Systemic lupus erythematosus (SLE) is a multisystem inflammatory disorder primarily affecting women of childbearing age. IgG antibodies to double stranded DNA (antidsDNAb) appear to be a critical pathogenetic factor in the renal disease of SLE. These antibodies are deposited in the kidneys of patients with SLE nephropathy and their levels correlate with severity of renal disease. However, not all antibodies that bind dsDNA are pathogenic. Despite intense study, the factors that contribute to renal pathogenicity have not been clearly elucidated. We are interested in studying the features of anti-dsDNAb that may be responsible for causing renal disease in SLE patients. Our approach will be to analyze anti-dsdnab reactive with three monoclonal anti-idiotypes: F4, that recognizes a heavy chain determinant on IgG anti-dsdnab; 8.12, that recognizes a lambda light chain determinant; and 3I that recognizes a kappa light chain determinant. F4 reactive heavy chains are often associated with 3I reactive light chains and these antibodies are preferentially DNA binding. F4 rarely associates with 8.12 but F4 and 8.12 both recognize positively charged (cationic) anti-dsdnab. Cationic anti-dsdnab are preferentially deposited in the kidneys of both mice and humans with SLE, and in fact, all three of our anti-idiotypes bind to Ig deposited in lupus kidneys. We propose to study a large cohort of SLE patients to correlate clinical disease activity with serum levels of 3I, F4 and 8.12 reactivity. In addition we will test polyclonal anti-dsdnab from serum and monoclonal anti-dsdnab derived from transformed B cell lines from SLE patients for renal sequestration in a rat perfusion model. We will perform immunolocalization studies on perfused rat kidneys and on kidneys from SLE patients undergoing renal biopsy to determine specific sites of deposition of pathogenic antibodies. We will further analyze the structural features of 3I, F4 and 8.12 reactive antibodies using immunochemical and molecular biology techniques and develop new antidiotypic reagents that preferentially recognize nephritogenic anti- dsdnab. These experiments will define the features of anti-dsdnab that make them likely to deposit in lupus kidneys and may help establish diagnostic tests that will allow us predict onset and follow the course of patients with lupus nephropathy.
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