulous, prospective study designed to determine the relationship between SLE relapse and genetic, immunologic, and clinical parameters. One hundred SLE patients with relapsing disease (50 with and 50 without renal manifestations) will be studied longitudinally over 5 years. In collaboration with Projects 1-3, serial quantitative measures of IC clearance proteins, chemokines, and specific clinical factors (stress, sex hormones, infection, UV radiation) will be obtained before, during, and after each of the more than 300 SLE relapses expected during follow-up. These variables will be correlated to disease activity and severity to determine which are """"""""triggers"""""""" for SLE relapse, and which are determinants of the renal manifestations of SLE. From this analysis should emerge, for the first time, a clear picture of the risk factors for SLE nephritis and its relapse in humans. Summary: Concepts fundamental to understanding the genetic and clinical risk factors for human SLE nephritis should be revealed, thus providing tools for predicting SLE nephritis relapse and severity, and strategies for its management.
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