The renal disease of systemic lupus erythematosus (SLE) is associated with the formation of immune deposits in glomeruli. The ability of chemically cationized antibodies to enhance deposition of immune complexes in glomeruli is a well established experimental observation. Cationic antibodies to DNA have been hypothesized to be an important part of the pathogenic population of IgG molecules causing the formation of immune deposits in the kidneys of patients with SLE. It is unclear if the cationic charge on these antibodies to DNA is responsible for their pathogenicity directly or due to association with other characteristics such as an increased affinity for DNA. This application proposes that an important pathogenic characteristic of IgG which mediates its initial deposition in glomeruli is the presence of cationic regions within IgG molecules. Sensitive in vitro techniques will be developed and utilized to detect cationic regions within naturally occurring IgG molecules and these will be correlated with the in vivo ability of IgG to bind to glomeruli either alone or as immune complexes. Goat IgG will be analyzed since it resembles human IgG closely in isoelectric focusing charge spectrum and goat IgG antibodies to human serum albumin have been shown to cause enhanced charge mediated immune deposit formation. The goat antibodies responsible for the enhanced deposition of immune complexes in glomeruli will be isolated and analyzed by proteolytic cleavage and dissociation of heavy and light chains in order to localize the cationic regions within the molecule. A mouse model producing IgG reactive with the arsonate hapten and containing molecules with regional cationic charge as detected by in vitro assays will be studied and used to produce monoclonal antibodies. Those monoclonal antibodies exhibiting the ability to bind to glomeruli or to mediate deposition of immune complexes in glomeruli will be examined by nucleotide sequence analysis to determine the amino acids responsible for generating the cationic region and to gain insight on the genetic events producing cationic antibodies. The same or similar alterations in autoantibodies in patients with SLE may be a critical determinant in the development of a pathogenic antibody population in lupus nephritis.
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